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1. Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?

Author: Pennisi A, Rötig A, Roux CJ, Lévy R, Henneke M, Gärtner J, Teke Kisa P, Sarioglu FC, Yiş U, Konczal LL, Burkardt DD, Wu S, Gaignard P, Besmond C, Hubert L, Rio M, Barcia G, Munnich A, Boddaert N, and Schiff M
Subjects: Adult, Brain pathology, Child, Child, Preschool, Humans, Interferon Type I genetics, Leigh Disease pathology, Leukoencephalopathies genetics, Leukoencephalopathies pathology, Mitochondrial Diseases diagnostic imaging, Neuroimaging, Whole Genome Sequencing, Brain diagnostic imaging, Exoribonucleases genetics, Leigh Disease genetics, Mitochondrial Diseases genetics, Mitochondrial Proteins genetics
Abstract: Background: Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs., Objective and Methods: To document neuroimaging data in six patients with PNPT1 highlighting novel findings., Results: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection., Conclusion: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2022
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2. A CBF decrease in the left supplementary motor areas: New insight into postoperative pediatric cerebellar mutism syndrome using arterial spin labeling perfusion MRI.

Author: Boisgontier J, Fillon L, Rutten C, Saitovitch A, Dufour C, Lemaître H, Beccaria K, Blauwblomme T, Levy R, Dangouloff-Ros V, Grévent D, Roux CJ, Grill J, Vinçon-Leite A, Saidoun L, Bourdeaut F, Zilbovicius M, Boddaert N, and Puget S
Subjects: Adolescent, Child, Child, Preschool, Female, Humans, Male, Perfusion, Spin Labels, Brain blood supply, Brain diagnostic imaging, Cerebellar Neoplasms diagnostic imaging, Cerebellar Neoplasms surgery, Cerebrovascular Circulation, Medulloblastoma diagnostic imaging, Medulloblastoma surgery, Mutism diagnostic imaging, Mutism etiology, Perfusion Imaging, Postoperative Complications diagnostic imaging
Abstract: Postoperative pediatric cerebellar mutism syndrome (pCMS), characterized mainly by delayed onset transient mutism is a poorly understood complication that may occur after pediatric medulloblastoma (MB) resection. Our aim was to investigate postoperative changes in whole-brain cerebral blood flow (CBF) at rest in pCMS patients using arterial spin labeling (ASL) perfusion imaging. This study compared preoperative and postoperative T2-weighted signal abnormalities and CBF using a voxel-wise, whole-brain analysis in 27 children undergoing MB resection, including 11 patients who developed mutism and 16 who did not. Comparison of postoperative T2 signal abnormalities between patients who developed pCMS (mean age 7.0 years) and those who did not showed that pCMS (mean age 8.9 years) patients were significantly more likely to present with T2-weighted hyperintensities in the right dentate nucleus (DN) (p = 0.02). Comparison of preoperative and postoperative CBF in patients with pCMS showed a significant postoperative CBF decrease in the left pre-supplementary motor area (pre-SMA) (p = 0.007) and SMA (p = 0.009). In patients who did not develop pCMS, no significant differences were observed. Findings provide evidence of an association between pCMS, injury to the right DN, and left pre-SMA/SMA hypoperfusion, areas responsible for speech. This supports the relevance of CBF investigations in pCMS.
Published: 2021
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3. Fetal Brain Magnetic Resonance Imaging Findings Predict Neurodevelopment in Children with Tuberous Sclerosis Complex.

Author: Hulshof HM, Slot EMH, Lequin M, Breuillard D, Boddaert N, Jozwiak S, Kotulska K, Riney K, Feucht M, Samueli S, Scholl T, Krsek P, Benova B, Braun KPJ, Jansen FE, and Nabbout R
Subjects: Child, Preschool, Cognition Disorders epidemiology, Cohort Studies, Epilepsy epidemiology, Female, Follow-Up Studies, Humans, Infant, Language Development Disorders epidemiology, Pregnancy, Retrospective Studies, Brain diagnostic imaging, Magnetic Resonance Imaging, Neurodevelopmental Disorders epidemiology, Tuberous Sclerosis epidemiology
Abstract: Objective: To correlate fetal brain magnetic resonance imaging (MRI) findings with epilepsy characteristics and neurodevelopment at 2 years of age in children with tuberous sclerosis complex (TSC) to improve prenatal counseling., Study Design: This retrospective cohort study was performed in a collaboration between centers of the EPISTOP consortium. We included children with definite TSC, fetal MRIs, and available follow-up data at 2 years of age. A pediatric neuroradiologist masked to the patient's clinical characteristics evaluated all fetal MRIs. MRIs were categorized for each of the 10 brain lobes as score 0: no (sub)cortical lesions or doubt; score 1: a single small lesion; score 2: more than one small lesion or at least one large lesion (>5 mm). Neurologic manifestations were correlated to lesion sum scores., Results: Forty-one children were included. Median gestational age at MRI was 33.3 weeks; (sub)cortical lesions were detected in 97.6%. Mean lesion sum score was 4.5. At 2 years, 58.5% of patients had epilepsy and 22% had drug-resistant epilepsy. Cognitive, language, and motor development were delayed in 38%, 81%, and 50% of patients, respectively. Autism spectrum disorder (ASD) was diagnosed in 20.5%. Fetal MRI lesion sum scores were significantly associated with cognitive and motor development, and with ASD diagnosis, but not with epilepsy characteristics., Conclusions: Fetal cerebral lesion scores correlate with neurodevelopment and ASD at 2 years in children with TSC., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2021
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4. Cerebral blood flow and acute episodes of Leigh syndrome in neurometabolic disorders.

Author: Loiselet K, Ruzzenente B, Roux CJ, Barcia G, Pennisi A, Desguerre I, Rötig A, Munnich A, and Boddaert N
Subjects: Adolescent, Brain physiopathology, Child, Child, Preschool, Female, Humans, Infant, Leigh Disease physiopathology, Magnetic Resonance Imaging, Male, Mitochondrial Diseases physiopathology, Spin Labels, Brain diagnostic imaging, Cerebrovascular Circulation physiology, Leigh Disease diagnostic imaging, Mitochondrial Diseases diagnostic imaging
Abstract: Aim: To investigate cerebral blood flow (CBF) in acute episodes of Leigh syndrome compared with basal state in patients carrying pathogenic mitochondrial disease gene variants responsible for neurometabolic disorders., Method: Arterial spin labelling (ASL) magnetic resonance imaging (MRI) sequences were used to measure CBF in 27 patients with mitochondrial respiratory chain enzyme deficiencies, ascribed to pathogenic variants of reported disease genes who were undergoing either urgent neuroimaging for acute episodes of Leigh syndrome (Group I: 15 MRI, seven females, eight males; mean age 7y; range 7mo-14y) or routine brain MRI (Group II: 15 MRI, eight females, seven males; mean age 5y 2mo; range 2mo-12y)., Results: Patients displayed markedly increased CBF in the striatum (2.8-fold greater, p<0.001 [1.05-2.53]) during acute episodes of Leigh syndrome compared to basal conditions. Detection of elevated CBF preceded identification of structural MRI lesions in four out of 15 cases., Interpretation: Our results suggest that increased CBF is an overt hallmark of Leigh syndrome episodes and ASL MRI sequences should facilitate early diagnosis of acute episodes of Leigh syndrome, especially during the first attack in young children, when structural MRI is insufficiently informative., (© 2021 Mac Keith Press.)
Published: 2021
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5. Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations.

Author: Roux CJ, Barcia G, Schiff M, Sissler M, Levy R, Dangouloff-Ros V, Desguerre I, Edvardson S, Elpeleg O, Rötig A, Munnich A, and Boddaert N
Subjects: Adolescent, Adult, Amino Acyl-tRNA Synthetases classification, Amino Acyl-tRNA Synthetases genetics, Brain pathology, Child, Child, Preschool, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Mutation genetics, Phenotype, Young Adult, Alanine-tRNA Ligase genetics, Arginine-tRNA Ligase genetics, Aspartate-tRNA Ligase genetics, Brain diagnostic imaging, Mitochondrial Proteins genetics, Phenylalanine-tRNA Ligase genetics
Abstract: Background and Purpose: Mitochondrial aminoacyl-tRNA synthetases-encoded by ARS2 genes-are evolutionarily conserved enzymes that catalyse the attachment of amino acids to their cognate tRNAs, ensuring the accuracy of the mitochondrial translation process. ARS2 gene mutations are associated with a wide range of clinical presentations affecting the CNS., Methods: Two senior neuroradiologists analysed brain MRI of 25 patients (age range: 3 d-25 yrs.; 11 males; 14 females) with biallelic pathogenic variants of 11 ARS2 genes in a retrospective study conducted between 2002 and 2019., Results: Though several combinations of brain MRI anomalies were highly suggestive of specific aetiologies (DARS2, EARS2, AARS2 and RARS2 mutations), our study detected no MRI pattern common to all patients. Stroke-like lesions were associated with pathogenic SARS2 and FARS2 variants. We also report early onset cerebellar atrophy and calcifications in AARS2 mutations, early white matter involvement in RARS2 mutations, and absent involvement of thalami in EARS2 mutations. Finally, our findings show that normal brain MRI results do not exclude the presence of ARS2 mutations: 5 patients with normal MRI images were carriers of pathogenic IARS2, YARS2, and FARS2 variants., Conclusion: Our study extends the spectrum of brain MRI anomalies associated with pathogenic ARS2 variants and suggests ARS2 mutations are largely underdiagnosed., (Copyright © 2021. Published by Elsevier Inc.)
Published: 2021
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6. Rest Functional Brain Maturation during the First Year of Life.

Author: Lemaître H, Augé P, Saitovitch A, Vinçon-Leite A, Tacchella JM, Fillon L, Calmon R, Dangouloff-Ros V, Lévy R, Grévent D, Brunelle F, Boddaert N, and Zilbovicius M
Subjects: Cerebrovascular Circulation physiology, Female, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging methods, Male, Rest, Brain growth & development, Neurogenesis physiology
Abstract: The first year of life is a key period of brain development, characterized by dramatic structural and functional modifications. Here, we measured rest cerebral blood flow (CBF) modifications throughout babies' first year of life using arterial spin labeling magnetic resonance imaging sequence in 52 infants, from 3 to 12 months of age. Overall, global rest CBF significantly increased during this age span. In addition, we found marked regional differences in local functional brain maturation. While primary sensorimotor cortices and insula showed early maturation, temporal and prefrontal region presented great rest CBF increase across the first year of life. Moreover, we highlighted a late and remarkably synchronous maturation of the prefrontal and posterior superior temporal cortices. These different patterns of regional cortical rest CBF modifications reflect a timetable of local functional brain maturation and are consistent with baby's cognitive development within the first year of life., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)
Published: 2021
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7. Arterial Spin Labeling and Central Precocious Puberty.

Author: Denis J, Dangouloff-Ros V, Pinto G, Flechtner I, Piketty M, Samara D, Levy R, Grévent D, Millischer AE, Brunelle F, Prevot V, Polak M, and Boddaert N
Subjects: Child, Female, Gonadotropin-Releasing Hormone blood, Humans, Male, Puberty, Precocious blood, Retrospective Studies, Sensitivity and Specificity, Spin Labels, Brain diagnostic imaging, Magnetic Resonance Imaging methods, Puberty, Precocious diagnostic imaging
Abstract: Purpose: To evaluate a non-invasive method to assess the progressivity of idiopathic central precocious puberty (CPP) by quantifying perfusion of the pituitary stalk with arterial spin labeling (ASL) and using the gonadotropin-releasing hormone (GnRH) test as a reference test to define progressive CPP., Methods: In a single center retrospective study, 52 consecutive patients, observed between October 2015 and April 2017 and referred with early signs of puberty, were evaluated using the GnRH test and cerebral magnetic resonance imaging (MRI). Patients with peripheral or non-idiopathic puberty were excluded. The distribution of perfusion values between patients with progressive and non-progressive CPP was compared using a nonparametric Mann-Whitney U‑test., Results: In this study 35 patients were included and 29 had progressive CPP. These patients displayed significantly higher cerebral blood flow (CBF) values than the 6 patients with non-progressive CPP (p = 0.006). The median CBF for patients with non-progressive and progressive CPP was 45.25 ml/min/100 g (interquartile range 36.9-54) vs. 65 ml/min/100 g (interquartile range 55.5-74.5), respectively. To determine if the CPP was progressive, the best CBF threshold was 55.5 ml/min/100 g with a sensitivity of 76%, a specificity of 83% and an accuracy of 77%. There were strong significant correlations between CBF and LH peak (r = 0.67, p < 0.001) and between CBF and LH/FSH peaks ratio [r = 0.71, p < 0.001] during the GnRH test., Conclusion: Arterial spin labelling (ASL) offers a novel tool to assess the progressivity of idiopathic CPP.
Published: 2020
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8. A novel de novo PDGFRB variant in a child with severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis.

Author: Guimier A, Gordon CT, Hully M, Blauwblomme T, Minard-Colin V, Bole-Feysot C, Nitschké P, Oufadem M, Boddaert N, Sarnacki S, and Amiel J
Subjects: Brain diagnostic imaging, Female, Humans, Infant, Newborn, Magnetic Resonance Imaging, Male, Mutation, Missense, Brain abnormalities, Calcinosis genetics, Myofibromatosis genetics, Receptor, Platelet-Derived Growth Factor beta genetics
Abstract: The spectrum of clinical consequences of variants in the Platelet derived growth factor receptor beta (PDGFRB) gene is wide. Missense variants leading to variable loss of signal transduction in vitro have been reported in the idiopathic basal ganglia calcification (IBGC) syndrome Type 4. In contrast, gain-of-function variants have been reported in infantile myofibromatosis, Penttinen syndrome, and Kosaki overgrowth syndrome. Here, we report a patient harboring a novel postzygotic variant in PDGFRB (c.1682_1684del, p.[Arg561_Tyr562delinsHis]) and presenting severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. This observation expands the phenotype associated with PDGFRB variants and illustrates the wide clinical spectrum linked to dysregulation of PDGFRB., (© 2019 Wiley Periodicals, Inc.)
Published: 2019
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9. Neural and behavioral signature of human social perception.

Author: Saitovitch A, Lemaitre H, Rechtman E, Vinçon-Leite A, Calmon R, Grévent D, Dangouloff-Ros V, Brunelle F, Boddaert N, and Zilbovicius M
Subjects: Adult, Brain Mapping, Female, Humans, Image Processing, Computer-Assisted, Male, Spin Labels, Brain blood supply, Cerebrovascular Circulation physiology, Eye Movements physiology, Rest physiology, Social Perception
Abstract: Social behavior is extremely variable among individuals, and the neural basis of this variability is still poorly understood. In this study, we aimed to investigate the neural basis of interindividual variability in the first step of social behavior, that is, social perception. For that purpose, we first used eye-tracking to measure social perception during the passive visualization of socially relevant movie clips. Second, we correlated eye-tracking data with measures of rest cerebral blood flow (CBF) obtained using arterial spin-labeling (ASL) MRI, an index of local rest brain function. The results showed a large interindividual variability in the number of fixations to the eyes of characters during passive visualization of movie clips displaying social interactions. Moreover, individual patterns remained stable across time, suggesting an individual signature of social behavior. Whole-brain analyses showed significant positive correlation between the number of fixations to the eyes and rest CBF: individuals who looked more to the eyes were those with higher rest CBF levels within the right superior temporal regions. Our results indicate the existence of a neural and behavioral signature associated with the interindividual variability in social perception.
Published: 2019
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10. Anatomical and functional abnormalities on MRI in kabuki syndrome.

Author: Boisgontier J, Tacchella JM, Lemaître H, Lehman N, Saitovitch A, Gatinois V, Boursier G, Sanchez E, Rechtman E, Fillon L, Lyonnet S, Le Quang Sang KH, Baujat G, Rio M, Boute O, Faivre L, Schaefer E, Sanlaville D, Zilbovicius M, Grévent D, Geneviève D, and Boddaert N
Subjects: Abnormalities, Multiple diagnostic imaging, Adolescent, Brain blood supply, Brain diagnostic imaging, Brain Mapping, Child, Face blood supply, Face diagnostic imaging, Face pathology, Face physiopathology, Female, Hematologic Diseases diagnostic imaging, Humans, Magnetic Resonance Imaging, Male, Spin Labels, Vestibular Diseases diagnostic imaging, Abnormalities, Multiple pathology, Abnormalities, Multiple physiopathology, Brain pathology, Brain physiopathology, Face abnormalities, Hematologic Diseases pathology, Hematologic Diseases physiopathology, Vestibular Diseases pathology, Vestibular Diseases physiopathology
Abstract: Kabuki syndrome (KS) is a rare congenital disorder (1/32000 births) characterized by distinctive facial features, intellectual disability, short stature, and dermatoglyphic and skeletal abnormalities. In the last decade, mutations in KMT2D and KDM6A were identified as a major cause of kabuki syndrome. Although genetic abnormalities have been highlighted in KS, brain abnormalities have been little explored. Here, we have investigated brain abnormalities in 6 patients with KS (4 males; M age  = 10.96 years, SD = 2.97 years) with KMT2D mutation in comparison with 26 healthy controls (17 males; M age  = 10.31 years, SD = 2.96 years). We have used MRI to explore anatomical and functional brain abnormalities in patients with KS. Anatomical abnormalities in grey matter volume were assessed by cortical and subcortical analyses. Functional abnormalities were assessed by comparing rest cerebral blood flow measured with arterial spin labeling-MRI. When compared to healthy controls, KS patients had anatomical alterations characterized by grey matter decrease localized in the bilateral precentral gyrus and middle frontal gyrus. In addition, KS patients also presented functional alterations characterized by cerebral blood flow decrease in the left precentral gyrus and middle frontal gyrus. Moreover, subcortical analyses revealed significantly decreased grey matter volume in the bilateral hippocampus and dentate gyrus in patients with KS. Our results strongly indicate anatomical and functional brain abnormalities in KS. They suggest a possible neural basis of the cognitive symptoms observed in KS, such as fine motor impairment, and indicate the need to further explore the consequences of such brain abnormalities in this disorder. Finally, our results encourage further imaging-genetics studies investigating the link between genetics, anatomical and functional brain alterations in KS., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2019
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11. High predictive value of brain MRI imaging in primary mitochondrial respiratory chain deficiency.

Author: de Beaurepaire I, Grévent D, Rio M, Desguerre I, de Lonlay P, Levy R, Dangouloff-Ros V, Bonnefont JP, Barcia G, Funalot B, Besmond C, Metodiev MD, Ruzzenente B, Assouline Z, Munnich A, Rötig A, and Boddaert N
Subjects: Adolescent, Adult, Atrophy diagnostic imaging, Atrophy physiopathology, Brain pathology, Child, Child, Preschool, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Middle Aged, Mitochondrial Diseases diagnostic imaging, Mitochondrial Diseases pathology, Predictive Value of Tests, Young Adult, Atrophy diagnosis, Brain diagnostic imaging, Diagnosis, Differential, Mitochondrial Diseases diagnosis
Abstract: Background: Because the mitochondrial respiratory chain (RC) is ubiquitous, its deficiency can theoretically give rise to any symptom in any organ or tissue at any age with any mode of inheritance, owing to the twofold genetic origin of respiratory enzyme machinery, that is, nuclear and mitochondrial. Not all respiratory enzyme deficiencies are primary and secondary or artefactual deficiency is frequently observed, leading to a number of misleading conclusions and inappropriate investigations in clinical practice. This study is aimed at investigating the potential role of brain MRI in distinguishing primary RC deficiency from phenocopies and other aetiologies., Methods: Starting from a large series of 189 patients (median age: 3.5 years (8 days-56 years), 58% males) showing signs of RC enzyme deficiency, for whom both brain MRIs and disease-causing mutations were available, we retrospectively studied the positive predictive value (PPV) and the positive likelihood ratio (LR+) of brain MRI imaging and its ability to discriminate between two groups: primary deficiency of the mitochondrial RC machinery and phenocopies., Results: Detection of (1) brainstem hyperintensity with basal ganglia involvement (P≤0.001) and (2) lactate peak with either brainstem or basal ganglia hyperintensity was highly suggestive of primary RC deficiency (P≤0.01). Fourteen items had a PPV>95% and LR+ was greater than 9 for seven signs. Biallelic SLC19A3 mutations represented the main differential diagnosis. Non-significant differences between the two groups were found for cortical/subcortical atrophy, leucoencephalopathy and involvement of caudate nuclei, spinothalamic tract and corpus callosum., Conclusion: Based on these results and owing to invasiveness of skeletal muscle biopsies and cost of high-throughput DNA sequencing, we suggest giving consideration to brain MRI imaging as a diagnostic marker and an informative investigation to be performed in patients showing signs of RC enzyme deficiency., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
Published: 2018
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12. Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation.

Author: Drecourt A, Babdor J, Dussiot M, Petit F, Goudin N, Garfa-Traoré M, Habarou F, Bole-Feysot C, Nitschké P, Ottolenghi C, Metodiev MD, Serre V, Desguerre I, Boddaert N, Hermine O, Munnich A, and Rötig A
Subjects: Amino Acid Sequence, Calcium-Binding Proteins, Carrier Proteins genetics, Fibroblasts metabolism, HEK293 Cells, HeLa Cells, Homeostasis, Humans, Mutation genetics, Receptors, Transferrin chemistry, Receptors, Transferrin genetics, Transferrin metabolism, Brain pathology, Endocytosis, Iron metabolism, Lipoylation, Nerve Degeneration metabolism, Nerve Degeneration pathology, Receptors, Transferrin metabolism
Abstract: Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2018
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13. Severe neuroimaging anomalies are usually associated with random X inactivation in leucocytes circulating DNA in X-linked dominant Incontinentia Pigmenti.

Author: Dangouloff-Ros V, Hadj-Rabia S, Oliveira Santos J, Bal E, Desguerre I, Kossorotoff M, An I, Smahi A, Bodemer C, Munnich A, Steffann J, and Boddaert N
Subjects: Adolescent, Adult, Aged, Brain diagnostic imaging, Child, Child, Preschool, DNA blood, Female, Humans, I-kappa B Kinase genetics, Incontinentia Pigmenti complications, Incontinentia Pigmenti physiopathology, Infant, Infant, Newborn, Mutation, Neuroimaging methods, Sequence Deletion, X Chromosome Inactivation, Young Adult, Brain physiopathology, Incontinentia Pigmenti diagnosis, Incontinentia Pigmenti genetics, Leukocytes, Magnetic Resonance Imaging statistics & numerical data, Neuroimaging statistics & numerical data
Abstract: Incontinentia Pigmenti (IP) is a skin disorder with neurological impairment in 30% of cases. The most common disease causing mutation is a deletion of exons 4-10 of the IKBKG gene, located on chromosome Xq28, with skewed X-chromosome inactivation in females, but few cases of random X-inactivation have been reported. We have correlated brain anomalies with X-chromosome inactivation status determined on leucocytes circulating DNA. We reviewed MRI of 18 girls with genetically proven IP. We found three patterns of MRI, normal MRI (n=5), mild white matter abnormalities with cortical and corpus callosum atrophy (n=6), and severe cortical abnormalities suggesting a vascular disease (n=7). Most patients with severe abnormalities had random X-inactivation (6/7,86%), while 80% (4/5) of patients with normal MRI and 100% (6/6) of patients with mild white matter abnormalities had skewed inactivation. These results suggest that skewed chromosome X-inactivation may protect brain from damage, while in case of random inactivation, expression of the mutated IKBKG gene may lead to severe brain lesions., (Copyright © 2017 Elsevier Inc. All rights reserved.)
Published: 2017
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14. Multimodal Magnetic Resonance Imaging of Treatment-Induced Changes to Diffuse Infiltrating Pontine Gliomas in Children and Correlation to Patient Progression-Free Survival.

Author: Calmon R, Puget S, Varlet P, Beccaria K, Blauwblomme T, Grevent D, Sainte-Rose C, Castel D, Dufour C, Dhermain F, Bolle S, Saitovitch A, Zilbovicius M, Brunelle F, Grill J, and Boddaert N
Subjects: Adolescent, Antineoplastic Agents therapeutic use, Brain radiation effects, Brain Stem Neoplasms blood supply, Brain Stem Neoplasms pathology, Chemotherapy, Adjuvant, Child, Child, Preschool, Contrast Media, Disease Progression, Disease-Free Survival, Erlotinib Hydrochloride administration & dosage, Female, Glioma blood supply, Glioma pathology, Humans, Magnetic Resonance Imaging methods, Male, Prospective Studies, Sirolimus administration & dosage, Statistics, Nonparametric, Survival Analysis, Time Factors, Tumor Burden radiation effects, Brain blood supply, Brain Stem Neoplasms diagnostic imaging, Brain Stem Neoplasms radiotherapy, Glioma diagnostic imaging, Glioma radiotherapy
Abstract: Purpose: To use multimodal magnetic resonance imaging (MRI) to quantify treatment-induced changes in the whole volume of diffuse infiltrating pontine gliomas and correlate them with progression-free survival (PFS)., Methods and Materials: This prospective study included 22 children aged 3.3 to 14.7 years (median, 5.9 years). Multimodal MRI was performed at 3 distinct time points: before treatment, the first week following radiation therapy (RT), and 2 months after RT. The imaging protocol included morphologic, multi b-value diffusion; arterial spin labeling; and dynamic susceptibility contrast-enhanced perfusion. Morphologic and multimodal data-lesion volume, diffusion coefficients, relative cerebral blood flow, and relative cerebral blood volume (rCBV)-were recorded at the 3 aforementioned time points. The Wilcoxon test was used to compare each individual parameter variation between time points, and its correlation with PFS was assessed by the Spearman test., Results: Following RT, the tumors' solid component volume decreased by 40% (P<.001). Their median diffusion coefficients decreased by 20% to 40% (P<.001), while median relative cerebral blood flow increased by 60% to 80% (P<.001) and median rCBV increased by 70% (P<.001). PFS was positively correlated with rCBV measured immediately after RT (P=.003), and in patients whose rCBV was above the cutoff value of 2.46, the median PFS was 4.6 months longer (P=.001). These indexes tended to return to baseline 2 months after RT. Lesion volume before or after RT was not correlated with survival., Conclusions: Multimodal MRI provides useful information about diffuse infiltrating pontine gliomas' response to treatment; rCBV increases following RT, and higher values are correlated with better PFS. High rCBV values following RT should not be mistaken for progression and could be an indicator of response to therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)
Published: 2017
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15. Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy.

Author: Habarou F, Hamel Y, Haack TB, Feichtinger RG, Lebigot E, Marquardt I, Busiah K, Laroche C, Madrange M, Grisel C, Pontoizeau C, Eisermann M, Boutron A, Chrétien D, Chadefaux-Vekemans B, Barouki R, Bole-Feysot C, Nitschke P, Goudin N, Boddaert N, Nemazanyy I, Delahodde A, Kölker S, Rodenburg RJ, Korenke GC, Meitinger T, Strom TM, Prokisch H, Rotig A, Ottolenghi C, Mayr JA, and de Lonlay P
Subjects: Amino Acids metabolism, Brain diagnostic imaging, Brain Diseases pathology, Brain Mapping methods, Cells, Cultured, Energy Metabolism genetics, Energy Metabolism physiology, Glycine blood, Humans, Infant, Newborn, Magnetic Resonance Imaging, Mitochondria genetics, Oxygen Consumption genetics, Protein Binding genetics, Thioctic Acid metabolism, Acyltransferases genetics, Atrophy pathology, Brain pathology, Brain Diseases genetics, Lipoylation genetics, Mitochondria metabolism
Abstract: Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2017
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16. Description and Contribution of Brain Magnetic Resonance Imaging in Nontraumatic Critically Ill Children.

Author: Mortamet G, Kossorotoff M, Baptiste A, Boddaert N, Castelle M, Hubert P, Lesage F, Renolleau S, and Oualha M
Subjects: Adolescent, Child, Child, Preschool, Clinical Decision-Making, Critical Illness mortality, Diagnosis, Differential, Female, Humans, Infant, Infant, Newborn, Intensive Care Units, Pediatric, Male, Neurologists, Prognosis, Retrospective Studies, Single-Blind Method, Brain diagnostic imaging, Critical Care, Critical Illness therapy, Magnetic Resonance Imaging
Abstract: Background: The authors aimed to collect all brain magnetic resonance imaging (MRI) performed in critically ill children in the authors' medical pediatric intensive care unit over a 2-year period (2012-2013) to (1) describe the findings and (2) assess its contribution on practical patient care., Methods: This is a single-center and retrospective study. All children without traumatic brain injury who underwent a brain MRI during pediatric intensive care unit stays were included. To assess the exam's contribution, the patient's medical condition at the time of the MRI exam was blindly and separately exposed to a pediatric neurologist and a pediatric intensivist., Results: During the study period, 87 patients (7.5%) underwent a brain MRI. Median age was 4 months and 13 children (14.9%) died in pediatric intensive care unit. The most common final diagnosis was postanoxic encephalopathy. Brain MRI was abnormal in 68 patients (78.2%). No serious adverse event occurred during the transport. The neurologist and the intensivist considered brain MRI as indicated during pediatric intensive care unit stay in 65 (74.7%) and 68 patients (78.2%). They deemed that brain MRI had a diagnostic contribution in 76 (87.4%) and 60 (69.0%) patients, respectively. A therapeutic change consecutive to MRI findings occurred in 19 patients (21.8%) and MRI results were associated with a decision to withdraw life-sustaining treatment in 21 patients (24.1%)., Conclusion: Brain MRI is one component of neuromonitoring, and this study suggests a substantial diagnostic contribution, although its therapeutic impact appears limited to specific diagnoses., (© The Author(s) 2016.)
Published: 2016
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17. Magnetic resonance imaging arterial-spin-labelling perfusion alterations in childhood migraine with atypical aura: a case-control study.

Author: Boulouis G, Shotar E, Dangouloff-Ros V, Grévent D, Calmon R, Brunelle F, Naggara O, Kossorotoff M, and Boddaert N
Subjects: Adolescent, Brain blood supply, Child, Child, Preschool, Cross-Sectional Studies, Female, Humans, Image Processing, Computer-Assisted, Male, Perfusion, Retrospective Studies, Spin Labels, Brain diagnostic imaging, Cerebrovascular Circulation physiology, Magnetic Resonance Imaging methods, Migraine with Aura diagnostic imaging, Migraine with Aura physiopathology
Abstract: Aim: Atypical migraine with aura can be challenging to diagnose. Arterial-spin-labelling (ASL) is able to non-invasively quantify brain perfusion. Our aim was to report cerebral blood flow (CBF) alterations using ASL, at the acute phase of atypical migraine with aura in children., Method: Paediatric patients were retrospectively included if (1) referred for acute neurological deficit(s), (2) underwent brain magnetic resonance imaging (MRI) at presentation with ASL sequence, and (3) had subsequent diagnosis of migraine with aura. Neurological symptom-free controls were matched for age. Twenty-eight regions of interest (ROIs) were drawn on CBF maps for each participant/control., Results: Ten patients were included (median age 13y, range 8-16y). Eight of 10 had multiple aura symptoms during the episode. For every patient, CBF was decreased in a brain region consistent with symptoms when MRI was performed less than 14 hours after onset (n=7 patients) and increased if the MRI was performed 17 hours or more after (n=4 MRIs)., Interpretation: MRI-ASL appears to be a promising tool for the diagnostic workup and differentials exclusion in paediatric migraine with aura. Constant and time-consistent non-territorial CBF modifications were found in our sample providing additional insight to migraine with aura pathophysiology. The authors encourage implementing this sequence at the acute phase of unexplained paediatric neurological deficits, with or without accompanying headache., (© 2016 Mac Keith Press.)
Published: 2016
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18. Arterial Spin Labeling MRI: a step forward in non-invasive delineation of focal cortical dysplasia in children.

Author: Blauwblomme T, Boddaert N, Chémaly N, Chiron C, Pages M, Varlet P, Bourgeois M, Bahi-Buisson N, Kaminska A, Grevent D, Brunelle F, Sainte-Rose C, Archambaud F, and Nabbout R
Subjects: Adolescent, Antigens, CD34 metabolism, Brain diagnostic imaging, Brain pathology, Cerebrovascular Circulation physiology, Child, Child, Preschool, Female, Fluorodeoxyglucose F18, Humans, Male, Malformations of Cortical Development diagnostic imaging, Malformations of Cortical Development pathology, Microvessels pathology, Microvessels physiopathology, Radionuclide Imaging, Radiopharmaceuticals, Retrospective Studies, Spin Labels, Brain physiopathology, Magnetic Resonance Imaging methods, Malformations of Cortical Development diagnosis, Malformations of Cortical Development physiopathology
Abstract: The aim was to localize the interictal cerebral perfusion abnormalities of focal cortical dysplasia (FCD) in children with Arterial Spin Labeling MRI (ASL) in a retrospective study of nine consecutive children explored with multimodal investigation during interictal periods. We analyzed brain morphology with a 1.5T MRI and a dedicated protocol for epilepsy. Brain perfusion was quantified with pseudo continuous ASL. Brain metabolism was imaged with (18)FDG-PET in six patients. Microvessel histology was studied in five children who underwent epilepsy surgery with CD34 immunostaining on FCD and control samples. Localized decrease of cerebral blood flow (CBF) was found on visual analysis in all patients with ASL. It was co-localized with the structural MRI abnormalities in every case, with PET hypo-metabolism in 5/6 cases, and with histologically proven FCD type IIb in 5/5 cases (all seizure free after surgery). CBF was lower (Kruskal-Wallis test, p=0.001) in FCD than in normal cortex. The total count of CD34+ microvessels was similar in FCD and control cases, but microvasculature showed disorganized architecture. Interictal ASL is a non-invasive method that may help to localize the epileptogenic zone showing hypo-perfusion in FCD. Whether this finding could be generalized to MRI-negative FCD needs to be further studied., (Copyright © 2014 Elsevier B.V. All rights reserved.)
Published: 2014
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19. Hemiconvulsion-hemiplegia syndrome revisited: longitudinal MRI findings in 10 children.

Author: Barcia G, Desguerre I, Carmona O, Barnerias C, Chemaly N, Gitiaux C, Brunelle F, Dulac O, Boddaert N, and Nabbout R
Subjects: Anticonvulsants therapeutic use, Brain drug effects, Child, Preschool, Diffusion Magnetic Resonance Imaging, Female, Hemiplegia complications, Humans, Infant, Longitudinal Studies, Male, Neurologic Examination, Status Epilepticus complications, Status Epilepticus drug therapy, Time Factors, Brain pathology, Hemiplegia pathology, Magnetic Resonance Imaging, Status Epilepticus pathology
Abstract: Aim: Hemiconvulsion-hemiplegia syndrome (HHS) is a rare severe epilepsy of infancy consisting of unilateral convulsive status epilepticus immediately followed by transient or lasting ipsilateral hemiplegia. HHS may occur either in patients with previous brain pathology or without any identified cause, so-called 'idiopathic HHS'., Method: We retrospectively analysed clinical and MRI longitudinal findings of a series of 10 patients (six females, four males) presenting with HHS. Age at the study inclusion ranged from 2 years 6 months to 15 years (mean of 5 y 10 mo, median 4 y 2 mo). After defining magnetic resonance imaging (MRI) features as 'typical', i.e. strictly unilateral involvement, and 'atypical', i.e. bilateral, we compared clinical data from both groups. Cognitive level was assessed using Brunet-Lézine or Wechsler scales., Results: HHS occurred at a mean age of 20.5 months (range 8-48 mo). In all cases, status epilepticus lasted for more than 1 hour and was characterised by unilateral clonic seizures followed by ipsilateral hemiplegia (persistent in five patients). Two patients in this series died: the first from multi-organ failure 2 weeks after the status epilepticus and the other from a second episode of ipsilateral intractable febrile status epilepticus 3 years after the first episode. Early MRI (days 1-7 from status epilepticus) showed hemispheric cytotoxic oedema in all, extending to the contralateral side for one. T2 hyperintensity in the basal ganglia was disclosed in 70% of patients and in the hippocampus in 60%. After 1 month (in intermediate and chronic phases), all surviving patients but one showed hemispheric cortical atrophy corresponding to the regions involved during the early stage. Comparing clinical features of patients presenting with 'typical' features, to those with 'atypical' findings, the second group presented psychomotor delay before status epilepticus., Interpretation: This series underlines the major value of early MRI for the prompt diagnosis of HHS, and shows that involvement of subcortical structures has been underestimated. Hippocampal involvement is not constant., (© 2013 Mac Keith Press.)
Published: 2013
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20. Brain magnetic resonance imaging pattern and outcome in children with haemolytic-uraemic syndrome and neurological impairment treated with eculizumab.

