Calcium/calmodulin dependent serine protein kinase (CASK)-related disorders are a group of genetic disorders that affect brain development.¹ The two main disorders are microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability (XL-ID), with or without nystagmus (uncontrollable movement of eyes).¹ CASK-related disorders are X-linked, caused by genetic changes (variants) in the calcium/calmodulin dependent serine protein kinase (CASK) gene on the X chromosome. Genetic variants that cause a loss of function of the CASK protein are often associated with MIPCH, whereas variants resulting in reduced CASK function tend to cause XL-ID.^1,2,3 CASK-related disorders (predominantly MICPCH) are more commonly reported in females than males, but males with CASK genetic variants are usually more severely affected.

There are no known synonyms.

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:163937 X-linked intellectual disability, Najm type

ICD-11: LD20.2 Syndromes with microcephaly as a major feature

ICD-11: LD90.Y Other specified conditions with disorders of intellectual development as a relevant clinical feature

There is a wide spectrum of symptoms associated with CASK-related disorders. Males usually have more severe symptoms compared to females.

Males with MICPCH have severe-to-profound developmental delay and may experience severe seizures.¹ Reported clinical characteristics for females include intellectual disability, progressive microcephaly (small head size), vision and hearing issues, movement disorders and seizures.^1,3

Individuals with XL-ID may have less severe symptoms, including milder intellectual disability, nystagmus (uncontrollable movement of eyes) and vision issues.^1,2

Please speak to your medical team to learn more about the symptoms and complications of CASK-related disorders.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

CASK-related disorders are genetic conditions. They are caused by disease-causing genetic variants (changes) in the calcium/calmodulin dependent serine protein kinase (CASK) gene, located on the X chromosome (X-linked condition).^1,2

Both males and females can be affected. As males only have one X chromosome, they have one copy of the CASK gene, so if their CASK gene has the disease-causing genetic variant, this would result in a CASK-related disorder. Females have two X chromosomes and two copies of the CASK gene – if at least one of their copies has the disease-causing genetic variant, they may be affected, with varying symptoms in females.

For most individuals with CASK-related disorders, their genetic variant in CASK gene occurs randomly (de novo) prior to birth and is not passed down (inherited) from their parents. In some reported cases, the X-linked condition was passed down (inherited) from their parents. More information on X-linked inheritance pattern can be found at Centre for Genetics Education: X-linked inheritance.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

There are no formal clinical diagnostic criteria established. A diagnosis of CASK-related disorder may be considered based on certain clinical characteristics, such as intellectual disability, and confirmed by genetic testing.¹

Please speak to your medical team to learn more about the available diagnostic pathways for CASK-related disorders.

There is no curative treatment for CASK-related disorders. Treatment is targeted at managing symptoms (symptomatic management) and involves a multidisciplinary care team. This may include speech therapy, occupational therapy, physiotherapy, feeding therapy, use of assistive equipment as well as augmentative and alternative communication (AAC) tools, seizure management and others.¹

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities.

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

Healthcare professionals involved in the treatment of CASK-related disorders may include general practitioners (GP), paediatricians, geneticists, neurologists, ophthalmologists, otolaryngologists (ENT), physiotherapists, occupational therapists and speech therapists. The need for different healthcare professionals may change over a person’s lifetime and may extend beyond those listed here.

We are not aware of any clinical care guidelines for CASK-related disorders in Australia. If you know of any relevant care guidelines, please let us know via the Contribute page.

The following guidance is available from international experts outside Australia; however, there may be information that is not relevant or applicable to the Australian context, and may not be up to date:

• GeneReviews®: CASK Disorders – Management has recommendations for evaluations following the initial diagnosis and treatment of symptoms.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

It may be important to consider the following when managing individuals living with CASK-related disorders at emergency departments/services:

• individuals with CASK-related disorders may present with seizures, including infantile spasms and absent seizures

Angelina Cask Neurological Research Foundation: Research has information about current research on CASK-related disorders, including Australian-research initiatives.

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in any clinical trials with your medical team to determine suitability and eligibility.

Please note that RVA does not necessarily monitor or endorse each group/organisation’s operational governance and activities.

Australian Organisation:

Angelina Cask Neurological Research Foundation (ACNRF)
Website: https://acnrf.com/

ACNRF mission is to advance innovations in medical research related to nature, diagnosis, prevention and treatment of CASK gene mutations and related conditions with a foremost objective being to find a cure. ACNRF facilitates the development and funding of this medical research.

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

CASK-related disorders vary between individuals, and each person’s experience is unique.

Personal story shared with Rare Voices Australia: Angelina’s Story

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease, including families and carers, often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many people find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information on CASK-related disorders can be found at:

•  Genetic and Rare Diseases (GARD) Information Center : X-linked intellectual disability, Najm type (MICPCH)
•  Genetic and Rare Diseases (GARD) Information Center: X-linked intellectual disability with or without nystagmus; FGS4
• National Organization for Rare Disorders (NORD): CASK-Related Disorders
• Unique: CASK-related disorders

• GeneReviews®: CASK Disorders
• Orphanet: X linked intellectual disability, Najm type
• Online Mendelian Inheritance in Man, OMIM®. #300172 – Calcium/calmodulin-dependent serine protein kinase; CASK
• Online Mendelian Inheritance in Man, OMIM® #300749 – Intellectual Developmental Disorder with Microcephaly and Pontine and Cerebellar Hypoplasia; MICPCH

This page has been co-developed by Rare Voices Australia (RVA)’s RARE Portal team in consultation with Angelina Cask Neurological Research Foundation (ACNRF).

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.