CASK-related intellectual disability

CASK-related intellectual disability is an X-linked genetic disorder of brain development that causes cognitive impairment, microcephaly, and movement difficulties, presenting with varying severity between males and females.

Overview & Types

CASK-related intellectual disability is a disorder of brain development that has two main forms: microcephaly with pontine and cerebellar hypoplasia (MICPCH), and X-linked intellectual disability (XL-ID) with or without nystagmus. Within each of these forms, males typically have more severe signs and symptoms than females. The more severe MICPCH mostly affects females, likely because only a small number of males survive to birth.

Microcephaly with Pontine and Cerebellar Hypoplasia (MICPCH)

MICPCH is the more severe form of the disorder. Its characteristics include:

• Brain Underdevelopment: Underdevelopment (hypoplasia) of the pons and cerebellum. The cerebellum coordinates movement, while the pons transmits signals from the cerebellum to the rest of the brain.
• Progressive Microcephaly: An unusually small head at birth, which does not grow at the same rate as the rest of the body, appearing to get smaller as the body grows.
• Cognitive and Behavioral Issues: Severe intellectual disability, sleep disturbances, and abnormal repetitive behaviors such as self-biting or hand flapping. Seizures are also common.
• Developmental Delays: Affected individuals do not usually develop language skills, and most do not learn to walk.
• Sensory Loss: Sensorineural hearing loss caused by nerve problems in the inner ear, and eye abnormalities including optic nerve hypoplasia, retinopathy, and strabismus (crossed eyes).
• Physical and Facial Features: Weak muscle tone (hypotonia) in the torso, increased muscle tone (hypertonia) and stiffness (spasticity) in the limbs, and involuntary muscle tensing (dystonia). Characteristic facial features include an arched unibrow (synophrys); a short, broad nose; a long, smooth area between the nose and mouth (philtrum); a protruding upper jaw (maxilla); a small chin; and large ears.

X-Linked Intellectual Disability (XL-ID) with or without Nystagmus

XL-ID is a milder form of the disorder. Its characteristics include:

• Cognitive Impairment: Intellectual disability ranging from mild to severe, though some affected females have normal intelligence.
• Vision and Movement Issues: About half of affected individuals have nystagmus (rapid, involuntary eye movements). Seizures and rhythmic shaking (tremors) may also occur.

Frequency

The prevalence of CASK-related intellectual disability is unknown. More than 50 females with MICPCH have been described in the medical literature, while only a few affected males have been described. By contrast, more than 20 males but only a few females have been diagnosed with the milder XL-ID form, which may go unrecognized in mildly affected females.

Causes

The condition is caused by mutations in the CASK gene, which provides instructions for making the calcium/calmodulin-dependent serine protein kinase (CASK) protein. The CASK protein is primarily found in nerve cells (neurons) in the brain, where it helps control the expression of other genes involved in brain development. It also regulates the movement of chemicals called neurotransmitters and charged atoms (ions) necessary for signaling between neurons. Research suggests CASK also interacts with the protein produced from the FRMD7 gene to promote the development of the nerves that control eye movement (the oculomotor neural network).

Mutations that eliminate CASK function cause the severe MICPCH form, while mutations that impair but do not eliminate the protein's function cause the milder XL-ID form. Affected individuals with nystagmus may have mutations that disrupt the interaction between the CASK protein and the FRMD7 protein, leading to abnormal eye movements.

Inheritance

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. In females, who have two X chromosomes, one altered copy of the gene in each cell is sufficient to cause the disorder. In males, who have only one X chromosome, a mutation in the only copy of the gene causes the condition. Males typically experience more severe symptoms than females. Fathers cannot pass X-linked traits to their sons.

Other Names for This Condition

• CASK-related disorders
• X-linked intellectual deficit, Najm type