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What is Cask ?

CASK is the name of a gene essential for healthy brain development. This is an abbreviation of the gene’s full name, calcium/calmodulin-dependent serine protein kinase.

The CASK Gene provides instructions for producing the CASK protein.

A CASK gene mutation refers to a change or alteration in the DNA sequence of the CASK gene. DNA is the body’s genetic instruction manual, made up of a series of chemical “letters” that tell our cells how to grow, develop, and function. The specific order of these letters within a gene is called its DNA sequence.

When a change occurs in the DNA sequence of the CASK gene, the instructions for making the CASK protein may be altered. This can affect how the protein works, or prevent it from being made properly, potentially leading to a range of neurodevelopmental disorders.

The main 2 disorders are:

  • Microcephaly with pontine and cerebellar hypoplasia (MICPCH); and
  • X-linked intellectual disability (XL-ID) with or without nystagmus.

Microcephaly with pontine and cerebellar hypoplasia (MICPCH)

Microcephaly means that the brain does not grow as it should which results in a smaller than expected head size. Brain imaging frequently shows abnormalities including underdevelopment of the cerebellum and pons, areas of the brain responsible for coordination, balance, movement, and other vital functions.

Individuals with MICPCH may experience a wide range of symptoms, including moderate to severe intellectual disability, low muscle tone (hypotonia), epilepsy, feeding difficulties, delayed or absent walking, impaired balance and coordination, and vision and/or hearing impairments. The severity and combination of symptoms can vary considerably between individuals.

MICPCH is most frequently diagnosed in girls and is generally associated with variants that result in little or no functional CASK protein being produced by affected cells.

X-linked intellectual disability (XL-ID) with or without nystagmus

X-linked intellectual disability (XL-ID) is a condition that affects learning, development, and everyday functioning.

Individuals with XL-ID may experience developmental delays, learning difficulties, speech and communication challenges, and varying degrees of intellectual disability. The severity can range from mild to significant and differs from person to person.

Some individuals with this condition also have nystagmus, which is a rapid, involuntary movement of the eyes that can affect vision and visual tracking. Others do not have nystagmus, which is why the condition is described as occurring “with or without nystagmus.”

Compared to MICPCH, individuals with CASK-related XL-ID often have milder symptoms and may not have the same degree of brain abnormalities seen on MRI scans. This appears to be most common in males.

As with all CASK-related disorders, every individual is unique, and symptoms can vary widely.

What is CASK

How Does a CASK Gene Variant Affect Boys and Girls Differently?

CASK gene disorders can affect both males and females, but there are some differences in how these disorders manifest in each gender. The primary reason for these differences is related to the X chromosome inheritance pattern, as the CASK gene is located on the X chromosome.

Girls have two X chromosomes, meaning they have two copies of the CASK gene in each cell. Typically, one copy carries the variant while the other copy functions normally. During early development, the body naturally switches off one X chromosome in each cell. This process happens randomly, so some cells use the healthy copy of the CASK gene while others use the altered copy. As a result, many girls have a mixture of cells that produce normal CASK protein and cells that do not, which can influence the severity of symptoms.

Boys have one X chromosome and one Y chromosome, meaning they have only a single copy of the CASK gene. If that copy contains a disease-causing variant, there is no second copy available to compensate. This often results in a more severe presentation of the condition.

To learn more, visit our Female CASK Page or Males CASK Pages.

CASK Population & Mortalities

CASK-related disorders are considered ultra-rare conditions. While the exact number of affected individuals worldwide is unknown, patient advocacy organisations and family networks within the global CASK community estimate that over 300 diagnosed individuals living with a CASK-related disorder worldwide. As awareness and access to genetic testing continue to improve, additional diagnoses are expected.

Based on reports shared within the international CASK community, at least 11 deaths were reported between 2016 and 2023. However, the true mortality rate remains unknown, as comprehensive natural history and population-based studies have not yet been completed.

These figures highlight both the rarity of CASK-related disorders and the urgent need for further research to better understand disease progression, improve clinical care, and develop effective treatments for affected individuals.

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Lavvina Thiyagarajan

MBBS

Lavvina is a clinical genetics fellow from NSW, Australia with a background in general paediatrics. She has practiced in multiple tertiary paediatric hospitals in Australia, both in general paediatrics and clinical genetics. She currently provides specialist advice for the NGO, Taking Paediatrics Abroad and is a member of GeneEQUAL, an inclusive research group aiming to improve accessibility of genetic testing and care for people with intellectual disability by co-design.

Lavvina’s clinical interests are in the genetics of autism, intellectual disability and immunogenomics. She is particularly passionate about including the patient groups she works with in research and healthcare decisions.

Lavvina is affiliated with The Children’s Hospital Westmead and the University of New South Wales where she is undertaking a Masters by Research, co-producing a model of genetic healthcare that aligns with the preferences of Autistic people.

Permission to Use Photos and Media

I, the undersigned, give my consent to the Angelina CASK Neurological Research Foundation Ltd and Angelina CASK Neurological Research Foundation Inc (ACNRF) to use photographs, videos, or other media featuring me, my child, or an individual under my legal guardianship (“Media Materials”).

This consent permits ACNRF to use these Media Materials for purposes such as:

  • Raising awareness of CASK-related disorders
  • Promoting ACNRF’s initiatives, campaigns, and programs
  • Sharing on ACNRF’s website, social media, newsletters, and other communication channels
  • Use in advertising, educational resources, and fundraising efforts.

I understand that these materials may be distributed publicly and may appear in print, digital, and other media formats worldwide and in perpetuity.

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1. Usage Rights: I grant ACNRF the right to edit, adapt, or modify the Media Materials as needed for the purposes outlined above.

2. No Compensation: I acknowledge that no monetary or other compensation will be provided for the use of the Media Materials.

3. Release of Claims: I waive any rights to inspect or approve the final product and release ACNRF from any claims, liabilities, or damages related to the use of the Media Materials, including but not limited to claims of defamation, privacy, or copyright infringement.

4. Ownership Confirmation: I confirm that I have the authority to grant these rights for the provided Media Materials and that they do not infringe on the rights of any third party.

This authorisation is voluntary and may be revoked by written notice to ACNRF at any time, though I understand that materials already published may not be withdrawn.

“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 progress. The 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