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To assess whether microcephaly with pontine and cerebellar hypoplasia (MICPCH) could manifest in the prenatal period in patients with calcium/calmodulin-dependent serine protein kinase (CASK) gene disorders.In this international multicentre retrospective study, we contacted a CASK parents' social media group and colleagues with expertise in cerebellar malformations and asked them to supply clinical and imaging information. Centiles and standard deviations (SD) were calculated according to age by nomograms.The study consisted of 49 patients (44 females and 5 males). Information regarding prenatal head circumference was available in 19 patients; 11 out of 19 had a fetal head circumference below -2SD (range -4.1SD to -2.02SD, mean gestational age at diagnosis 20 weeks). Progressive prenatal deceleration of head circumference growth rate was observed in 15 out of 19. At birth, 20 out of 42 had a head circumference below -2SD. A total of 6 out of 15 fetuses had a TCD z-score below -2 (range -5.88 to -2.02).This study expands the natural history of CASK-related disorders to the prenatal period, showing evidence of progressive deceleration of head circumference growth rate, head circumference below -2SD, or small TCD. Most cases will not be diagnosed according to current recommendations for fetal central nervous system routine assessment. Consecutive measurements and genetic studies are advised in the presence of progressive deceleration of head circumference growth rates or small TCD.

Aim: Periventricular leukomalacia (PVL) is a term reserved to describe white matter injury in the premature brain. In this review article, the authors highlight the common and rare pathologies mimicking the chronic stage of PVL and propose practical clinico-radiological criteria that would aid in diagnosis and management. Methods and Results: The authors first describe the typical brain MRI (magnetic resonance imaging) features of PVL. Based on their clinical presentation, pathologic entities and their neuroimaging findings were clustered into distinct categories. Three clinical subgroups were identified: healthy children, children with stable/nonprogressive neurological disorder, and those with progressive neurological disorder. The neuroradiological discriminators are described in each subgroup with relevant differential diagnoses. The mimics were broadly classified into normal variants, acquired, and inherited disorders. Conclusions: The term “PVL” should be used appropriately as it reflects its pathomechanism. The phrase “white matter injury of prematurity” or “brain injury of prematurity” is more specific. Discrepancies in imaging and clinical presentation must be tread with caution and warrant further investigations to exclude other possibilities.

We report on the conventional and diffusion tensor imaging (DTI) findings of a 2-year-old child with clinical presentation of Joubert's Syndrome (JS) and brainstem structural abnormalities as depicted by neuroimaging.Conventional magnetic resonance imaging (MRI) showed a “molar tooth” configuration of the brainstem. A band-like formation coursing in an apparent axial plane anterior to the interpeduncular fossa was noted and appeared to partially cover the interpeduncular fossa.DTI maps and three-dimensional (3D) tractography demonstrated a prominent red-encoded white matter bundle anterior to the midbrain. Probable aberrant course of the bilateral corticospinal tracts (CST) was also depicted. Absence of the decussation of the superior cerebellar peduncles and elongated thickened, horizontal superior cerebellar peduncle (SCP) reflecting the molar tooth sign were also shown.Our report and the review of the published cases suggest that DTI and tractography may be very helpful to differentiate between interpeduncular heterotopias and similarly located white matter bundles corroborating the underlying etiology of axonal guidance disorders in the complex group of ciliopathies including JS. Our case represents an important additional puzzle piece to explore the variability of these ciliopathies.

Contains fulltext : 283140.pdf (Publisher’s version ) (Open Access) The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

SUMMARY: Ectopic cerebellar tissue is a rare entity likely secondary to multiple, interacting, developmental errors during embryogenesis. Multiple sites of ectopic cerebellar tissue have been reported, including extracranial locations; however, an intracranial location is most common. We report on the MR imaging findings of a multi-institutional series of 7 ectopic cerebellar tissue cases (2 males, 4 females, 1 fetal) ranging from 22 weeks 5 days’ gestational age to 18 years of age. All cases of ectopic cerebellar tissue were diagnosed incidentally, while imaging was performed for other causes. Ectopic cerebellar tissue was infratentorial in 6/7 patients and supratentorial in 1/7 patients. All infratentorial ectopic cerebellar tissue was connected with the brain stem or cerebellum. MR imaging signal intensity was identical to the cerebellar gray and white matter signal intensity on all MR imaging sequences in all cases. Ectopic cerebellar tissue should be considered in the differential diagnoses of extra-axial masses with signal characteristics similar to those of the cerebellum. Surgical biopsy or resection is rarely necessary, and in most cases, MR imaging is diagnostic.

