GTR Home > Conditions/Phenotypes > Mental retardation, CASK-related, X-linked


Excerpted from the GeneReview: CASK-Related Disorders
CASK-related disorders include a spectrum of phenotypes in both females and males. The two main types of clinical presentation are: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK; and X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate to severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. To date a total of 53 females with MICPCH have been reported, the eldest of whom is 21 years old. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures. Behaviors may include sleep disturbances, hand stereotypies, and self-biting. To date, only seven males have been reported with the severe phenotype. The under-representation in this cohort is likely to be a consequence of early male lethality. These males typically present with intellectual disability and MICPCH, or early-infantile epileptic encephalopathy (Ohtahara syndrome, West syndrome, or early myoclonic epilepsy). In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of X-linked intellectual disability (XLID) with or without nystagmus and additional clinical features. More than 24 males and nine females have been reported. The males have mild to severe intellectual disability, with or without nystagmus and other ocular features. Females are typically normal, with some displaying mild intellectual disability with or without ocular features.

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