The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple disease-causing missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C. We find a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus implicated in unexplained MCD. The mutations in KIF5C, KIF2A and DYNC1H1 drastically affect ATP hydrolysis, productive protein folding or microtubule binding, while suppression of Tubg1 expression in vivo interferes with proper neuronal migration and expression of Tubg1 mutations in S. cerevisiae results in disruption of normal microtubule behaviour. Our data reinforce the importance of centrosome- and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and post-mitotic processes are major contributors to the pathogenesis of MCD.
This descriptive analysis of a large cohort of children indicates that paroxysmal ocular movements are an early, highly suggestive symptom, followed by paroxysmal episodes of focal dystonia or flaccid, alternating hemiplegia in early infancy in the majority of subjects. Current challenges in diagnosis and management contribute to poor outcomes. Early diagnosis and multicenter collaboration are needed to facilitate trials to identify more effective therapies.
ObjectiveTo provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome.MethodsWe analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations.ResultsA total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.ConclusionsThese findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.
The purpose of this study was to evaluate the value of MRI in studying optic pathway tumours associated with neurofibromatosis, and to look for potentially helpful criteria for the management of such lesions. This retrospective study included 14 children with neurofibromatosis type 1 (NF-1) as well as a lesion of the optic pathway. Clinical data and MRI findings were analysed with regard to location, structure and course of the tumours, and were compared with 13 optic pathway tumours in patients without NF-1. The median age of onset was 4.1 years. 11 patients with NF-1 were asymptomatic. In the NF-1 group, the optic nerves were involved in 10 cases without a cystic component at the time of diagnosis. In the non-NF-1 group, the tumour was located in the chiasma in 11 cases; 12 cases had a cystic component. 10 of the NF-1 group had no tumour progression over an average follow-up of 3.2 years without treatment. These findings suggest that optic astrocytomas in association with NF-1 are distinct lesions from isolated optic gliomas. In NF-1, most such tumours show only slight progression, and may correspond to perineural gliomatosis rather than a true pilocytic astrocytoma. Among NF-1 patients, initial MRI provides no prognostic criteria in children who subsequently show tumour progression. Nevertheless, MRI can be useful in establishing the diagnosis of NF-1 and can serve as a baseline study.
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