Mild clinical phenotypes of ataxia-telangiectasia (variant A-T) are associated with biallelic ATM variants resulting in residual function of the ATM kinase. At least one regulatory, missense, or leaky splice site mutation resulting in expression of ATM with low level kinase activity was identified in subjects with variant A-T. Studies on the pathogenicity of the germline splicing ATM variant c.1066-6T>G have provided conflicting results. Using whole-exome sequencing, we identified two splice site ATM variants, c.1066-6T>G; [p.?], and c.2250G>A, [p.Ile709_Lys750del], in a compound heterozygous state in a 27-year-old woman who had been diagnosed as having congenital ocular motor apraxia type Cogan in her childhood. Reappraisal of her clinical phenotype revealed consistency with variant A-T. Functional analyses showed reduced expression of ATM protein and residual activity of the ATM kinase at a level consistent with variant A-T. Our results provide evidence for pathogenicity of the leaky ATM splice site variant c.1066-6T>G.

Few studies report radiologic and clinical outcome of post-hemorrhagic isolated fourth ventricle (IFV) with focus on surgical versus conservative management in neonates and children. Our aim is to investigate differences in radiological and clinical findings of IFV between patients who had surgical intervention versus patients who were treated conservatively.A retrospective analysis of patients diagnosed with IFV was performed. Data included demographics, clinical exam findings, surgical history, and imaging findings (dilated FV extent, supratentorial ventricle dilation, brainstem and cerebellar deformity, tectal plate elevation, basal cistern and cerebellar hemisphere effacement, posterior fossa upward/downward herniation).Sixty-four (30 females) patients were included. Prematurity was 94% with 90% being 28 weeks of gestation. Mean age at first ventricular shunt was 3.6 (range 1-19); at diagnosis of IFV, post-lateral ventricular shunting was 26.2 (1-173) months. Conservatively treated patients were 87.5% versus 12.5% treated with FV shunt/endoscopic fenestration. Severe FV dilation (41%), severe deformity of brainstem (39%) and cerebellum (47%) were noted at initial diagnosis and stable findings (34%, 47%, and 52%, respectively) were seen at last follow-up imaging. FV dilation (p = 0.0001) and upward herniation (p = 0.01) showed significant differences between surgery versus conservative management. No other radiologic or clinical outcome parameters were different between two groups.Only radiologic outcome results showed stable or normal FV dilation and stable or decreased upward herniation in the surgically treated group.

BackgroundJoubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the ‘molar tooth sign’. Over 40 JS-associated genes are known, accounting for two-thirds of cases.MethodsWhile most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known ‘founder variants’ in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA.ResultsAll variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant (TMEM216c.218G>T) was significantly enriched in American compared with European patients with JS, whileMKS1c.1476T>G was about 10 times more frequent among European JS. Frequencies of other variants were comparable in the two cohorts. Genotyping of several markers identified four novel European founder haplotypes.Two recurrent variants (MKS1c.1476T>G andKIAA0586c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. However, while fibroblasts from aMKS1c.1476T>G healthy homozygote showed impaired ability to form primary cilia and mildly reduced ciliary length, ciliary parameters were normal in cells from aKIAA0586c.428delG healthy homozygote.ConclusionThis study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants.

Paediatric neurology syndromes are a broad and complex group of conditions with a large spectrum of clinical phenotypes. Joubert syndrome is a genetically heterogeneous neurological ciliopathy syndrome with molar tooth sign as the neuroimaging hallmark. We reviewed the clinical, radiological and genetic data for several families with a clinical diagnosis of Joubert syndrome but negative genetic analysis. We detected biallelic pathogenic variants in LAMA1, including novel alleles, in each of the four cases we report, thereby establishing a firm diagnosis of Poretti–Boltshauser syndrome. Analysis of brain MRI revealed cerebellar dysplasia and cerebellar cysts, associated with Poretti–Boltshauser syndrome and the absence of typical molar tooth signs. Using large UK patient cohorts, the relative prevalence of Joubert syndrome as a cause of intellectual disability was 0.2% and of Poretti–Boltshauser syndrome was 0.02%. We conclude that children with congenital brain disorders that mimic Joubert syndrome may have a delayed diagnosis due to poor recognition of key features on brain imaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We advocate the inclusion of LAMA1 genetic analysis on all intellectual disability and Joubert syndrome gene panels and promote a wider awareness of the clinical and radiological features of these syndromes., Graphical Abstract Graphical Abstract

