CASK-Related Disorders

Developmental Anomalies X-linked Genetic Disorders

Rare Disease Classifications:

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

IMPORTANT INFORMATION

The information on the Rare Awareness Rare Education (RARE) Portal is intended for educational purposes only and does not replace professional advice.

Rare diseases typically display a high level of symptom complexity and variability. Individuals diagnosed with the same rare disease may be impacted differently and each person’s experience is unique. Please seek support from qualified healthcare professionals to learn more about the most suitable care and support options for you.

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.

Contributors

This page has been co-developed with RVA Partner, Angelina Cask Neurological Research Foundation (ACNRF).¹

Emergency Management

There may be special considerations for the emergency management of individuals living with CASK-related disorders presenting to emergency departments. Individuals with CASK-related disorders may present with seizures, including infantile spasms and absent seizures.

Clinical Care Guidelines

We are not aware of any clinical care guidelines for CASK-related disorders in Australia.

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

Summary

Calcium/calmodulin dependent Serine protein Kinase (CASK)-related disorders are a group of genetic disorders that affect brain development.^1,2 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).² CASK-related disorders are X-linked, caused by a mutation in the calcium/calmodulin dependent serine protein kinase (CASK) gene on the X chromosome. Mutations causing a loss of function of the CASK protein are often associated with MIPCH, whereas mutations resulting in reduced CASK function tend to cause XL-ID.^2,3,4 CASK-related disorders (predominantly MICPCH) are more commonly reported in females than males, but males with CASK mutations are usually more severely affected.

Useful Links for Professionals

GeneReviews®: CASK Disorders

Orphanet: X linked intellectual disability, Najm type

Personal Stories

Angelina’s Story

Angelina is also one of the official Rare Disease Day Heroes

Symptoms

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.² Reported clinical characteristics for females include intellectual disability, progressive microcephaly (small head size), vision and hearing issues, movement disorders and seizures.^2,4

Individuals with XL-ID may have less severe symptoms, including milder intellectual disability, nystagmus (uncontrollable movement of eyes) and vision issues.^2,3

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

Cause/Inheritance

CASK-related disorders are caused by mutations in the calcium/calmodulin dependent serine protein kinase (CASK) gene, located on the X chromosome.^1,2,3

As males have one X chromosome, they only have one copy of the CASK gene (hemizygous) and will present with a CASK-related disorder if there is a mutation in that CASK gene.

Females have two X chromosomes and thus two copies of the CASK gene; however only one CASK gene is active due to a process called X chromosome inactivation, where one X chromosome is randomly silenced in each cell.¹ Not every cell will have the same active X chromosome but if the CASK mutation is on the active X chromosome in any cell, it will contribute to the presentation of a CASK-related disorder in females.

CASK-related disorders tend to be more severe in males as the mutation is usually expressed in every cell of their body. As for females, the CASK mutation may not be expressed in all cells – the mutation will only be expressed in cells where the mutation is on the active X chromosome but for those cells where the mutation is on the silenced (inactivated) X, those cells will have normal CASK protein, which can contribute to a less severe presentation.

Most CASK mutations are de novo (new) mutations that occur randomly in affected individuals before birth; however, there are some reports of X-linked inheritance in some families.³

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 on genetic counselling can be found on the National Services page and specific State and Territory Services pages on the RARE Portal.

Diagnosis

Diagnosis of CASK-related disorders may be done by molecular genetic testing to identify mutations in the CASK gene.

GeneReviews®: CASK Disorders – Diagnosis has recommendations for the types of genetic testing that can be conducted to establish a diagnosis.

Treatment

Treatment is targeted at managing symptoms and may involve a multidisciplinary team.

It is best to speak with your medical team to learn more about the possible management strategies that is suitable and appropriate.

GeneReviews®: CASK Disorders (Management) provides information for clinicians on management, including recommended evaluations following initial diagnosis, treatment of manifestations and surveillance.

Clinical Care

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. However, the need for different healthcare professionals may change over a person’s lifetime and may extend beyond those listed here.^1,2

Research

The CASK Data Collection Program collects and stores health-related information on people with CASK. Information is provided by individuals and their families and de-identified information will be shared with researchers and rare disease groups/ organisations globally if permission is provided.

For research updates, please visit:

Please visit Australian Clinical Trials to learn about clinical trials for CASK-related disorders in Australia; there may not be any clinical trials currently available.

Information regarding clinical trials for CASK-related disorders in other countries can be found at ClinicalTrials.gov; there may not be any clinical trials currently available.

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

Rare Disease Organisation(s)

Angelina Cask Neurological Research Foundation (ACNRF) RVA Partner Australian Organisation

Website: https://acnrf.com/
Contact Form: https://acnrf.com/contact-us

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 necessarily monitor or endorse each group/organisation’s operational governance.

Please visit the National and State Services pages.

Mental Health

Please visit the ‘Mental Health’ sections listed on the National and State Services pages.

Other

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

References

Angelina Cask Neurological Research Foundation [Internet]. Available from: https://acnrf.com/
Moog U., Kutsche, K. CASK Disorders [2013, updated 2020 May 14] In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. Gene Reviews® [Internet]. Seattle, University of Washington; 1993 [cited 2022 August 15]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK169825/
OMIM – Online Mendelian Inheritance in Man. #300172 – Calcium/calmodulin-dependent serine protein kinase; CASK. Accessed August 15, 2022. https://www.omim.org/entry/300172
OMIM – Online Mendelian Inheritance in Man. #300749 – Intellectual Developmental Disorder with Microcephaly and Pontine and Cerebellar Hypoplasia; MICPCH. Accessed August 15, 2022. https://www.omim.org/entry/300749

Page Last Updated

10/08/2023 13:44

Developmental Anomalies X-linked Genetic Disorders