O que é o CASK?

CASK is the most frequently mutated gene associated with pontocerebellar hypoplasia (8). There are over forty individuals known in the UK with a CASK mutation. We don't know exactly how common CASK disorders are, but it is clear they are ultra-rare. It is especially important that every patient is signed up to a registry, since there is no other way to calculate prevalence.

CASK-related MICPCH was only discovered in 2008. Other forms of PCH have been studied for much longer and so are more well-known than CASK, even though they are less prevalent.

The majority of children with MICPCH don't develop speech (1), but some do. If the child has XL-ID there is a much greater chance they will learn to talk.

Approximately half of individuals achieve the ability to sit without support. Sitting is generally acquired between 6 months and 3 years (10).

Approximately 25% of children with a CASK-related mutation learn to walk (1, 10). Walking is usually developed later and, in the literature, ranges from 18 months to 6 years (10).

There is no official prognosis for CASK disorders since the spectrum is so broad. Males with MICPCH often pass away in early infancy, although one male is known to have survived to at least 17 years of age (5). Females with MICPCH have an unknown life span; however, there are individuals currently living over the age of forty. Some females do pass away in childhood and the reasons for this are unclear and undocumented.

There are some cases, anecdotally and published, where MICPCH appears to be neurodegenerative, possibly after adolescence in females (2) and from birth in males (4). 39% of RARE-X respondents stated their child had stopped progressing in skills or that their development had halted or plateaued (RARE-X data pull April 2025). This is a symptom that requires further research, and it is important that every CASK patient is registered with RARE-X and the relevant surveys are completed.

It is not possible to predict the prognosis of a child with a CASK mutation based on their genotype. Two individuals with the exact same mutation can vary greatly. It is also not possible to predict severity based on an MRI. What is known is that individuals with a missense mutation in particular locations of the gene may only display with intellectual disability (and in some cases epilepsy), whereas missense mutations in other areas of the gene lead to microcephaly and PCH (6). Individuals with a mutation that results in no CASK protein being made (such as deletions, and some missense mutations) will likely have MICPCH.

Although we do not know if seizures lead to a worse prognosis, a recent paper on CASK (10) found that, in general, the presence of epilepsy predicts poorer adaptive ability in those with a CASK-related disorder.

MICPCH is the more common disorder and most common in females. It is often diagnosed by MRI or the presence of microcephaly, and the pons and cerebellum will be small. The mutation causes an absence of CASK protein in the affected cells. XL-ID with or without nystagmus is rarer but most common in males. It probably has a lower diagnosis rate because the symptom is developmental delay / intellectual disability / autism. It is caused by mutations that cause partial loss of gene function (the result of a missense or splice mutation), rather than whole loss. These variants are called hypomorphic (1).

One possible reason for the spectrum is the phenomenon called X inactivation skewing. In females with MICPCH, on average 50% of their brain cells should be healthy whilst 50% should carry the mutant CASK gene. However, this is just probability — in reality there could be a skewed ratio, for example 70% healthy cells. This undoubtedly would present with a milder phenotype depending on the tissues where this skewing occurs.

Small stature is not uncommon in CASK, with 33% reporting small stature (RARE-X data pull April 2025). 60% of RARE-X respondents said growth was a concern. It is not yet known what about a CASK mutation may cause growth differences.

Around 35–50% of children with a CASK mutation will develop epilepsy at some point in their lives (10). Epilepsy can occur at any age (3). 40% develop epilepsy by the age of ten (1). In males with MICPCH, when seizures are present they occur early and may be intractable (1).

Infantile Spasms are the most common form of epilepsy in children with MICPCH (3). These are difficult to treat and diagnose.

Drug resistance is around 50% (3) and there is no known 'most effective' drug to treat epilepsy. Anecdotally, front-line infantile spasms drugs appear to be most effective at reducing some seizure types.

A 2025 literature review (10) found that feeding difficulties were reported 57% of the time, making them the most commonly reported clinical issue. Difficulties included issues with swallowing and reflux. Children required interventions including thickened liquids, pureed foods, nasogastric tubes, and gastrostomy tubes. Feeding difficulties have been observed to improve with age in some individuals (11, 12).

Most affected females and males are one-off cases and the mutation is de novo (has not been inherited). It is therefore unlikely a sibling will also have a CASK disorder. There is a very small chance that the mutation has been inherited, so it is important that both parents are tested. You can speak to your geneticist about other options such as amniocentesis or non-invasive prenatal screening, which tests the foetal DNA in the mother's blood as early as 9 weeks' gestation. This procedure may require the test to be set up prior to pregnancy in order to ensure rapid diagnosis.

One US study suggested that children with MICPCH are responsive to intensive therapy aimed at increasing functional skills and independence (9). Register with the CASK data collection programme via RARE-X — make sure your genetic test is uploaded and surveys are completed. This will make it more likely that CASK disorders will eventually have licenced drugs available.

Our Cambridge University study found that in a cohort of 28 children and adults with a confirmed CASK mutation rates of self-injury were 43%, 46% exhibited physical aggression and 50% had stereotyped behaviour. If you are struggling with your child's behaviour please show our paper to your paediatrician.