BACKGROUND AND PURPOSE: Acute cerebellitis is an acute neurologic condition attributable to a recent or concurrent infection or a recent vaccination or ingestion of medication, with MR imaging evidence of cerebellar edema. MR imaging can confirm an anatomic abnormality and may allow the radiologist to establish a differential diagnosis. The purpose of this research was to evaluate the MR imaging findings in children with acute cerebellitis due to infectious versus immune-related conditions, in particular whether MR imaging findings allow differentiation. MATERIALS AND METHODS: Electronic medical records were reviewed between 2003 and 2020 in our quaternary children’s hospital. Data included demographics and clinical records: presentation/symptoms, final diagnosis including acute cerebellitis and immune-related acute cerebellitis, length of stay, treatment, condition at discharge, and laboratory findings. Retrospective independent review of all brain MR imaging studies was performed. RESULTS: Forty-three patients (male/female ratio, 28:15) were included in this study. Average age at presentation was 7.08 years (range, 0.05–17.52 years). Thirty-five children had infectious and 8 children had immune-related acute cerebellitis. Significant differences in neuroimaging were the following: 1) T2-FLAIR hyperintense signal in the brainstem (37.50% versus 2.85%, P = .016); 2) T2-FLAIR hyperintense signal in the supratentorial brain higher in the immune-related group (37.50% versus 0.00%, P = .004); and 3) downward herniation, higher in the infectious acute cerebellitis group (42.85% versus 0.00%, P = .03). CONCLUSIONS: Acute cerebellitis is a rare condition, and MR imaging is helpful in the differential diagnosis. T2-FLAIR hyperintense signal in the brainstem and supratentorial brain may be indicative of immune-related acute cerebellitis, and downward herniation may be indicative of infectious acute cerebellitis.

PURPOSE: This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. METHODS: We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts. RESULTS: In 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient-derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. CONCLUSION: Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.

Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder., Canadian Institutes of Health Research [201610PJT-377869, MOP-G2-341146-159133-BRIDG]; Fondation Les Amis d'Elliot; Leuco-Action; Fondation Lueur d'Espoir pour Ayden; Fondation le Tout pour Loo; Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante; Compute Canada; Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship; Fondation du Grand defi Pierre Lavoie Doctoral Scholarship; McGill Faculty of Medicine F. S.B. Miller Fellowship; Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research; Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia; CIHR [201603PJT-148695]; BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP); National Institute for Neurological Disorders and Stroke [R01NS082094]; Jakob Kamens Chair in Translational Neurotherapeutics; Fonds de Recherche du Quebec-Sante (FRQS); Canadian Institutes of Health Research; European Reference Network for Rare Neurological Disorders (ERN-RND) [739510], This study was supported by grants from the Canadian Institutes of Health Research (201610PJT-377869, MOP-G2-341146-159133-BRIDG), Fondation Les Amis d'Elliot, Leuco-Action, Fondation Lueur d'Espoir pour Ayden, Fondation le Tout pour Loo, and Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante to G. Bernard. This research was enabled in part by support provided by Compute Canada (www.computecanada.ca).S.Perrier is supported by the Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship, the Fondation du Grand defi Pierre Lavoie Doctoral Scholarship, the McGill Faculty of Medicine F. S.B. Miller Fellowship, and the Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research. F. K.C. is a recipient of the Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia. W.T. G. received funding from the CIHR (201603PJT-148695) and is supported by the BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP). B.L. F. was supported by the National Institute for Neurological Disorders and Stroke (R01NS082094). A.V. receives funding from the Jakob Kamens Chair in Translational Neurotherapeutics. G. Bernard has received a Research Scholar Junior 1 award from the Fonds de Recherche du Quebec-Sante (FRQS) (2012-2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017-2022). I.K.M., M. Synofzik, D. Tonduti, B.P.v.d.W., M.S. V.d.K., and N.I.W. are members of the European Reference Network for Rare Neurological Disorders (ERN-RND), project ID 739510.

