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Background  Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to  TSEN54  mutations being the most frequent. PCH is most often autosomal recessive though  de novo  anomalies in the X-linked gene  CASK  have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH).    Methods  Fourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The  CASK  gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected.    Results  We observed a high frequency of patients with a  CASK  mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the  CASK  gene. All were  de novo  mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype.    Conclusion  This study describes a new series of PCH female patients with  CASK  inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a  de novo CASK  mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre,  CASK  related PCH is the second most frequent cause of PCH. The identification of a  de novo  mutation in these patients enables accurate and reassuring genetic counselling.

orphanet journal of rare diseases

Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient