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Objective Adamantinomatous craniopharyngioma mainly affects children. Excessive weight gain is a major long-term complication. The primary objective of this study was to assess long-term weight changes in children treated for craniopharyngioma. The secondary objectives were to identify risk factors for excessive weight gain and to look for associations with hypothalamic damage by the tumour or treatment. Design Single-centre retrospective cohort study. Method Children managed for craniopharyngioma at our centre between 1990 and 2019 were included. The body mass index (BMI) standard deviation scores (SDS) at baseline and at last follow-up were compared. Univariate and multivariate analyses were performed in order to identify variables associated with the long-term BMI-SDS variation. Results The 108 patients had a mean follow-up of 10.4 years. The mean BMI-SDS increase over time was 2.11 (P <.001) overall, 1.21 (P <.001) in the group without hypothalamic involvement by the tumour, and 1.95 (P <.001) in the group managed using intended hypothalamus-sparing surgery. The absence of hypothalamic involvement by the tumour or treatment was significantly associated with less weight gain (P =.046 and P <.01, respectively). After adjustment, factors associated with a BMI-SDS change greater than 2 were female sex (P =.023), tumour involving the hypothalamus (P =.04), and higher baseline BMI (P <.001). Conclusion Clinically significant weight gain occurred in nearly all children treated for craniopharyngioma, including those whose hypothalamus was spared by the tumour and intentionally by treatment. However, hypothalamus integrity was associated with less weight gain. Despite hypothalamus-sparing strategies, hypothalamic obesity remains a major concern, indicating a need for novel treatment approaches. [ABSTRACT FROM AUTHOR]

Claudin-5 is the most enriched tight junction protein at the blood-brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl- ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood-brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5. [ABSTRACT FROM AUTHOR]

Sulphated proteoglycans are essential in skeletal and brain development. Recently, pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis have been identified in a range of chondrodysplasia associated with intellectual disability. Nevertheless, several patients remain with unidentified molecular basis. This study aimed to contribute to the deciphering of new molecular bases in patients with chondrodysplasia and neurodevelopmental disease. Exome sequencing was performed to identify pathogenic variants in patients presenting with chondrodysplasia and intellectual disability. The pathogenic effects of the potentially causative variants were analysed by functional studies. We identified homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2 in two patients with pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy. By functional analyses, we showed that the variants affect SLC35B2 mRNA expression and protein subcellular localization leading to a functional impairment of the protein. Consistent with those results, we detected proteoglycan sulphation impairment in SLC35B2 patient fibroblasts and serum. Our data support that SLC35B2 functional impairment causes a novel syndromic chondrodysplasia with hypomyelinating leukodystrophy, most likely through a proteoglycan sulphation defect. This is the first time that SLC35B2 variants are associated with bone and brain development in human. [ABSTRACT FROM AUTHOR]

Aims  In this study, we will describe a comprehensive haemodynamic analysis and its relationship to the dilation of the aorta in transposition of the great artery (TGA) patients post-arterial switch operation (ASO) and controls using 4D-flow magnetic resonance imaging (MRI) data. Methods and results  Using 4D-flow MRI data of 14 TGA young patients and 8 age-matched normal controls obtained with 1.5 T GE-MR scanner, we evaluate 3D maps of 15 different haemodynamics parameters in six regions; three of them in the aortic root and three of them in the ascending aorta (anterior-left, -right, and posterior for both cases) to find its relationship with the aortic arch curvature and root dilation. Differences between controls and patients were evaluated using Mann–Whitney U test, and the relationship with the curvature was accessed by unpaired t- test. For statistical significance, we consider a P -value of 0.05. The aortic arch curvature was significantly different between patients 46.238 ± 5.581 m−1 and controls 41.066 ± 5.323 m−1. Haemodynamic parameters as wall shear stress circumferential (WSS-C), and eccentricity (ECC), were significantly different between TGA patients and controls in both the root and ascending aorta regions. The distribution of forces along the ascending aorta is highly inhomogeneous in TGA patients. We found that the backward velocity (B-VEL), WSS-C, velocity angle (VEL-A), regurgitation fraction (RF), and ECC are highly correlated with the aortic arch curvature and root dilatation. Conclusion  We have identified six potential biomarkers (B-VEL, WSS-C, VEL-A, RF, and ECC), which may be helpful for follow-up evaluation and early prediction of aortic root dilatation in this patient population. [ABSTRACT FROM AUTHOR]

We thank our colleagues Panagiotakaki I et al i .[1] for their interest in our recent work elucidating the functional relevance of the G60R mutation in the I CLDN5 i gene in two unrelated cases of children presenting with alternating hemiplegia. Recurrent de novo mutations in CLDN5 induce an anion-selective blood-brain barrier and alternating hemiplegia. [Extracted from the article]

Objectives: Childhood traumatic brain injury (TBI) is a public health issue. Our objectives were to determine the prevalence of permanent pituitary hormone deficiency and to detect the emergence of other pituitary dysfunctions or central precocious puberty several years after severe TBI. Design: Follow-up at least 5 years post severe TBI of a prospective longitudinal study. Patients: Overall, 66/87 children, who had endocrine evaluation 1 year post severe TBI, were included (24 with pituitary dysfunction 1 year post TBI). Main outcome measures: In all children, the pituitary hormones basal levels were assessed at least 5 years post TBI. Growth hormone (GH) stimulation tests were performed 3-4 years post TBI in children with GH deficiency (GHD) 1 year post TBI and in all children with low height velocity (<-1 DS) or low IGF-1 (<-2 DS). Central precocious puberty (CPP) was confirmed by GnRH stimulation test. Results: Overall, 61/66 children were followed up 7 (5-10) years post TBI (median; (range)); 17/61 children had GHD 1 year post TBI, and GHD was confirmed in 5/17 patients. For one boy, with normal pituitary function 1 year post TBI, GHD was diagnosed 6.5 years post TBI. 4/61 patients developed CPP, 5.7 (2.4-6.1) years post-TBI. Having a pituitary dysfunction 1 year post TBI was significantly associated with pituitary dysfunction or CPP more than 5 years post TBI. Conclusion: Severe TBI in childhood can lead to permanent pituitary dysfunction; GHD and CPP may appear after many years. We recommend systematic hormonal assessment in children 1 year after severe TBI and a prolonged monitoring of growth and pubertal maturation. Recommendations should be elaborated for the families and treating physicians. [ABSTRACT FROM AUTHOR]

Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l+/- mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival. [ABSTRACT FROM AUTHOR]

Aims To analyse the predictive role of myocardial inflammation assessed by cardiac magnetic resonance (CMR) on the outcome of recently diagnosed dilated cardiomyopathy in children. Methods and results Over a period of 4 years, 66 children underwent CMR within 2 weeks after the diagnosis of dilated cardiomyopathy. CMR sequences sensitive for oedema, hyperaemia, and irreversible injury were applied: unenhanced cine steady-state free precession (SSFP), black-blood-prepared T1-weighted images, T2-weighted images, gadolinium-enhanced T1-weighted images (EGE), and late gadolinium-enhanced (LGE) images. Inflammatory cardiomyopathy defined as the presence of at least two CMR criteria was diagnosed in 31/66 children (CMR positive) while no criterion was present in the remaining 33 (CMR-negative). Only two patients had one positive criterion and were excluded from subsequent analysis. After a mean follow-up of 24 months, LV function recovery (LV ejection fraction > 55%) was more frequent in the CMR-positive group (24 vs. 11, P < 0.05). The presence of myocardial inflammation and elevated troponin levels at baseline were the two predictors of LV function recovery with an odds ratio of 3.76 (P = 0.02) and 2.76 (P = 0.03), respectively, in a logistic regression model. Persisting LGE was rare in patients of the CMR-positive group at control CMR (6/22) and was never observed in the CMR-negative group (0/16). Conclusion The presence of myocardial inflammation on CM Rat time of diagnosis of a dilated cardiomyopathy in children is a strong predictor of LV recovery. [ABSTRACT FROM AUTHOR]

Complex cortical malformations associated with mutations in tubulin genes, or ‘tubulinopathies’, are a heterogeneous group of disorders. Bahi-Buisson et al. review neuroimaging and neuropathological data in patients and distinguish five cortical malformation patterns: microlissencephaly, lissencephaly, central pachygyria and polymicrogyria-like cortical dysplasia, generalized polymicrogyria-like cortical dysplasia, and a ‘simplified’ gyral pattern.Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients’ neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a ‘simplified’ gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype–genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Dominant optic atrophy is a rare inherited optic nerve degeneration caused by mutations in the mitochondrial fusion gene OPA1. Recently, the clinical spectrum of dominant optic atrophy has been extended to frequent syndromic forms, exhibiting various degrees of neurological and muscle impairments frequently found in mitochondrial diseases. Although characterized by a specific loss of retinal ganglion cells, the pathophysiology of dominant optic atrophy is still poorly understood. We generated an Opa1 mouse model carrying the recurrent Opa1delTTAG mutation, which is found in 30% of all patients with dominant optic atrophy. We show that this mouse displays a multi-systemic poly-degenerative phenotype, with a presentation associating signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiomyopathy. Moreover, we found premature age-related axonal and myelin degenerations, increased autophagy and mitophagy and mitochondrial supercomplex instability preceding degeneration and cell death. Thus, these results support the concept that Opa1 protects against neuronal degeneration and opens new perspectives for the exploration and the treatment of mitochondrial diseases. [ABSTRACT FROM PUBLISHER]

GPR56 mutations cause an autosomal recessive polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestone-like features in GPR56 bilateral bifrontoparietal polymicrogyria in a sample of 14 patients. We identified homozygous GPR56 mutations in 14 patients from eight consanguineous families with typical bilateral bifrontoparietal polymicrogyria and in one foetal case, out of 30 patients with bifrontoparietal polymicrogyria referred for molecular screening. The foetal case, which was terminated at 35 weeks of gestation in view of suspicion of Walker Warburg syndrome, showed a cobblestone-like lissencephaly with a succession of normal, polymicrogyric and ‘cobblestone-like’ cortex with ectopic neuronal overmigration, agenesis of the cerebellar vermis and hypoplastic cerebellar hemispheres with additional neuronal overmigration in the pons and the cerebellar cortex. The 14 patients with GPR56 mutations (median 8.25 years, range 1.5–33 years) were phenotypically homogeneous with a distinctive clinical course characterized by pseudomyopathic behaviour at onset that subsequently evolved into severe mental and motor retardation. Generalized seizures (12/14) occurred later with onset ranging from 2.5 to 10 years with consistent electroencephalogram findings of predominantly anterior bursts of low amplitude α-like activity. Neuroimaging demonstrated a common phenotype with bilateral frontoparietally predominant polymicrogyria (13/13), cerebellar dysplasia with cysts mainly affecting the superior vermis (11/13) and patchy to diffuse myelination abnormalities (13/13). Additionally, the white matter abnormalities showed a peculiar evolution from severe hypomyelination at 4 months to patchy lesions later in childhood. Taken as a whole, these observations collectively demonstrate that GPR56 bilateral bifrontoparietal polymicrogyria combines all the features of a cobblestone-like lissencephaly and also suggest that GRP56-related defects produce a phenotypic continuum ranging from bilateral bifrontoparietal polymicrogyria to cobblestone-like lissencephaly. [ABSTRACT FROM PUBLISHER]