Paediatric neurology syndromes are a broad and complex group of conditions with a large spectrum of clinical phenotypes. Joubert syndrome is a genetically heterogeneous neurological ciliopathy syndrome with molar tooth sign as the neuroimaging hallmark. We reviewed the clinical, radiological and genetic data for several families with a clinical diagnosis of Joubert syndrome but negative genetic analysis. We detected biallelic pathogenic variants in LAMA1, including novel alleles, in each of the four cases we report, thereby establishing a firm diagnosis of Poretti–Boltshauser syndrome. Analysis of brain MRI revealed cerebellar dysplasia and cerebellar cysts, associated with Poretti–Boltshauser syndrome and the absence of typical molar tooth signs. Using large UK patient cohorts, the relative prevalence of Joubert syndrome as a cause of intellectual disability was 0.2% and of Poretti–Boltshauser syndrome was 0.02%. We conclude that children with congenital brain disorders that mimic Joubert syndrome may have a delayed diagnosis due to poor recognition of key features on brain imaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We advocate the inclusion of LAMA1 genetic analysis on all intellectual disability and Joubert syndrome gene panels and promote a wider awareness of the clinical and radiological features of these syndromes.

BackgroundJoubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%–75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.MethodsWe reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.ResultsHeterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.ConclusionHeterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.

Pontocerebellar hypoplasias (PCH) represent a heterogeneous group of very rare disorders with reduced volume of pons and cerebellum. The term is purely descriptive and does not imply a genetic progressive disease. Currently (as of Jan 01, 2020), 13 different types are listed in OMIM (Online Mendelian Inheritance in Man), associated with 19 different genes. However, a large group of similar imaging patterns is known, and it is unclear why some are labeled as PCH, while others are not. The latter include CASK- and VLDLR-associated disorders, some tubulinopathies, certain dystroglycanopathies, a few congenital disorders of glycosylation (CDG) syndromes, several forms associated with rare variants (e.g., DCK1, WDR81, ITPR1), and "cerebellar disruption of prematurity"-an acquired etiology. The objective of this paper is to elaborate a pattern recognition approach, mainly imaging-based, to facilitate a timely and accurate diagnosis, to narrow the differential diagnosis, and to enable targeted additional (genetic) investigations. We describe magnetic resonance imaging (MRI) findings and offer "checklists" for infratentorial findings (e.g., non-lobulated vermis, dragonfly pattern of the cerebellum, cerebellar cysts, brainstem kinking, longitudinal grooves along the brainstem, flat pons) as well as for supratentorial anomalies (e.g., agenesis of corpus callosum, optic atrophy, simplified gyral pattern, and hypomyelination). The clinical context and laboratory investigations need to be considered as well. We also provide a "checklist" for clinical features. A systematic analysis of imaging and clinical features can assist in narrowing the differential diagnosis and permitting more targeted genetic testing. Some imaging patterns are diagnostic.

Purpose BiallelicCADvariants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. Methods Retrospective case series of 20 patients. Results Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients. Conclusion We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.

Entwicklungsstorungen des Zentralnervensystems stellen mit einer Haufigkeit von 1 pro 100 Lebendgeborene die haufigsten Entwicklungsstorungen des Menschen dar und werden meist bereits im Rahmen der Feindiagnostik im Verlauf einer Schwangerschaft diagnostiziert. Sie konnen isoliert oder im Rahmen von Syndromen auftreten. Pra- und postnatale Mortalitat und Morbiditat hangen entscheidend ab von Art der Entwicklungsstorung und Beteiligung weiterer Organsysteme. Ursachlich spielen sowohl genetische Veranderungen als auch umweltbedingte Faktoren eine Rolle. Zu Letzteren zahlen teratogene Substanzen, Virusinfektionen, Toxoplasmose-Infektion, Strahlenexposition, Stoffwechselkrankheiten, schwere Mangel- und Fehlernahrung, Hyperthermie, Adipositas und Diabetes mellitus der Schwangeren. Die Kenntnis des zeitlichen Ablaufs der ZNS-Entwicklung ermoglicht eine zeitliche Einordnung der Entstehung unterschiedlicher Entwicklungsstorungen. Fur eine atiologische und prognostische Einordnung einer Malformation des ZNS ist neben einer detaillierten Anamnese und klinischen Untersuchung die pra- und postnatale Bildgebung entscheidend. Wahrend pranatal die Ultraschalldiagnostik, oft erganzt durch fetale MRT, von groser Bedeutung ist, ist postnatal die MRT die Methode der Wahl. Haufig fallen als klinische Zeichen einer Entwicklungsstorung des Gehirns eine Mikro- oder Makrozephalie auf. Fur einen Teil der ZNS-Entwicklungsstorungen besteht die Moglichkeit, die zugrunde liegende genetische Ursache mittels Chromosomenanalyse, Array-CGH oder Kandidatengen-Sequenzierung anhand fetalen Gewebes, welches durch Chorionzottenbiopsie oder Amniozentese gewonnen werden kann, zu identifizieren. Postnatal kommt auch der Next-Generation-Sequenzierung in der Routinediagnostik eine zunehmend grose Rolle zu.

Basal ganglia infarction in young children, mostly after mild head trauma, has been repeatedly reported. The pathogenesis and the risk factors are not fully understood. Lenticulostriate vasculopathy, usually referred to as basal ganglia calcification, is discussed as one of them. We describe five young (7–13 months old on presentation) male children who suffered from hemiparesis due to ischemic stroke of the basal ganglia, four of them after minor head trauma. All of them had calcification in the basal ganglia visible on computed tomography or cranial ultrasound but not on magnetic resonance imaging. Follow-up care was remarkable for recurrent infarction in three patients. One patient had a second symptomatic stroke on the contralateral side, and two patients showed new asymptomatic infarctions in the contralateral basal ganglia on imaging. In view of the scant literature, this clinic-radiologic entity seems under recognized. We review the published cases and hypothesize that male sex and iron deficiency anemia are risk factors for basal ganglia stroke after minor trauma in the context of basal ganglia calcification in infants. We suggest to perform appropriate targeted neuroimaging in case of infantile basal ganglia stroke, and to consider prophylactic medical treatment, although its value in this context is not proven.

Although individual cases of inherited metabolic disorders are rare, overall they account for a substantial number of disorders affecting the central nervous system. Organic acidemias and aminoacidopathies include a variety of inborn errors of metabolism that are caused by defects in the intermediary metabolic pathways of carbohydrates, amino acids, and fatty acid oxidation. These defects can lead to the abnormal accumulation of organic acids and amino acids in multiple organs, including the brain. Early diagnosis is mandatory to initiate therapy and prevent permanent long-term neurologic impairments or death. Neuroimaging findings can be nonspecific, and metabolism- and genetics-based laboratory investigations are needed to confirm the diagnosis. However, neuroimaging has a key role in guiding the diagnostic workup. The findings at conventional and advanced magnetic resonance imaging may suggest the correct diagnosis, help narrow the differential diagnosis, and consequently facilitate early initiation of targeted metabolism- and genetics-based laboratory investigations and treatment. Neuroimaging may be especially helpful for distinguishing organic acidemias and aminoacidopathies from other more common diseases with similar manifestations, such as hypoxic-ischemic injury and neonatal sepsis. Therefore, it is important that radiologists, neuroradiologists, pediatric neuroradiologists, and clinicians are familiar with the neuroimaging findings of organic acidemias and aminoacidopathies. ©RSNA, 2018.

To determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations. Twenty-eight patients harbouring 23 heterozygous pathogenic variants (ten novel) in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8) or TUBB3 (n = 5) were studied by a brain MRI scan performed either on a 1.5 T (n = 10) or 3 T (n = 18) MR scanner with focus on the posterior fossa. Cerebellar anomalies were detected in 24/28 patients (86%). CD was recognised in 19/28 (68%) including cortical cerebellar dysplasia (CCD) in 18/28, either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). CCD was located only in the right hemisphere in 13/18 (72%), including four TUBB2B-, four TUBB3- and five TUBA1A-mutated patients, while in the other five TUBA1A cases it was located only in the left hemisphere or in both hemispheres. The postero-superior region of the cerebellar hemispheres was most frequently affected. The cerebellar involvement in tubulinopathies shows specific features that may be labelled as ‘tubulin-related CD’. This pattern is unique and differs from other genetic causes of cerebellar dysplasia. • Cortical cerebellar dysplasia without cysts is suggestive of tubulin-related disorder. • Cerebellar dysplasia in tubulinopathies shows specific features labelled as ‘tubulin-related CD’. • Focal and unilateral involvement of cerebellar hemispheres has important implications for counselling.

