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

Abstract

BackgroundPontocerebellar 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).MethodsFourteen 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.ResultsWe 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.ConclusionThis 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.

Congenital Abnormalities of the Posterior Fossa

“…Patients with mutations in CASK present with ataxia, nystagmus, postnatal microcephaly, severe cognitive impairment, and sensorineural hearing loss (50). The neuroimaging correlate includes severe global cerebellar hypoplasia, pontine hypoplasia, reduced gyral pattern, and unmyelinated corpus callosum (51,52). Mutations in CASK are inherited with an X-linked pattern.…”

Hipoplasia pontocerebelosa secundaria a deleción en el gen CASK: Caso clínico

“…In a series of 8 cases in men with mutations in the CASK gene 8,14 , they propose that patients with a more severe phenotype present a type of compromise in the germinal line, finding mosaicisms in patients with attenuated phenotype 15 . Several studies report the association of epilepsy in patients with PCH, but only in one previously published 16 , we describe the presence of a West Syndrome, just as our patient, which was detected in the video-EEG, tracing hypsarrhythmia. In this study, Burglen and colleagues performed an aCGH on 14 patients with PCH, and only in one case it was observed an intellectual disability associated with microcephaly.…”

“…They detected mutations in the CASK gene in 13 patients, all of them 'De novo'. Although the cohort is small, they could observe a more serious phenotype among males, and also they could suggest that those cases in which the mutation causes an inactivation of the protein, it would be recognizable, although the phenotype is variable 16 .…”

Intellectual disability, coarse face, relative macrocephaly, and cerebellar hypotrophy in two sisters

“…Mutations in CASK (OMIM 300749) cause an X-linked dominant intellectual disability-pontocerebellar hypoplasia syndrome with absent speech, axial hypotonia, and spasticity [Burglen et al, 2012]. Contrary to the phenotype presented here, there is typically a progressive microcephaly and no facial coarsening.…”