Author: Gitiaux C, Krug P, Grevent D, Kossorotoff M, Poncet S, Eisermann M, Oualha M, Boddaert N, Salomon R, and Desguerre I
Subjects: Acute Disease, Basal Ganglia Diseases drug therapy, Basal Ganglia Diseases etiology, Basal Ganglia Diseases pathology, Child, Child, Preschool, Complement Inactivating Agents therapeutic use, Diffusion Magnetic Resonance Imaging, Female, Hemolytic-Uremic Syndrome drug therapy, Humans, Infant, Leukoencephalopathies drug therapy, Leukoencephalopathies etiology, Leukoencephalopathies pathology, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Prospective Studies, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Brain pathology, Brain physiopathology, Hemolytic-Uremic Syndrome complications, Hemolytic-Uremic Syndrome pathology
Abstract: Aim: The aim of this study was to describe the magnetic resonance imaging (MRI) findings and the neurological and neuropsychological outcomes in paediatric, diarrhoea-associated haemolytic-uraemic syndrome (D+HUS) with central nervous system impairment treated with eculizumab, a monoclonal antibody., Method: The 14-month single-centre prospective study included seven children (three males, four females; age range 16 mo-7 y 8 mo; median age 3 y 7 mo) with typical D+HUS and acute neurological impairment. In the acute phase of the disease, neurological assessment and brain magnetic resonance imaging (MRI), including measurement of the apparent diffusion coefficient (ADC), were performed, and neuropsychological evaluation and brain MRI were also carried out 6 months after disease onset., Results: In the acute phase, basal ganglia and white matter abnormalities with ADC restriction were a common and reversible MRI finding. In all the surviving patients (5/7), follow-up MRI after 6 months was normal, indicating reversible lesions. Clinical and neuropsychological evaluations after 6 months were also normal., Interpretation: This specific brain MRI pattern consisting of an ADC decrease in basal ganglia and white matter without major T2/fluid-attenuated inversion recovery (FLAIR) injury may be a key finding in the acute phase of the disease in favour of a vasculitis hypothesis. These reversible lesions were associated with a good neurological outcome. These results call for further evaluation of the potential role of eculizumab in the choice of treatment for severe D+HUS, particularly in the case of early neurological signs., (© 2013 Mac Keith Press.)
Published: 2013
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21. β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

Author: Hayflick SJ, Kruer MC, Gregory A, Haack TB, Kurian MA, Houlden HH, Anderson J, Boddaert N, Sanford L, Harik SI, Dandu VH, Nardocci N, Zorzi G, Dunaway T, Tarnopolsky M, Skinner S, Holden KR, Frucht S, Hanspal E, Schrander-Stumpel C, Mignot C, Héron D, Saunders DE, Kaminska M, Lin JP, Lascelles K, Cuno SM, Meyer E, Garavaglia B, Bhatia K, de Silva R, Crisp S, Lunt P, Carey M, Hardy J, Meitinger T, Prokisch H, and Hogarth P
Subjects: Adolescent, Adult, Cohort Studies, Female, Genetic Diseases, X-Linked diagnosis, Humans, Male, Middle Aged, Mutation genetics, Neurodegenerative Diseases diagnosis, Young Adult, Brain metabolism, Carrier Proteins genetics, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked metabolism, Iron metabolism, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism
Abstract: Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.
Published: 2013
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22. Topography of brain damage in metabolic hypoglycaemia is determined by age at which hypoglycaemia occurred.

Author: Gataullina S, Lonlay P, Dellatolas G, Valayannapoulos V, Napuri S, Damaj L, Touati G, Altuzarra C, Dulac O, and Boddaert N
Subjects: Age Factors, Brain metabolism, Child, Preschool, Disease Progression, Female, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Neuroimaging, Brain pathology, Hypoglycemia pathology
Abstract: Aim: Having previously shown that comorbidity is a major determinant of neurological sequelae in hypoglycaemia, our aim was to describe the neuroimaging patterns of brain damage in different hypoglycaemic situations and to elucidate the factors that determine lesion topography., Method: We reviewed 50 patients (31 females, 19 males) with symptomatic hypoglycaemia (<2.8 mmol/L) occurring between 1 day and 5 years of age (median 4 d) who had undergone magnetic resonance imaging (MRI; at least axial T2-weighted, sagittal T1-weighted, and coronal fluid-attenuated inversion recovery [FLAIR]-weighted imaging). MRI was performed during the follow-up examination at least 1 month after the occurrence of symptomatic hypoglycaemia, i.e. between 1 month and 5 years of age (median 3 mo). Hypoglycaemia resulted from three inborn errors of metabolism: congenital hyperinsulinism (33 patients), fatty acid β-oxidation disorders (13 patients), or glycogen storage disease type I (four patients). We selected the patients with clear MRI abnormalities and analysed their topography according to aetiology and age at occurrence of the lesion., Results: The topography of the brain lesions depended on age: from the neonatal period to 6 months of age, lesions predominantly involved the posterior white matter; between 6 and 22 months the basal ganglia, and after 22 months the parietotemporal cortex (p=0.04)., Interpretation: The relationship between brain lesions and age could reflect the maturation sequence of the brain., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)
Published: 2013
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23. NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications.

Author: Philippe O, Rio M, Malan V, Van Esch H, Baujat G, Bahi-Buisson N, Valayannopoulos V, Gesny R, Bonnefont JP, Munnich A, Froyen G, Amiel J, Boddaert N, and Colleaux L
Subjects: Axons metabolism, Central Nervous System metabolism, Central Nervous System physiopathology, Genetic Association Studies, Humans, Magnetic Resonance Angiography, Male, Oligodendroglia cytology, Oligodendroglia metabolism, Radiography, Schwann Cells cytology, Schwann Cells metabolism, Signal Transduction, Brain abnormalities, Brain diagnostic imaging, Brain metabolism, Chromosome Duplication genetics, Craniofacial Abnormalities genetics, Craniofacial Abnormalities metabolism, Craniofacial Abnormalities physiopathology, Facies, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked metabolism, Genetic Diseases, X-Linked physiopathology, I-kappa B Kinase genetics, I-kappa B Kinase metabolism, Intellectual Disability genetics, Intellectual Disability metabolism, Intellectual Disability physiopathology, Myelin Sheath genetics, Myelin Sheath metabolism, Myelin Sheath pathology, NF-kappa B genetics, NF-kappa B metabolism, Sex Chromosome Disorders genetics, Sex Chromosome Disorders metabolism, Sex Chromosome Disorders physiopathology
Abstract: One of the key signals regulating peripheral myelin formation by Schwann cell is the activation of the transcription factor NF-κB. Yet, whether NF-κB exerts similar functions in central myelin formation by oligodendrocytes remains largely unknown. We previously reported white matter abnormalities with unusual discordance between T2 and FLAIR sequences in a patient with intellectual disability and defective NF-κB signalling. These observations prompted us to hypothesise that NF-κB signalling may have a role in the axon myelination process of central neurons. We report here on five male patients with Xq28 duplications encompassing MECP2, three of which presented white matter anomalies on brain MRI. Array-CGH and FISH analyses demonstrated that brain abnormalities correlate with additional copies of the IKBKG, a gene encoding a key regulator of NF-κB activation. Quantitative RT-PCR experiments and κB-responsive reporter gene assays provide evidence that IKBKG overexpression causes impaired NF-κB signalling in skin fibroblasts derived from patients with white matter anomalies. These data further support the role of NF-κB signalling in astroglial cells for normal myelin formation of the central nervous system.
Published: 2013
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24. Sporadic NF1 mutation associated with a de-novo 20q11.3 deletion explains the association of unusual facies, Moyamoya vasculopathy, and developmental delay, reported by Bertoli et al. in 2009.

Author: Santoro C, Malan V, Bertoli M, Boddaert N, Vidaud D, and Lyonnet S
Subjects: Female, Humans, Brain blood supply, Developmental Disabilities, Face abnormalities, Facies
Published: 2013
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25. New insights into genotype-phenotype correlations for the doublecortin-related lissencephaly spectrum.

Author: Bahi-Buisson N, Souville I, Fourniol FJ, Toussaint A, Moores CA, Houdusse A, Lemaitre JY, Poirier K, Khalaf-Nazzal R, Hully M, Leger PL, Elie C, Boddaert N, Beldjord C, Chelly J, and Francis F
Subjects: Adolescent, Adult, Child, Child, Preschool, Classical Lissencephalies and Subcortical Band Heterotopias pathology, DNA Mutational Analysis, Doublecortin Domain Proteins, Doublecortin Protein, Female, Genetic Association Studies, Humans, Infant, Male, Middle Aged, Nerve Fibers, Myelinated pathology, Organ Size genetics, Brain pathology, Classical Lissencephalies and Subcortical Band Heterotopias genetics, Microtubule-Associated Proteins genetics, Mutation, Neuropeptides genetics
Abstract: X-linked isolated lissencephaly sequence and subcortical band heterotopia are allelic human disorders associated with mutations of doublecortin (DCX), giving both familial and sporadic forms. DCX encodes a microtubule-associated protein involved in neuronal migration during brain development. Structural data show that mutations can fall either in surface residues, likely to impair partner interactions, or in buried residues, likely to impair protein stability. Despite the progress in understanding the molecular basis of these disorders, the prognosis value of the location and impact of individual DCX mutations has largely remained unclear. To clarify this point, we investigated a cohort of 180 patients who were referred with the agyria-pachygyria subcortical band heterotopia spectrum. DCX mutations were identified in 136 individuals. Analysis of the parents' DNA revealed the de novo occurrence of DCX mutations in 76 cases [62 of 70 females screened (88.5%) and 14 of 60 males screened (23%)], whereas in the remaining cases, mutations were inherited from asymptomatic (n = 14) or symptomatic mothers (n = 11). This represents 100% of families screened. Female patients with DCX mutation demonstrated three degrees of clinical-radiological severity: a severe form with a thick band (n = 54), a milder form (n = 24) with either an anterior thin or an intermediate thickness band and asymptomatic carrier females (n = 14) with normal magnetic resonance imaging results. A higher proportion of nonsense and frameshift mutations were identified in patients with de novo mutations. An analysis of predicted effects of missense mutations showed that those destabilizing the structure of the protein were often associated with more severe phenotypes. We identified several severe- and mild-effect mutations affecting surface residues and observed that the substituted amino acid is also critical in determining severity. Recurrent mutations representing 34.5% of all DCX mutations often lead to similar phenotypes, for example, either severe in sporadic subcortical band heterotopia owing to Arg186 mutations or milder in familial cases owing to Arg196 mutations. Taken as a whole, these observations demonstrate that DCX-related disorders are clinically heterogeneous, with severe sporadic and milder familial subcortical band heterotopia, each associated with specific DCX mutations. There is a clear influence of the individual mutated residue and the substituted amino acid in determining phenotype severity.
Published: 2013
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26. Clinical and imaging diagnosis for heredodegenerative diseases.

Author: Boddaert N, Brunelle F, and Desguerre I
Subjects: Humans, Radiography, Radionuclide Imaging, Brain diagnostic imaging, Brain pathology, Diagnostic Imaging methods, Heredodegenerative Disorders, Nervous System diagnosis, Heredodegenerative Disorders, Nervous System therapy
Abstract: Clinical features (progressive psychomotor retardation, seizures, movement disorders and motor signs in both central and peripheral systems, sensorineural defects, and psychiatric symptoms) and brain imaging are the keys to diagnosis. CT is indicated for the detection of calcifications and blood, and for angiography. MRI in all three axes requires T1, T2, FLAIR (from 1 year on), eventually T2* or contrast administration, and diffusion in any acute condition. MR spectroscopy allows the dectection of lactate and creatine deficiency, elevated choline in high membrane turnover, and low NAA in neuronal death. The normal sequence of myelination needs to be taken into account. Pre- and neonatal anomalies include cystic and basal ganglia lesions, gyral and myelin anomalies, callosal agenesis, and large subdural spaces. Anomalies disclosed after 3 months of age include basal ganglia appearing hyper- or hypointense on T2, hypointense on T2*, or calcified white matter anomalies mainly periventricular or subcortical, or with contrast enhancement, associated with macrocephaly and/or large or very small cysts, and hypomyelination; there may be "vascular" or pseudostroke disorders, cortical atrophy, hypoplasia, or abnormal signal of the brainstem and/or cerebellum. Spectroscopy should investigate basal ganglia, white matter, and the cerebellum. MRI may reveal typical alterations of the brain at the preclinical stage in siblings of affected children., (Copyright © 2013 Elsevier B.V. All rights reserved.)
Published: 2013
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27. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.

Author: Haack TB, Hogarth P, Kruer MC, Gregory A, Wieland T, Schwarzmayr T, Graf E, Sanford L, Meyer E, Kara E, Cuno SM, Harik SI, Dandu VH, Nardocci N, Zorzi G, Dunaway T, Tarnopolsky M, Skinner S, Frucht S, Hanspal E, Schrander-Stumpel C, Héron D, Mignot C, Garavaglia B, Bhatia K, Hardy J, Strom TM, Boddaert N, Houlden HH, Kurian MA, Meitinger T, Prokisch H, and Hayflick SJ
Subjects: Alleles, Amino Acid Sequence, Base Sequence, Brain pathology, Female, Gene Order, High-Throughput Nucleotide Sequencing, Humans, Iron Overload diagnosis, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Brain metabolism, Carrier Proteins genetics, Exome, Genes, X-Linked, Iron Overload genetics, Mutation, Phenotype
Abstract: Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2012
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28. [Brain imaging in seizures].

Author: Grévent D, Calmon R, Brunelle F, and Boddaert N
Subjects: Age of Onset, Brain pathology, Child, Humans, Magnetic Resonance Imaging, Seizures diagnostic imaging, Seizures epidemiology, Seizures pathology, Tomography, X-Ray Computed, Brain diagnostic imaging, Neuroimaging methods
Abstract: Cerebral imaging studies are performed systematically in children with non-idiopathic epilepsy. Magnetic resonance imaging (MRI) of the brain is the preferred technique. In emergency settings, when immediate neurosurgical treatment may be required (acute haemorrhage, etc.) non-enhanced computed tomography (NECT) is indicated, due to the shorter exam duration and the greater availability. Despite a normal NECT scan, the MRI scan is always indicated for non-idiopathic epileptic patients to search for small cortical sub-cortical abnormalities often overlooked in CT scans. On the other hand, a second intention CT scan to look for calcification may be indicated when tuberous sclerosis, Aicardi-Goutieres syndrome, infectious foetal diseases are suspected. The MRI protocol is adapted to each case based on clinical and EEG findings, but will always include a T1 weighted-3-dimensional (isotropic) acquisition, axial and coronal T2 and T2-Flair weighted images and T2*. Contrast injection is mandatory especially when abnormal findings are seen on the MRI precontrast images.
Published: 2012

29. Mutations of TSEN and CASK genes are prevalent in pontocerebellar hypoplasias type 2 and 4.

Author: Valayannopoulos V, Michot C, Rodriguez D, Hubert L, Saillour Y, Labrune P, de Laveaucoupet J, Brunelle F, Amiel J, Lyonnet S, Enza-Razavi F, Attié-Bitach T, Lacombe D, Bahi-Buisson N, Desguerre I, Chelly J, Burglen L, Boddaert N, and de Lonlay P
Subjects: Female, Humans, Male, Arginine-tRNA Ligase genetics, Brain pathology, Endoribonucleases genetics
Published: 2012
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30. Feature selection and classification of imbalanced datasets: application to PET images of children with autistic spectrum disorders.

Author: Duchesnay E, Cachia A, Boddaert N, Chabane N, Mangin JF, Martinot JL, Brunelle F, and Zilbovicius M
Subjects: Adolescent, Artificial Intelligence, Child, Child, Preschool, Female, Humans, Male, Positron-Emission Tomography, Algorithms, Brain diagnostic imaging, Brain Mapping methods, Child Development Disorders, Pervasive diagnostic imaging, Image Interpretation, Computer-Assisted methods
Abstract: Learning with discriminative methods is generally based on minimizing the misclassification of training samples, which may be unsuitable for imbalanced datasets where the recognition might be biased in favor of the most numerous class. This problem can be addressed with a generative approach, which typically requires more parameters to be determined leading to reduced performances in high dimension. In such situations, dimension reduction becomes a crucial issue. We propose a feature selection/classification algorithm based on generative methods in order to predict the clinical status of a highly imbalanced dataset made of PET scans of forty-five low-functioning children with autism spectrum disorders (ASD) and thirteen non-ASD low functioning children. ASDs are typically characterized by impaired social interaction, narrow interests, and repetitive behaviors, with a high variability in expression and severity. The numerous findings revealed by brain imaging studies suggest that ASD is associated with a complex and distributed pattern of abnormalities that makes the identification of a shared and common neuroimaging profile a difficult task. In this context, our goal is to identify the rest functional brain imaging abnormalities pattern associated with ASD and to validate its efficiency in individual classification. The proposed feature selection algorithm detected a characteristic pattern in the ASD group that included a hypoperfusion in the right Superior Temporal Sulcus (STS) and a hyperperfusion in the contralateral postcentral area. Our algorithm allowed for a significantly accurate (88%), sensitive (91%) and specific (77%) prediction of clinical category. For this imbalanced dataset, with only 13 control scans, the proposed generative algorithm outperformed other state-of-the-art discriminant methods. The high predictive power of the characteristic pattern, which has been automatically identified on whole brains without any priors, confirms previous findings concerning the role of STS in ASD. This work offers exciting possibilities for early autism detection and/or the evaluation of treatment response in individual patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)
Published: 2011
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31. Neuropathological and neuroradiological spectrum of pediatric malignant gliomas: correlation with outcome.

Author: Puget S, Boddaert N, Veillard AS, Garnett M, Miquel C, Andreiuolo F, Sainte-Rose C, Roujeau T, DiRocco F, Bourgeois M, Zerah M, Doz F, Grill J, and Varlet P
Subjects: Adolescent, Brain metabolism, Brain Neoplasms mortality, Brain Neoplasms surgery, Child, Child, Preschool, Chromosomal Proteins, Non-Histone metabolism, DNA-Binding Proteins metabolism, Female, Glioma mortality, Glioma surgery, Humans, Infant, Infant, Newborn, Ki-67 Antigen metabolism, Longitudinal Studies, Magnetic Resonance Imaging methods, Male, Nerve Tissue Proteins metabolism, Radiography, Regression Analysis, Reproducibility of Results, Retrospective Studies, SMARCB1 Protein, Survival Analysis, Transcription Factors metabolism, Brain diagnostic imaging, Brain pathology, Brain Neoplasms diagnosis, Glioma diagnosis
Abstract: Background: The diagnostic accuracy and reproducibility for glioma histological diagnosis are suboptimal., Objective: To characterize radiological and histological features in pediatric malignant gliomas and to determine whether they had an impact on survival., Methods: We retrospectively reviewed a series of 96 pediatric malignant gliomas. All histological samples were blindly and independently reviewed and classified according to World Health Organization 2007 and Sainte-Anne classifications. Radiological features were reviewed independently. Statistical analyses were performed to investigate the relationship between clinical, radiological, and histological features and survival., Results: Cohort median age was 7.8 years; median follow-up was 4.8 years. Tumors involved cerebral hemispheres or basal ganglia in 82% of cases and brainstem in the remaining 18%. After histopathological review, low-grade gliomas and nonglial tumors were excluded (n = 27). The World Health Organization classification was not able to demonstrate differences between groups and patients survival. The Sainte-Anne classification identified a 3-year survival rate difference between the histological subgroups (oligodendroglioma A, oligodendroglioma B, malignant glioneuronal tumors, and glioblastomas; P = .02). The malignant glioneuronal tumor was the only glioma subtype with specific radiological features. Tumor location was significantly associated with 3-year survival rate (P = .005). Meningeal attachment was the only radiological criteria associated with longer survival (P = .02)., Conclusion: The Sainte-Anne classification was better able to distinguish pediatric malignant gliomas in terms of survival compared with the World Health Organization classification. In this series, neither of these 2 histological classifications provided a prognostic stratification of the patients.
Published: 2011
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32. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA).

Author: Kruer MC, Paisán-Ruiz C, Boddaert N, Yoon MY, Hama H, Gregory A, Malandrini A, Woltjer RL, Munnich A, Gobin S, Polster BJ, Palmeri S, Edvardson S, Hardy J, Houlden H, and Hayflick SJ
Subjects: Adolescent, Adult, Brain pathology, Child, Chromosome Mapping methods, Diagnostic Imaging methods, Female, Heredodegenerative Disorders, Nervous System pathology, Humans, Male, Mutation, Pedigree, Brain metabolism, Heredodegenerative Disorders, Nervous System genetics, Heredodegenerative Disorders, Nervous System metabolism, Iron metabolism, Mixed Function Oxygenases genetics
Abstract: Objective: Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA., Methods: Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA., Results: Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy., Interpretation: These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA.
Published: 2010
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33. LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity.

Author: Saillour Y, Carion N, Quelin C, Leger PL, Boddaert N, Elie C, Toutain A, Mercier S, Barthez MA, Milh M, Joriot S, des Portes V, Philip N, Broglin D, Roubertie A, Pitelet G, Moutard ML, Pinard JM, Cances C, Kaminska A, Chelly J, Beldjord C, and Bahi-Buisson N
Subjects: Adolescent, Adult, Child, Child, Preschool, Classical Lissencephalies and Subcortical Band Heterotopias classification, Classical Lissencephalies and Subcortical Band Heterotopias diagnosis, Female, Humans, Infant, Male, Phenotype, Young Adult, 1-Alkyl-2-acetylglycerophosphocholine Esterase genetics, Brain pathology, Classical Lissencephalies and Subcortical Band Heterotopias genetics, DNA Mutational Analysis, Genotype, Magnetic Resonance Imaging, Microtubule-Associated Proteins genetics, Neurologic Examination
Abstract: Objective: With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype., Design: Retrospective study. Subjects A total of 63 patients with posteriorly predominant lissencephaly., Interventions: Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined., Results: Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly., Conclusion: Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.
Published: 2009
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34. Sporadic case of unusual facies, cerebral vascular anomalies and developmental delay.

Author: Bertoli M, Boddaert N, Raoul O, Amiel J, and Lyonnet S
Subjects: Brain abnormalities, Brain diagnostic imaging, Cerebrum abnormalities, Cerebrum blood supply, Cerebrum diagnostic imaging, Child, Preschool, Female, Humans, Radiography, Brain blood supply, Developmental Disabilities, Face abnormalities, Facies
Published: 2009
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35. Transient magnetic resonance diffusion abnormalities in West syndrome: the radiological expression of non-convulsive status epilepticus?

Author: Desguerre I, Marti I, Valayannopoulos V, Bahi-Buisson N, Dulac O, Plouin P, Delonlay P, Hertz-Pannier L, and Boddaert N
Subjects: Basal Ganglia diagnostic imaging, Brain pathology, Cerebellar Nuclei diagnostic imaging, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Male, Mesencephalon diagnostic imaging, Radiography, Thalamus diagnostic imaging, Brain diagnostic imaging, Magnetic Resonance Imaging, Spasms, Infantile diagnostic imaging, Spasms, Infantile pathology, Status Epilepticus diagnostic imaging, Status Epilepticus pathology
Abstract: The purpose of this study was to report patients with pharmacoresistant West syndrome of unknown cause whose magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) showed a transient decrease of diffusion in subcortical structures. Of 20 patients investigated over a 2-year period, three males and three females constitute the present series. They had daily clusters of infantile spasms with hypsarrhythmia for 4 to 24 months before the first investigation. Four were severely hypotonic. All aetiological studies involving intermediary metabolism, peroxysomes, mitochondria, and neurotransmitters in cerebrospinal fluid were negative. Patients underwent DWI when first examined at the mean age of 13 months, and on follow-up examination 6 to 18 months later. Diffusion was decreased in the pallidi and posterior brainstem. It was also decreased for five patients in thalami and for three in dentate nuclei. Repeat MRI, performed when spasms were still present but hypsarrhythmia had ceased, did not show the same abnormalities. Because of recruitment bias, this series probably overestimates the true incidence of such DWI abnormalities. The eventuality of toxic lesions, including some inborn error of metabolism or drug toxicity, is considered unlikely although it could not be excluded. The contribution of the epileptic encephalopathy itself appears the most likely course.
Published: 2008
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36. Selective iron chelation in Friedreich ataxia: biologic and clinical implications.

Author: Boddaert N, Le Quan Sang KH, Rötig A, Leroy-Willig A, Gallet S, Brunelle F, Sidi D, Thalabard JC, Munnich A, and Cabantchik ZI
Subjects: Adolescent, Adult, Biological Transport, Case-Control Studies, Deferiprone, Female, Humans, Iron metabolism, Iron Chelating Agents pharmacokinetics, Iron Chelating Agents therapeutic use, Magnetic Resonance Imaging, Male, Pyridones pharmacokinetics, Pyridones therapeutic use, Treatment Outcome, Brain metabolism, Brain Chemistry drug effects, Friedreich Ataxia drug therapy, Iron Chelating Agents administration & dosage, Pyridones administration & dosage
Abstract: Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membrane-permeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with age-matched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s(-1) (+/- 1.6 s(-1)) to 15.7 s(-1) (+/- 0.7 s(-1); P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r = 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neuropathy and ataxic gait in the youngest patients. To our knowledge, this is the first clinical demonstration of chelation removing labile iron accumulated in a specific brain area implicated in a neurodegenerative disease. The use of moderate chelation for relocating iron from areas of deposition to areas of deprivation has clinical implications for various neurodegenerative and hematologic disorders.
Published: 2007
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37. [Autism: neuroimaging].

