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AUSTRALIA

Females and CASK

Loss of Function variants

Girls who have a change to one copy of their CASK gene that causes a loss of function will have moderate to severe intellectual disability (ID) and progressive microcephaly (a small head and brain) with underdevelopment of specific parts of the brain called the pons and the cerebellum. This is known as microcephaly with pontine and cerebellar hypoplasia (MICPCH).

Symptoms and features can also include:

  • absent or severely impaired speech in most girls and difficulties using alternative means of communication;
  • about 25% of girls will learn to walk unassisted, but the majority will require mobility equipment;
  • seizures: about 40% of girls have seizures before the age of 10 years that can be hard to control (intractable);
  • weak muscle tone (hypotonia);
  • tight muscle tone in legs and/or arms (hypertonia/spasticity);
  • difficulties sitting independently;
  • movement disorders e.g. dystonia (unintended muscle contractions);
  • eye and/or sight anomalies;
  • sensorineural hearing loss;
  • sleep disturbances;
  • feeding issues;
  • hand stereotypies (and self biting).

Females who have a change in one copy of their CASK gene, that causes it to have a reduced function, can be relatively unaffected with intelligence within the standard range or they can have ID (which can be mild to severe). They may also have an eye anomaly, which can vary, and/or other features (that have been found in a few but not all girls).

“In some ways, that CASK-linked pathology is degenerative in nature provides a positive outlook. Because microcephaly in CASK-linked pathology progresses postnatally, there may be a temporal window when therapeutic intervention might prevent or slow further brain cell loss. Regression, even in adolescence, has also been observed in some cases of MICPCH [119], again offering the tantalizing possibility that a therapeutic approach might prevent such decline under conditions when degeneration is known to progressThe potential benefits of intervention might extend even further given that non-cell-autonomous toxicity could also affect functioning of the remaining neurons; reduction of such toxicity, especially when coupled with high-intensity rehabilitative measures [120], might offer real hope for a positive impact on functional outcomes.”   

https://www.mdpi.com/2073-4409/11/7/1131/htm