Congenital brainstem disconnection (CBSD) is an enigmatic embryo-fetal defect presenting as (sub)total absence of a segment between mesencephalon and lower brainstem. Rostro-caudal limits of the defect vary while the basal pons is always involved and the cerebellum is globally hypoplastic. A recent update and review[1] lists 14 cases, including 3 brain autopsy studies[1-3]. Necrosis and glial- or inflammatory reactions were absent. Inferior olivary nuclei were small or absent, pontine nuclei depleted, and the cerebellar dentate nuclei dysplastic. Supra-tentorial parts were normal in size, shape and microscopic structure. Frequent associated findings were vertebral segmentation defects(4/14) and hydronephrosis(3/14). No intra-familial recurrence or consanguinity were recorded. We considered interference with the developing rhombencephalon by an epigenetic mechanism as possible cause of CBSD. We probed the role of PRC2 (Polycomb Repressive Complex 2), member of the polycomb group of chromatin modifying proteins (PcG) with a cell-fate conserving function in organ development[4-7]. PRC2 acts by promotor binding as well as by modification of histone H3 through its catalytic subunit EZH2 (Enhancer of Zeste2) that tri-methylates the free ending tail of H3 at lysine 27 to H3K27me3 (with H3K27me2 as intermediate step). H3K27me3 blocks transcription of developmental genes to consolidate the mature stage of cell lineage on completed development[7]. Advantageous use can be made of anti-H3K27me3 antibody staining of nuclear chromatin on routinely prepared autopsy tissue sections to study EZH2 activity, an application more commonly used in neoplastic studies[8], but not routinely applied in human malformations. The absence of immunoreactivity in a developmental setting is due to immaturity, as in embryonic stem cells, or to an abnormal persistence (or even reversal) to that state with loss of control over tissue specific development. A large number of genes are known to undergo maturational silencing by histone modification. For example, EZH2 stabilizes the identity of individual vertebral body segments as well as brainstem development by silencing HOX genes[9,10]. Another role for EZH2, sustaining normal pontine neuron migration from the embryonic rhombic lip to the mature site of function has been identified by rhombomere specific knockout of Ezh2 in mouse embryos[11]. This finding prompted the present study. This article is protected by copyright. All rights reserved.

Pontine tegmental cap dysplasia is a rare hindbrain malformation syndrome with a hypoplastic pons, a tissue protrusion into the fourth ventricle, and cranial nerve dysfunction. We here report clinical, imaging, and genetic findings of the first extremely low-birth-weight preterm infant with pontine tegmental cap dysplasia born at 25 weeks of gestation and provide an overview of 29 sporadic cases. A prenatally diagnosed hypoplastic and rostrally shifted cerebellum was indicative of a hindbrain defect and later identified as an early sign of pontine tegmental cap dysplasia in our patient. The neonate exhibited severe muscle hypotonia, persistent thermolability, and clinical signs of an involvement of facial, cochlear, and hypoglossal nerves. Furthermore, paroxysmal episodes of agonizing pain with facial tics, tonic and clonic muscle contractions, blepharospasm, and singultus are highlighted as new phenotypic features of pontine tegmental cap dysplasia. With our report, we present a severe case of pontine tegmental cap dysplasia and provide a brief overview of current knowledge on this rare disease.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

The clinical variability of Blakeʼs pouch cysts (BPC) may range from asymptomatic via ataxia to sequelae of decompensated hydrocephalus. On the other hand, Dandy-Walker malformation (DWM) and cerebellar vermis hypoplasia generally correlate with less favorable neurologic development. The aim was to illustrate the potential of prenatal and postnatal neuroimaging to distinguish a BPC or persistent BP from other posterior fossa malformations. This pictorial review addresses the inconsistent nomenclature, clinical features, and magnetic resonance imaging (MRI) patterns of BPC and five differential diagnoses. The MRI findings of 11 patients, acquired at up to 3 T in 3 institutions, are demonstrated. Furthermore, the literature was searched for recent improvements in genetic and embryological background knowledge. Posterior fossa malformations often resemble each other and may even be imitated by sequelae of hemorrhagic, ischemic or infectious disruptions, i.e. congenital anomalies of morphology despite normal developmental potential. Hydrocephalus is a typical, albeit not always congenital finding in BPC. It is frequently associated with cerebellar disruptions and DWM; however, it is also a rare complication of posterior fossa arachnoid cysts. A moderately elevated vermis needs follow-up to confirm persistent BP versus vermian hypoplasia or DWM. The fetal cerebellar tail, previously assumed to be specific for DWM, may be imitated in cases of persistent BP. The accurate diagnosis of isolated BPC is not always straightforward, which is especially critical in the context of fetomaternal medicine. A detailed description of posterior fossa malformations is to be preferred over unspecific terminology.

Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•−) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis. In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity. The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype. These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease and should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis.

Background Fetal magnetic resonance imaging (MRI), mainly performed at standard field strength, plays a role in the classification of posterior fossa malformations. In the context of early second-trimester screening, upward rotation of the cerebellar vermis per se is usually compatible with a more favorable outcome than Dandy-Walker malformation and profound vermian hypoplasia. Delayed fenestration of Blake’s pouch may either mimic vermian hypoplasia by compression or be associated with it in individual cases. To increase specificity, there is a growing interest in the use of high-field MRI which is believed to be safe as long as the specific absorption rate is kept within accepted limits. We aim to illustrate its added value during the second and third trimester. Case presentation In the first case, fetal MRI at 1.5 Tesla was performed at 21 and 27 weeks’ gestation with sonographic follow up postnataly. In the second case, 3 Tesla MR images were acquired at 21 and 34 weeks’ gestation as well as in the neonatal period. Conclusions This pictorial case vignette supports the suggestion that mid-gestational MRI at 3 Tesla has the potential to exclude pronounced vermian hypoplasia with higher confidence than at 1.5 Tesla. However, the discrimination of mild hypoplasia from slight deformation of the cerebellar vermis will likely remain challenging.

To describe the spectrum of brainstem malformations associated to mutations in the tubulin genes taking advantage of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Fifteen patients (six males; median age, 1.25 years; range, 1 month to 31 years) with mutations in the tubulin genes (TUBA1A = 8, TUBB2B = 4, TUBB3 = 3) studied with MRI and DTI were included in the study. Brain MR exams were reviewed to describe the malformative aspects of the brainstem. Malformations of the supratentorial brain and cerebellum were also recorded. Tractography was performed in seven selected cases. Fourteen patients (93%) showed complex malformations of the brainstem. Most common findings, apparent on anatomical MR sequences, were brainstem asymmetry (12 cases, 5 of which with a crossed pattern characterised by a hypertrophic right medulla oblongata and hypertrophic left pons), short and small pons on midline (10 cases) and anterior brainstem clefting (6 cases). DTI revealed abnormal transverse pontine fibres (13 cases), fusion of corticospinal tracts and medial lemnisci (9 cases) and a small decussation of the superior cerebellar peduncles (7 cases). Conventional/anatomical MRI and DTI reveal a complex pattern of brainstem malformations associated with tubulin genes mutations. • Brainstem malformations affect 93% patients with mutated tubulin genes • MRI shows homolateral and crossed brainstem asymmetries, clefts and pons hypoplasia • DTI demonstrates irregular representation of transverse pontine fibres and fusion of corticospinal tracts

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Mitochondrial DNA depletion syndromes (MDS) are a group of clinically and genetically heterogeneous autosomal recessive disorders characterized by a reduction of mtDNA. We report two siblings of Armenian origin with early onset neurodegenerative disease characterized by encephalopathy, severe hypotonia, facial dyskinetic movements, abnormal eye movements, severe failure to thrive, and abnormal renal and hepatic function. Sanger sequencing confirmed two variants in the C10orf2 gene (TWNK) and indicated a diagnosis of MDS. Our recent observation confirms that nephrocalcinosis and proximal tubulopathy can be a part of a clinical picture of MDS associated with TWNK mutations and document peculiar ocular and orobuccolingual dyskinesias. Wrist myoclonia and tongue tremor were new clinical features in our patients. We suggest that the above-mentioned clinical constellation could potentially provide the basis for the diagnosis of MDS.

Background Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. Methods Exome sequencing was performed in 145 patients with Joubert syndrome ( JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. Results We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy ( JATD). The CEP120- associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. Conclusion Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.