There are just over thirty individuals known in the UK with a CASK mutation. In a recent study, CASK mutations were found to be the main cause of pontocerebellar hypoplasia (PCH) in Italy⁽⁸⁾, although most other literature fails to even acknowledge CASK as a PCH gene. We don’t know exactly how common the CASK disorders are but it is clear they are ultra-rare (probably around 2 in a million). It is especially important that every patient is signed up to the registries RARE-X (everyone) and UK CASK registry (if living in the UK) since there is no other way to calculate prevalence.

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. 

Most children with a CASK disorder are eventually able to sit independently ⁽¹⁾

Approximately 20-25% of children with MICPCH learn to walk⁽¹⁾. Walking is usually developed late.

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. Anecdotally it seems to be linked with the presence of seizures, although the most recent paper on CASK and epilepsy⁽³⁾ states that seizures do not affect prognosis in CASK.  

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⁾. The latest RARE-X data indicates regression or skill loss is seen in over 30% of individuals with CASK disorder. 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 (mutation). 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 epilepsy and intellectual disability, whereas missense mutations in other areas of the gene lead to microcephaly and PCH (MICPCH)⁽⁶⁾. Individuals with a mutation that results in no CASK protein being made (such as deletions, and some missense mutations) will likely have MICPCH.

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. This is thought to be because the mutation is leading to an absence of CASK protein in the affected cells.

XL-ID with or without nystagmus is rarer and most common in males. It probably has a lower diagnosis rate because the symptom is developmental delay/intellectual disability/autism. (Many gene mutations cause these symptoms and therefore genetic testing is needed to get a correct diagnosis.) 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⁾. In these cases the CASK protein remains intact but has an altered function or there is less of it⁽⁷⁾.

The likely reason for the spectrum is a result of 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, but in reality there could be a skewed ratio, for example 70% healthy cells. This undoubtedly would present with a milder phenotype.

Small stature is not uncommon in CASK, with round 40% reporting small stature (RARE-X data June 2023). It is not known why this is.

Around 50% of children with a CASK mutation will develop epilepsy at some point in their lives. 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 for 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.

Feeding problems are common with CASK disorders and they are more frequent in patients with epilepsy⁽³⁾.

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. Frustratingly this still can’t completely remove the chance. 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/independence⁽⁹⁾. Click here for a list of intensive therapy centres.

Register with the CASK data collection programme (RARE-X) and 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.