CASK-Related Disorders

DISEASE CHARACTERISTICS:

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 loss-of-function CASK mutations; and X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK mutations. 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) mutations, 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.

DIAGNOSIS/TESTING:

The diagnosis of a CASK-related disorder is established in a female who is heterozygous for a CASK mutation and in a male who is hemizygous for a CASK mutation. Molecular genetic testing can be performed as single gene testing or as part of a multi-gene panel.

MANAGEMENT:

Treatment of manifestations: Treatment is symptomatic and includes nutritional support, treatment of hearing loss, and use of physiotherapy. Management of seizures in children with MICPCH is standard treatment and based on the specific seizure type and frequency.

GENETIC COUNSELING:

CASK-related disorders are inherited in an X-linked manner. MICPCH phenotype: Most affected females and males are simplex cases (i.e., the only affected family member) resulting from a de novo CASK mutation. Because heterozygous females manifest the phenotype, a phenotypically normal mother is unlikely to have the CASK mutation. Note: It is possible (though unlikely) that one parent of an affected individual will have germline mosaicism (or germline and somatic mosaicism), which would place male and female sibs at risk (when the mother has mosaicism) or female sibs only at risk (when the father has mosaicism). XLID phenotype: The father of an affected male will not have the disease or the CASK mutation. In a family with more than one affected individual, the mother of an affected male is likely to be an obligate heterozygote and may be variably affected. For all CASK-related disorders: The risk to the sibs of a proband depends on the genetic status of the mother. If the mother is heterozygous for the mutation, the chance of transmitting the CASK mutation in each pregnancy is 50%; sons who inherit the mutation will be affected; daughters who inherit the mutation will be unaffected or affected to a variable degree. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family has been identified