Author: Zilbovicius M, Meresse I, and Boddaert N
Subjects: Auditory Perception, Humans, Interpersonal Relations, Magnetic Resonance Imaging, Memory, Positron-Emission Tomography, Radiography, Social Perception, Temporal Lobe abnormalities, Temporal Lobe physiopathology, Tomography, Emission-Computed, Single-Photon, Autistic Disorder diagnostic imaging, Autistic Disorder pathology, Brain abnormalities, Image Processing, Computer-Assisted
Abstract: Autism is a neurodevelopmental disorder with a range of clinical presentations. These presentations vary from mild to severe and are referred to as autism spectrum disorders. The most common clinical sign of autism spectrum disorders is social interaction impairment, which is associated with verbal and non-verbal communication deficits and stereotyped and repetitive behaviors. Thanks to recent brain imaging studies, scientists are getting a better idea of the neural circuits involved in autism spectrum disorders. Indeed, functional brain imaging, such as positron emission tomography, single foton emission tomography and functional MRI have opened a new perspective to study normal and pathological brain functioning. Three independent studies have found anatomical and rest functional temporal lobe abnormalities in autistic patients. These alterations are localized in the superior temporal sulcus bilaterally, an area which is critical for perception of key social stimuli. In addition, functional studies have shown hypoactivation of most areas implicated in social perception (face and voice perception) and social cognition (theory of mind). These data suggest an abnormal functioning of the social brain network in autism. The understanding of the functional alterations of this important mechanism may drive the elaboration of new and more adequate social re-educative strategies for autistic patients.
Published: 2006
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38. Autism: functional brain mapping of exceptional calendar capacity.

Author: Boddaert N, Barthélémy C, Poline JB, Samson Y, Brunelle F, and Zilbovicius M
Subjects: Adult, Autistic Disorder diagnostic imaging, Autistic Disorder psychology, Brain diagnostic imaging, Humans, Image Processing, Computer-Assisted methods, Male, Positron-Emission Tomography, Autistic Disorder physiopathology, Brain physiopathology, Brain Mapping methods
Abstract: Background: 'Autistic savants' are individuals with autism who have extraordinary skills. Brain mechanisms underlying such capacities are still unknown., Aims: To map the exceptional calendar capacity of a man with primary autism., Method: Positron emission tomography was used to map brain activity in a man who is able to associate a day of the week with the corresponding calendar date., Results: During the calendar task, the left hippocampus, the left frontal cortex and the left middle temporal lobe were activated., Conclusions: The cerebral circuit involved in this man's prodigious calendar skill is similar to that normally involved in memory retrieval tasks. These results suggest that the prodigious capacities may be sustained by memory processing.
Published: 2005
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39. Specific brain MRI features of constitutional mismatch repair deficiency syndrome in children with high-grade gliomas

Author: Raveneau, Magali, Guerrini-Rousseau, Léa, Levy, Raphael, Roux, Charles-Joris, Bolle, Stéphanie, Doz, François, Bourdeaut, Franck, Colas, Chrystelle, Blauwblomme, Thomas, Beccaria, Kevin, Tauziède-Espariat, Arnault, Varlet, Pascale, Dufour, Christelle, Grill, Jacques, Boddaert, Nathalie, and Dangouloff-Ros, Volodia
Published: 2024
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40. FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model

Author: Cornille, Maxence, Moriceau, Stéphanie, Khonsari, Roman, Heuzé, Yann, Loisay, Léa, Boitez, Valérie, Morice, Anne, Arnaud, Eric, Collet, Corinne, Bensidhoum, Morad, Kaci, Nabil, Boddaert, Nathalie, Paternoster, Giovanna, Rauschendorfer, Theresa, Werner, Sabine, Mansour, Suzanne, Di Rocco, Federico, Oury, Franck, Legeai-Mallet, Laurence, Heuzé, Yann, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), National Cystic Fibrosis Reference Center [CHU Necker] (CNR - INSERM U1151), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de chirurgie plastique et maxillofaciale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Hôpital Lariboisière-Fernand-Widal [APHP], Laboratoire de Biomécanique et Biomatériaux Ostéo-Articulaires (B2OA), Université Paris Diderot - Paris 7 (UPD7), Service de radiologie pédiatrique [CHU Necker], Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of Utah, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), and Hospices Civils de Lyon (HCL)
Subjects: [SDV] Life Sciences [q-bio], Craniosynostoses, Disease Models, Animal, Memory Disorders, Mice, [SDV]Life Sciences [q-bio], Craniofacial Dysostosis, Animals, Brain, Receptor, Fibroblast Growth Factor, Type 3, Acanthosis Nigricans
Abstract: International audience; Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3 A385E/+) of this syndrome. Surprisingly, Fgfr3 A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3 A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis.
Published: 2020

41. Brain perfusion magnetic resonance imaging using pseudocontinuous arterial spin labeling in 314 dogs and cats.

Author: Hoffmann, Anne‐Cécile, Ruel, Yannick, Gnirs, Kirsten, Papageorgiou, Stella, Zilberstein, Luca, Nahmani, Sarah, Boddaert, Nathalie, and Gaillot, Hugues
Subjects: SPIN labels, MAGNETIC resonance angiography, DOGS, THALAMIC nuclei, CAT diseases, CEREBRAL circulation, FELIDAE, PERCH
Abstract: Background: Arterial spin labeling (ASL) is a noninvasive brain perfusion magnetic resonance imaging (MRI) technique that has not been assessed in clinical veterinary medicine. Hypothesis/Objectives: To test the feasibility of ASL using a 1.5 Tesla scanner and provide recommendations for optimal quantification of cerebral blood flow (CBF) in dogs and cats. Animals: Three hundred fourteen prospectively selected client‐owned dogs and cats. Methods: Each animal underwent brain MRI including morphological sequences and ≥1 ASL sequences using different sites of blood labeling and postlabeling delays (PLD). Calculated ASL success rates were compared. The CBF was quantified in animals that had morphologically normal brain MRI results and parameters of ASL optimization were investigated. Results: Arterial spin labeling was easily implemented with an overall success rate of 95% in animals with normal brain MRI. Technical recommendations included (a) positioning of the imaging slab at the foramen magnum and (b) selected PLD of 1025 ms in cats and dogs <7 kg, 1525 ms in dogs 7 to 38 kg, and 2025 ms in dogs >38 kg. In 37 dogs, median optimal CBF in the cortex and thalamic nuclei were 114 and 95 mL/100 g/min, respectively. In 28 cats, median CBF in the cortex and thalamic nuclei were 113 and 114 mL/100 g/min, respectively. Conclusions and Clinical Importance: Our survey of brain perfusion ASL‐MRI demonstrated the feasibility of ASL at 1.5 Tesla, suggested technical recommendations and provided CBF values that should be helpful in the characterization of various brain diseases in dogs and cats. [ABSTRACT FROM AUTHOR]
Published: 2021
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42. Common genetic variants influence human subcortical brain structures

Author: Hibar, Derrek P, Stein, Jason L, Aribisala, Benjamin S, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Armstrong, Nicola J, Gibbs, J Raphael, Göring, Harald H H, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Bernard, Manon, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Ikeda, Masashi, Jack, Clifford R, Jenkinson, Mark, Johnson, Robert, Kanai, Ryota, Keil, Maria, Bohlken, Marc M, Kent, Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Meisenzahl, Eva, Melle, Ingrid, Mohnke, Sebastian, Boks, Marco P, Montgomery, Grant W, Mostert, Jeanette C, Mühleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Nöthen, Markus M, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Bralten, Janita, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Rietschel, Marcella, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Rujescu, Dan, Schnell, Knut, Schofield, Peter R, Brown, Andrew A, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Thalamuthu, Anbupalam, Toga, Arthur W, Traynor, Bryan J, Troncoso, Juan, Turner, Jessica A, Valdés Hernández, Maria C, van 't Ent, Dennis, Chakravarty, M Mallar, van der Brug, Marcel, van der Wee, Nic J A, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Zonderman, Alan B, Ashbrook, David G, Hager, Reinmar, Chen, Qiang, Lu, Lu, McMahon, Francis J, Morris, Derek W, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Ching, Christopher R K, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Renteria, Miguel E, Cuellar-Partida, Gabriel, Hoffmann, Wolfgang, Hosten, Norbert, Kahn, René S, Le Hellard, Stephanie, Meyer-Lindenberg, Andreas, Müller-Myhsok, Bertram, Nauck, Matthias, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda W J H, den Braber, Anouk, Roffman, Joshua L, Sisodiya, Sanjay M, Smoller, Jordan W, van Bokhoven, Hans, van Haren, Neeltje E M, Völzke, Henry, Walter, Henrik, Weiner, Michael W, Wen, Wei, White, Tonya, Giddaluru, Sudheer, Agartz, Ingrid, Andreassen, Ole A, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, de Geus, Eco J C, Deary, Ian J, Donohoe, Gary, Goldman, Aaron L, Fernández, Guillén, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Gruber, Oliver, Hardy, John, Hashimoto, Ryota, Hulshoff Pol, Hilleke E, Jönsson, Erik G, Grimm, Oliver, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, McDonald, Colm, McIntosh, Andrew M, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Guadalupe, Tulio, Sachdev, Perminder S, Saykin, Andrew J, Simmons, Andy, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Weinberger, Daniel R, Adams, Hieab H H, Launer, Lenore J, Hass, Johanna, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa, van der Lee, Sven J, Ebling, Maritza, Fischl, Bruce, Longstreth, W. T., Woldehawariat, Girma, Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Xue, Luting, Mazoyer, Bernard, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Holmes, Avram J, Ikram, M Arfan, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, EPIGEN, IMAGEN, SYS, Martin, Nicholas G, Wright, Margaret J, Schumann, Gunter, Franke, Barbara, Hoogman, Martine, Thompson, Paul M, Medland, Sarah E, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Beckett, Laurel, Arias-Vasquez, Alejandro, Janowitz, Deborah, Morris, John, Shaw, Leslie M, Khachaturian, Zaven, Sorensen, Greg, Carrillo, Maria, Kuller, Lew, Raichle, Marc, Paul, Steven, Jia, Tianye, Davies, Peter, Fillit, Howard, Hefti, Franz, Holtzman, Davie, Mesulman, M Marcel, Potter, William, Snyder, Peter, Schwartz, Adam, Montine, Tom, Kim, Sungeun, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Klein, Marieke, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCarli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Kraemer, Bernd, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Lee, Phil H, Landau, Susan, Cairns, Nigel J, Householder, Erin, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Figurski, Michal, Olde Loohuis, Loes M, Crawford, Karen, Neu, Scott, Potkin, Steven, Shen, Li, Faber, Kelley, Nho, Kwangsik, Luciano, Michelle, Thal, Leon, Frank, Richard, Snyder, Peter J, Buckholtz, Neil, Macare, Christine, Albert, Marilyn, Hsiao, John, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Gutman, Boris A, Schneider, Lon S, Mather, Karen A, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Desrivières, Sylvane, Mattheisen, Manuel, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Milaneschi, Yuri, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Oliver, Angela, Marson, Daniel, Griffith, Randall, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, deToledo-Morrell, Leyla, Shah, Raj C, Papmeyer, Martina, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Roberts, Peggy, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Pogorelec, Dana M, Ramasamy, Adaikalavan, Cerbone, Brittany, Michel, Christina A, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Risacher, Shannon L, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Roiz-Santiañez, Roberto, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Rose, Emma J, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Lah, James J, Salami, Alireza, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Sämann, Philipp G, Graff-Radford, Neill R, Parfitt, Francine, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Jahanshad, Neda, Schmaal, Lianne, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Yuek Robin, Feldman, Howard, Schork, Andrew J, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristine, Shin, Jean, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Strike, Lachlan T, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Teumer, Alexander, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, van Donkelaar, Marjolein M J, Ogrocki, Paula, Hudson, Leon, Fletcher, Evan, Carmichael, Owen, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, van Eijk, Kristel R, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Walters, Raymond K, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Westlye, Lars T, Anderson, Karen, Santulli, Robert B, Kitzmiller, Tamar J, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Whelan, Christopher D, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Toro, Roberto, Winkler, Anderson M, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Zwiers, Marcel P, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Amin, Najaf, Becker, Diane, Alhusaini, Saud, Beiser, Alexa, Debette, Stéphanie, DeStefano, Anita, Hofer, Edith, Hofman, Albert, Niessen, Wiro J, Smith, Albert, Tzourio, Christophe, Vaidya, Dhananjay, Athanasiu, Lavinia, Vernooij, Meike W, Goldstein, David B, Heinzen, Erin L, Shianna, Kevin, Radtke, Rodney, Ottmann, Ruth, Albrecht, Lisa, Andrew, Chris, Arroyo, Mercedes, Artiges, Eric, Ehrlich, Stefan, Aydin, Semiha, Bach, Christine, Banaschewski, Tobias, Barbot, Alexis, Barker, Gareth, Boddaert, Nathalie, Bokde, Arun, Bricaud, Zuleima, Bromberg, Uli, Bruehl, Ruediger, Hakobjan, Marina M H, Büchel, Christian, Cachia, Arnaud, Cattrell, Anna, Conrod, Patricia, Constant, Patrick, Crombag, Hans, Czech, Katharina, Dalley, Jeffrey, Decideur, Benjamin, Desrivieres, Sylvane, Hartberg, Cecilie B, Fadai, Tahmine, Flor, Herta, Frouin, Vincent, Fuchs, Birgit, Gallinat, Jürgen, Garavan, Hugh, Briand, Fanny Gollier, Gowland, Penny, Head, Kay, Heinrichs, Bert, Haukvik, Unn K, Heym, Nadja, Hübner, Thomas, Ihlenfeld, Albrecht, Ireland, James, Ittermann, Bernd, Ivanov, Nikolay, Jones, Jennifer, Klaassen, Arno, Heister, Angelien J G A M, Lalanne, Christophe, Lathrop, Mark, Lanzerath, Dirk, Lemaitre, Hervé, Lüdemann, Katharina, Mallik, Catherine, Mangin, Jean-François, Mann, Karl, Mar, Adam, Hoehn, David, Martinot, Jean-Luc, Massicotte, Jessica, Mennigen, Eva, Mesquita de Carvahlo, Fabiana, Mignon, Xavier, Miranda, Ruben, Müller, Kathrin, Nees, Frauke, Nymberg, Charlotte, Paillere, Marie-Laure, Wittfeld, Katharina, Kasperaviciute, Dalia, Pena-Oliver, Yolanda, Poline, Jean-Baptiste, Poustka, Luise, Rapp, Michael, Reed, Laurence, Robert, Gabriel, Reuter, Jan, Liewald, David C M, Ripke, Stephan, Ripley, Tamzin, Robbins, Trevor, Rodehacke, Sarah, Romanowski, Alexander, Ruggeri, Barbara, Schilling, Christina, Schmäl, Christine, Schmidt, Dirk, Lopez, Lorna M, Schneider, Sophia, Schroeder, Markus, Schubert, Florian, Schwartz, Yannick, Smolka, Michael, Sommer, Wolfgang, Spanagel, Rainer, Speiser, Claudia, Spranger, Tade, Stedman, Alicia, Makkinje, Remco R R, Steiner, Sabina, Stephens, Dai, Strache, Nicole, Ströhle, Andreas, Struve, Maren, Subramaniam, Naresh, Theobald, David, Topper, Lauren, Vollstaedt-Klein, Sabine, Walaszek, Bernadeta, Matarin, Mar, Weiß, Katharina, Werts, Helen, Whelan, Robert, Williams, Steve, Yacubian, Juliana, Ziesch, Veronika, Zilbovicius, Monica, Wong, C Peng, Lubbe, Steven, Naber, Marlies A M, Martinez-Medina, Lourdes, Kepa, Agnes, Fernandes, Alinda, Tahmasebi, Amir, Abrahamowicz, Michal, Gaudet, Daniel, Leonard, Gabriel, Perron, Michel, Richer, Louis, Seguin, Jean, McKay, D Reese, Veillette, Suzanne, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Abramovic, Lucija, Royle, Natalie A, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia S L, van Hulzen, Kimm J E, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Andersson, Micael, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, Czisch, Michael, MUMC+: DA Klinische Genetica (5), RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Université de Montréal. Faculté de médecine. Département de psychiatrie et d'addictologie, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), QIMR Berghofer Medical Research Institute, Department of Psychiatry, Donders Centre for Neuroscience, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, PRES Sorbonne Paris Cité, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, University Medical Center [Utrecht], European Commission, University of Edinburgh, Lagos State University (LASU), Heriot-Watt University [Edinburgh] (HWU), Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], University of Oslo (UiO), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], School of Technical Physics, Xidian University, Dept. of Mechanical Engineering, McMaster University [Hamilton, Ontario], Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Haukeland University Hospital, University of Bergen (UiB), Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 (PC2A), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Universität Heidelberg [Heidelberg] = Heidelberg University, Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, International Max Planck Research School for Language Sciences (IMPRS ), Georgia Institute of Technology [Atlanta], National Institutes of Health [Bethesda] (NIH), Yale University [New Haven], Massachusetts General Hospital [Boston], Mental Health Sciences Unit, University College of London [London] (UCL), Beijing Normal University (BNU), Indiana University School of Medicine, Indiana University System, Indiana Alzheimer Disease Center, Indiana University System-Indiana University System, Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, University of California (UC), Medstar Research Institute, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], VU University Medical Center [Amsterdam], Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå 901 87, Sweden, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), The Hospital for sick children [Toronto] (SickKids), Queensland Institute of Medical Research, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, Department of Genomics of Common Disease, Imperial College London, Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), MetaGenoPolis, Department of Psychiatric Research and Development, Diakonhjemmet Hospital, Oslo 0319, Norway, UCL Institute of Neurology and Epilepsy Society, Department of Medicine, Clinical And Experimental Epilepsy, Dpt of Psychiatry [New Haven], Yale School of Medicine [New Haven, Connecticut] (YSM), Hartford Hospital, Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, State Key Laboratory of Lead Compound Research, WuXi AppTec, Co., Ltd, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Department of Genetics, King Faisal Specialist Hospital and Research Centre (KFSH & RC), Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Dundee Technopole, CXR Biosciences Ltd, Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Dementia Collaborative Research Centre, N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Texas Biomedical Research Institute [San Antonio, TX], Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Trinity College Dublin-St. James's Hospital, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], School of Psychology, University of Queensland, Laboratory of Neurogenetics, The University of Texas Health Science Center at Houston (UTHealth), Department of Genomics, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Biofunctional Imaging, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan, Public Health Genomics Unit, Department of Biomolecular Engineering, Rheinische Friedrich-Wilhelms-Universität Bonn, Estación Experimental de Pastos y Forrajes 'Indio Hatuey', University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake 470-1192, Japan, Department of Radiology, Mayo Clinic, Department of Clinical Neurology [Oxford], University of Oxford-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], University of Maryland School of Medicine, University of Maryland System, University of Sussex, Institute of Cognitive Neuroscience, United Kingdom Met Office [Exeter], University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Columbia University Irving Medical Center (CUIMC), Lymphocyte Cell Biology Unit, Laboratory of Genetics, Centre for Advanced Imaging, Psychiatry and Psychotherapy, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Statistics [Warwick], University of Warwick [Coventry], Osaka University [Osaka], Institute of Psychiatry, King’s College London, London SE5 8AF, UK, University of Calgary, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, University of California [Irvine] (UC Irvine), Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Space and Naval Warfare Systems Center, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Department of Psychiatry, Division of Medical Psychology, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Développement et amélioration des plantes (UMR DAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Laboratory of Neuro Imaging [Los Angeles] (LONI), Departamento de Física Aplicada, Universidade de Vigo, Georgia State University, University System of Georgia (USG), Genentech, Inc. [San Francisco], Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Universiteit Leiden, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Department of Neurobiology, Care Sciences and Society, Karolinska Institutet [Stockholm], University of Manchester [Manchester], The University of Tennessee Health Science Center [Memphis] (UTHSC), iangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong 226001, China, Centre for Ultrahigh Bandwidth Devices for Optical Systems (CUDOS), Macquarie University, Cognitive Neuroscience Laboratory (CNL), Harvard University, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Division of Molecular and Cellular Therapeutics, Scottish Association for Marine Science (SAMS), Structural Biology Laboratory, Department of Chemistry, University of York, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], Institute for Community Medicine, Department Epidemiology of Health Care and Community Health, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Institute of Clinical Chemistry and Laboratory Medicine, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Psychiatric and Neurodevelopmental Genetics Unit, 849 Department of Human Genetics, Institute for Community Medicine, Institute for Energy Systems and Thermodynamics, Renyi Institute, Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000 CB, The Netherlands, Department of Radiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands, Vrije Universiteit Amsterdam [Amsterdam] (VU), Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Dept of Psychology, Laboratoire de Recherche Magellan, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations (ISEOR), Institut de socio-économie des entreprises et des organisations, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Centre for Allergy Research, Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Medical University of Łódź (MUL), Psychiatry Institute, Department of Health and Human Services, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia = University of Perugia (UNIPG), Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Australian Centre for Research into Injury in Sport and its Prevention, Monash University [Clayton], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, School of Psychology [Nottingham], University of Nottingham, UK (UON), McConnell Brain Imaging Centre (MNI), SickKids - The Hospital for sick children, European Centre for Medium-Range Weather Forecasts (ECMWF), University of Eastern Finland, Centre for Population Health Sciences, Lieber Institute for Brain Development [Baltimore] (LIBD), Johns Hopkins University (JHU), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz 8010, Austria, Austrian Institute of Technology [Vienna] (AIT), INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, INSERM, Neuroepidemiology U708, Bordeaux, France, Karlsruhe Institute of Technology (KIT), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Harvard Medical School [Boston] (HMS), Computer Science and Artificial Intelligence Laboratory [Cambridge] (CSAIL), Massachusetts Institute of Technology (MIT), University of Washington [Seattle], Department of Physics [Stockholm], Stockholm University, Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Boston University [Boston] (BU), Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine, University of Iceland [Reykjavik], Icelandic Heart Association, Kopavogur, Iceland., Boston University School of Medicine (BUSM), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of California-University of California, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Gènes, Synapses et Cognition, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), UE 1354 Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Unité d'expérimentation sur les Ruminants de Theix (UE RT), Radboud university [Nijmegen], McGill University, University of Bergen (UIB), Universität Heidelberg [Heidelberg], Beijing Normal University, University of California, University of Bonn, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Neurosciences [San Diego], Department of Cognitive Sciences [San Diego], The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada, McGill University-McGill University, US 1367 MetaGénoPolis, Institut National de la Recherche Agronomique (INRA)-Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA)-MetaGénoPolis (MGP), Yale University School of Medicine, King Faisal Specialist Hospital and Research Centre, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne 3101, Australia, Department of Genomics, Life & Brain Center, University of Bonn, Bonn D-53127, Germany, University of Oxford [Oxford]-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], School of Psychology, University of Sussex, Brighton BN1 9QH, UK, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Neurology [University of Calgary], Department of Clinical Neuroscience [University of Calgary], University of California [Irvine] (UCI), Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Universidate de Vigo, Harvard University [Cambridge], Radboud university [Nijmegen]-Radboud university [Nijmegen], Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Centre de Recherche Magellan, Institut d'Administration des Entreprises (IAE) - Lyon-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Università degli Studi di Perugia (UNIPG), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Bretagne Sud (UBS)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), The Alzheimer’s Disease Neuroimaging Initiative, The CHARGE Consortium, EPIGEN, IMAGEN, SYS, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital]-University of Oxford [Oxford], Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-FMRIB Centre, Neurology, Psychiatry, Anatomy and neurosciences, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Biological Psychology, Cognitive Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, EMGO+ - Mental Health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Radiology & Nuclear Medicine, Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, MRC- SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK, Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald 17487, Germany, Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands, Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK, Department of Computer Science, Lagos State University, Lagos, Nigeria, Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Heriot-Watt University [Edinburgh] ( HWU ), Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Unité d'expérimentation sur les Ruminants de Theix ( UE RT ), Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway, NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0424, Norway, Montreal Neurological Institute [Montréal], NORMENT - KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway, Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 ( PC2A ), Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands, International Max Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands, Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA, Department of Psychology, Yale University, New Haven, Connecticut 06511, USA, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA, University College of London [London] ( UCL ), Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Neurobehavioral Genetics, University of California, Los Angeles, California 90095, USA, Université de Bonn, Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands, Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK, Imperial College London-School of public health-MRC-HPA Centre for Environment and Health, Cibersam (Centro Investigación Biomédica en Red Salud Mental), Madrid 28029, Spain, Institut Parisien de Chimie Moléculaire ( IPCM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Aging Research Center [Karolinska Institutet] ( ARC ), Max Planck Institute of Psychiatry, Munich 80804, Germany, Multimodal Imaging Laboratory, Department of Neurosciences, University of California, San Diego, California 92093, USA, Department of Cognitive Sciences, University of California, San Diego, California 92161, USA, Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, Department of Psychology, University of Oslo, Oslo 0373, Norway, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada, Molecular and Cellular Therapeutics, The Royal College of Surgeons, Dublin 2, Ireland, Institut National de la Recherche Agronomique ( INRA ) -MetaGénoPolis ( MGP ) -Microbiologie et Chaîne Alimentaire ( MICA ), UCL Institute of Neurology, London, United Kingdom and Epilepsy Society, London WC1N 3BG, UK, Department of Medicine, Imperial College London, London W12 0NN, UK, Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK, Yale School of Medicine, Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut 06106, USA, University College Dublin [Dublin] ( UCD ), Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK, Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia, Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), School of public health-Tehran University of Medical Siences, University of New South Wales [Sydney] ( UNSW ), Texas Biomedical Research Institute, San Antonio, Texas 78245, USA, Institute of Neuroscience and Medicine ( INM-1 ), University of Basel ( Unibas ), Cambridge University, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA, University of Texas Health Science Center, San Antonio, Texas 78229, USA, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland 20892, USA, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald 17475, Germany, University Medical Center Groningen, University of Groningen, University of Greifswald, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA, nstitute of Cognitive Neuroscience, University College London, London WC1N 3AR, UK, Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21201, USA, Department of Pathology and Cell Biology, Columbia University Medical Center, New York 10032, USA, Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA, University of Oslo ( UiO ) -Institute of Clinical Medicine-Oslo University Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo ( UiO ) -European Network of Bipolar Research Expert Centers (ENBREC) Group, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany, Erasmus MC, Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland, USA, Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Central Institute of Mental Health, UMR 1098 Développement et Amélioration des Plantes, Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -MontpellierSupAgro ( MontpellierSupAgro ) -Génétique et amélioration des plantes ( G.A.P. ) -Développement et Amélioration des Plantes ( DAP ), Laboratory of Neuro Imaging [Los Angeles] ( LONI ), University of California at Los Angeles [Los Angeles] ( UCLA ), Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Genentech, South San Francisco, California 94080, USA, Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands, LUMC, Carver College of Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm SE-141 83, Sweden, Behavioral Epidemiology Section, National Institute on Aging Intramural Research Program, Baltimore, Maryland 20892, USA, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Centre Interlangues - Texte, Image, Langage ( TIL ), Université de Bourgogne ( UB ), Centre for Ultrahigh Bandwidth Devices for Optical Systems ( CUDOS ), Icahn School of Medicine at Mount Sinai [New York], The Mind Research Network & LBERI, Albuquerque, New Mexico 87106, USA, Department of ECE, University of New Mexico, Albuquerque, New Mexico 87131, USA, Scottish Association for Marine Science ( SAMS ), Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels 1070, Belgium, National Institutes of Health ( NIH ) -National Institute of Mental Health (NIMH), Harvard Medical School [Boston] ( HMS ) -Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA, Luleå University of Technology ( LUT ), Broad Institute of MIT and Harvard, Massachusetts General Hospital, Vrije Universiteit Amsterdam [Amsterdam] ( VU ), Université Jean Moulin - Lyon III-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations ( ISEOR ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Laboratoire d'Informatique de Grenoble ( LIG ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National Polytechnique de Grenoble ( INPG ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan, Karolinska University Hospital (Solna), Medical University of Łódź ( MUL ), National Institutes of Health ( NIH ), University of Perugia, Commonwealth Scientific and Industrial Research Organisation, University Medical Center Utrecht-Brain Center Rudolf Magnus, University of Nottingham, UK ( UON ), McConnell Brain Imaging Centre ( MNI ), The Hospital for sick children [Toronto] ( SickKids ), Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK, European Centre for Medium-Range Weather Forecasts ( ECMWF ), Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA, Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, Austrian Institute of Technology [Vienna] ( AIT ), Karlsruhe Institute of Technology ( KIT ), General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA, Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA, Computer Science and Artificial Intelligence Laboratory [Cambridge] ( CSAIL ), Massachusetts Institute of Technology ( MIT ), Department of Epidemiology, University of Washington, Seattle, Washington, USA, Department of Neurology, University of Washington, Seattle, Washington, USA, Department of Physics, Stockholm University ( Department of Physics, Stockholm University ), Université de Lille, Sciences Humaines et Sociales, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA, Groupe d'Imagerie Neurofonctionnelle ( GIN - UMR 5296 ), Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ), Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA, Faculty of Medicine, University of Iceland, Reykjavik, Iceland, Department of Neurology, Boston University School of Medicine, Framingham Heart Study, Boston, MA, Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -Université de Brest ( UBO ), King's College, Department of Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, and Broad Institute of © 2012 Nature America, Inc. All rights reserved. Nature Ge N etics aDV a NCE ONLINE PUBLIC a TION 7 l e t t e r s Harvard and MIT, Cambridge, Massachusetts, US
Subjects: CHROMATIN, Male, Netherlands Twin Register (NTR), Aging, Identification, nervous-system, human geography, SEGMENTATION, Caudate nucleus, Apoptosis, Expression, Genome-wide association study, Striatum, Hippocampal formation, Hippocampus, BASAL GANGLIA, 130 000 Cognitive Neurology & Memory, Basal ganglia, genetics [Gene Expression Regulation, Developmental], Hippocampal, Child, anatomy & histology [Skull], Aged, 80 and over, Genetics, Sex Characteristics, KINECTIN, Genome-wide association, Multidisciplinary, Putamen, Brain, Gene Expression Regulation, Developmental, blood, brain, disease incidence, genetic variation, neurology, Organ Size, Human brain, Middle Aged, organization, Magnetic Resonance Imaging, genetics [Genetic Variation], Chromatin, Dynamics, genetics [Membrane Proteins], medicine.anatomical_structure, genetics [Aging], Anatomy & histology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Female, ddc:500, anatomy & histology [Caudate Nucleus], Neuroinformatics, EXPRESSION, Adult, Adolescent, Evolution, anatomy & histology [Hippocampus], ORGANIZATION, genetics [Genetic Loci], Biology, Article, Young Adult, SDG 3 - Good Health and Well-being, Journal Article, medicine, Humans, GENOME-WIDE ASSOCIATION, General, genetics [Apoptosis], Kinectin, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], HIPPOCAMPAL, IDENTIFICATION, genetics [Organ Size], [SCCO.NEUR]Cognitive science/Neuroscience, Skull, segmentation, Genetic Variation, Membrane Proteins, NERVOUS-SYSTEM, anatomy & histology [Putamen], Genetic Loci, KTN1 protein, human, Caudate Nucleus, anatomy & histology [Brain], Neuroscience, Genome-Wide Association Study
Abstract: Contains fulltext : 144426.pdf (Publisher’s version ) (Closed access) Contains fulltext : 144426pre.pdf (Author’s version preprint ) (Open Access) The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 x 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. 6 p.
Published: 2015

43. LIS1-Related Isolated Lissencephaly: Spectrum of Mutations and Relationships With Malformation Severity

Author: Saillour, Yoann, Carion, Nathalie, Quelin, Chloe, Leger, Pierre-Louis, Boddaert, Nathalie, Elie, Caroline, Toutain, Annick, Mercier, Sandra, Barthez, Marie Anne, Milh, Mathieu, Joriot, Sylvie, Des Portes, Vincent, Philip, Nicole, Broglin, Dominique, ROUBERTIE, Agathe, Pitelet, Gaëlle, Moutard, Marie Laure, Pinard, Jean-Marc, Cancès, Clément, Cances, Claude, Kaminska, Anna, Chelly, Jamel, Beldjord, Chérif, Bahi-Buisson, Nadia, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neuro-pédiatrie[Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Neuropédiatrie, Université de Lyon-CHU de Lyon, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neuropédiatrie, CHU Hôpital, Hôpital l'Archet, Unité de Neurologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP]-Département de Pédiatrie, Laboratoire Jacques-Louis Lions (LJLL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de Pédiatrie, CHU Toulouse [Toulouse], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This study was supported by the French National Programme Hospitalier de Recherche Clinique (2003-32) and the Société d'Etudes et de Soins pour les Enfants Paralysés et Polymalformés., Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5), Service de Réanimation Néonatale et Pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Référence Maladies Rares ' malformations et maladies congénitales du cervelet ', Hospices Civils de Lyon (HCL)-CHU Trousseau [APHP]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Raymond Poincaré [Garches]-Département de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris Diderot - Paris 7 ( UPD7 ) -IFR2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Bretonneau-CHRU Tours, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Hospices Civils de Lyon ( HCL ) -CHU Trousseau [APHP]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP Hôpital Raymond Poincaré [Garches]-Département de Pédiatrie, Laboratoire Jacques-Louis Lions ( LJLL ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Genotype, DNA Mutational Analysis, Lissencephaly, Classical Lissencephalies and Subcortical Band Heterotopias, MESH : 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics* Adolescent Adult Brain/pathology* Child Child, Preschool Classical Lissencephalies and Subcortical Band Heterotopias/classification Classical Lissencephalies and Subcortical Band Heterotopias/diagnosis Classical Lissencephalies and Subcortical Band Heterotopias/genetics* DNA Mutational Analysis* Female Genotype* Humans Infant Magnetic Resonance Imaging* Male Microtubule-Associated Proteins/genetics* Neurologic Examination* Phenotype Young Adult, medicine.disease_cause, Central nervous system disease, 03 medical and health sciences, PAFAH1B1, Young Adult, 0302 clinical medicine, Arts and Humanities (miscellaneous), medicine, Medication Resistant Epilepsy, Humans, Child, 030304 developmental biology, Neurologic Examination, 0303 health sciences, Mutation, [ SDV ] Life Sciences [q-bio], business.industry, Brain, Infant, medicine.disease, Phenotype, Magnetic Resonance Imaging, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [ SCCO ] Cognitive science, business, Microtubule-Associated Proteins, 030217 neurology & neurosurgery
Abstract: International audience; Objective: With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype.Design: Retrospective study.Subjects: A total of 63 patients with posteriorly predominant lissencephaly.Interventions: Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined.Results: Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly.Conclusion: Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.
Published: 2009

44. Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population.

Author: Megahed, Hisham, Nicouleau, Michaël, Barcia, Giulia, Medina-Cano, Daniel, Siquier-Pernet, Karine, Bole-Feysot, Christine, Parisot, Mélanie, Masson, Cécile, Nitschké, Patrick, Rio, Marlène, Bahi-Buisson, Nadia, Desguerre, Isabelle, Munnich, Arnold, Boddaert, Nathalie, Colleaux, Laurence, and Cantagrel, Vincent
Subjects: EXOMES, GENETIC disorders, DIAGNOSIS of epilepsy, BRAIN imaging, MAGNETIC resonance imaging, DIAGNOSIS of developmental disabilities, BRAIN metabolism, BRAIN, CEREBELLAR ataxia, COMPARATIVE studies, DEVELOPMENTAL disabilities, GENOMES, RESEARCH methodology, MEDICAL cooperation, GENETIC mutation, RESEARCH, PHENOTYPES, EVALUATION research, ATROPHY, EARLY diagnosis, SEQUENCE analysis, DIAGNOSIS
Abstract: Background: Cerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly heterogeneous on both the genetic and clinical levels. Patients with these signs also typically present with non-specific neuroimaging results that can help prioritize further investigation but don't suggest a specific molecular diagnosis.Methods: To genetically explore a cohort of 18 Egyptian families with undiagnosed cerebellar atrophy identified on MRI, we sequenced probands and some non-affected family members via high-coverage whole exome sequencing (WES; >97 % of the exome covered at least by 30x). Patients were mostly from consanguineous families, either sporadic or multiplex. We analyzed WES data and filtered variants according to dominant and recessive inheritance models.Results: We successfully identified disease-causing mutations in half of the families screened (9/18). These mutations are located in seven different genes, PLA2G6 being the gene most frequently mutated (n = 3). We also identified a recurrent de novo mutation in the KIF1A gene and a molybdenum cofactor deficiency caused by the loss of the start codon in the MOCS2A open-reading frame in a mildly affected subject.Conclusions: This study illustrates the necessity of screening for dominant mutations in WES data from consanguineous families. Our identification of a patient with a mild and improving phenotype carrying a previously characterized severe loss of function mutation also broadens the clinical spectrum associated with molybdenum cofactor deficiency. [ABSTRACT FROM AUTHOR]
Published: 2016
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