Skip Navigation
Genetics Home Reference: your guide to understanding genetic conditions
http://ghr.nlm.nih.gov/     A service of the U.S. National Library of Medicine®

CASK-related intellectual disability

Reviewed March 2014

What is CASK-related intellectual disability?

CASK-related intellectual disability is a disorder of brain development that has two main forms: microcephaly with pontine and cerebellar hypoplasia (MICPCH), and X-linked intellectual disability (XL-ID) with or without nystagmus. Within each of these forms, males typically have more severe signs and symptoms than do females; the more severe MICPCH mostly affects females, likely because only a small number of males survive to birth.

People with MICPCH often have an unusually small head at birth, and the head does not grow at the same rate as the rest of the body, so it appears that the head is getting smaller as the body grows (progressive microcephaly). Individuals with this condition have underdevelopment (hypoplasia) of areas of the brain called the cerebellum and the pons. The cerebellum is the part of the brain that coordinates movement. The pons is located at the base of the brain in an area called the brainstem, where it transmits signals from the cerebellum to the rest of the brain.

Individuals with MICPCH have intellectual disability that is usually severe. They may have sleep disturbances and exhibit self-biting, hand flapping, or other abnormal repetitive behaviors. Seizures are also common in this form of the disorder.

People with MICPCH do not usually develop language skills, and most do not learn to walk. They have hearing loss caused by nerve problems in the inner ear (sensorineural hearing loss), and most also have abnormalities affecting the eyes. These abnormalities include underdevelopment of the nerves that carry information from the eyes to the brain (optic nerve hypoplasia), breakdown of the light-sensing tissue at the back of the eyes (retinopathy), and eyes that do not look in the same direction (strabismus). Characteristic facial features may include arched eyebrows; a short, broad nose; a lengthened area between the nose and mouth (philtrum); a protruding upper jaw (maxilla); a short chin; and large ears.

Individuals with MICPCH may have weak muscle tone (hypotonia) in the torso along with increased muscle tone (hypertonia) and stiffness (spasticity) in the limbs. Movement problems such as involuntary tensing of various muscles (dystonia) may also occur in this form of the disorder.

XL-ID with or without nystagmus (rapid, involuntary eye movements) is a milder form of CASK-related intellectual disability. The intellectual disability in this form of the disorder can range from mild to severe; some affected females have normal intelligence. About half of affected individuals have nystagmus. Seizures and rhythmic shaking (tremors) may also occur in this form.

How common is CASK-related intellectual disability?

The prevalence of CASK-related intellectual disability is unknown. More than 50 females with MICPCH have been described in the medical literature, while only a few affected males have been described.

By contrast, more than 20 males but only a few females have been diagnosed with the milder form of the disorder, XL-ID with or without nystagmus. This form of the disorder may go unrecognized in mildly affected females.

What genes are related to CASK-related intellectual disability?

CASK-related intellectual disability, as its name suggests, is caused by mutations in the CASK gene. This gene provides instructions for making a protein called calcium/calmodulin-dependent serine protein kinase (CASK). The CASK protein is primarily found in nerve cells (neurons) in the brain, where it helps control the activity (expression) of other genes that are involved in brain development. It also helps regulate the movement of chemicals called neurotransmitters and of charged atoms (ions), which are necessary for signaling between neurons. Research suggests that the CASK protein may also interact with the protein produced from another gene, FRMD7, to promote development of the nerves that control eye movement (the oculomotor neural network).

Mutations in the CASK gene affect the role of the CASK protein in brain development and function, resulting in the signs and symptoms of CASK-related intellectual disability. The severe form of this disorder, MICPCH, is caused by mutations that eliminate CASK function, while mutations that impair the function of this protein cause the milder form, XL-ID with or without nystagmus. Affected individuals with nystagmus may have CASK gene mutations that disrupt the interaction between the CASK protein and the protein produced from the FRMD7 gene, leading to problems with the development of the oculomotor neural network and resulting in abnormal eye movements.

Related Gene(s)

Changes in this gene are associated with CASK-related intellectual disability.

  • CASK

How do people inherit CASK-related intellectual disability?

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In females, who have two copies of the X chromosome, one altered copy of the gene in each cell is sufficient to cause the disorder. In males, who have only one X chromosome, a mutation in the only copy of the gene in each cell causes the condition. In most cases, males experience more severe symptoms of the disorder than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Where can I find information about diagnosis or management of CASK-related intellectual disability?

These resources address the diagnosis or management of CASK-related intellectual disability and may include treatment providers.

  • Gene Review: CASK-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK169825)
  • Genetic Testing Registry: Mental retardation and microcephaly with pontine and cerebellar hypoplasia (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2677903)

You might also find information on the diagnosis or management of CASK-related intellectual disability in Educational resources (http://www.ghr.nlm.nih.gov/condition/cask-related-intellectual-disability/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/cask-related-intellectual-disability/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about CASK-related intellectual disability?

You may find the following resources about CASK-related intellectual disability helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for CASK-related intellectual disability?

  • CASK-related disorders
  • X-linked intellectual deficit, Najm type

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about CASK-related intellectual disability?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding CASK-related intellectual disability?

brainstem ; breakdown ; calcium ; cell ; cerebellum ; chromosome ; disability ; dystonia ; gene ; hypoplasia ; hypotonia ; inheritance ; inherited ; involuntary ; ions ; kinase ; maxilla ; microcephaly ; muscle tone ; mutation ; neurotransmitters ; nystagmus ; optic nerve ; philtrum ; prevalence ; protein ; sensorineural ; sensorineural hearing loss ; serine ; sex chromosomes ; spasticity ; strabismus ; tissue ; upper jaw

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Burglen L, Chantot-Bastaraud S, Garel C, Milh M, Touraine R, Zanni G, Petit F, Afenjar A, Goizet C, Barresi S, Coussement A, Ioos C, Lazaro L, Joriot S, Desguerre I, Lacombe D, des Portes V, Bertini E, Siffroi JP, de Villemeur TB, Rodriguez D. Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient. Orphanet J Rare Dis. 2012 Mar 27;7:18. doi: 10.1186/1750-1172-7-18. (http://www.ncbi.nlm.nih.gov/pubmed/22452838?dopt=Abstract)
  • Gene Review: CASK-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK169825)
  • Hackett A, Tarpey PS, Licata A, Cox J, Whibley A, Boyle J, Rogers C, Grigg J, Partington M, Stevenson RE, Tolmie J, Yates JR, Turner G, Wilson M, Futreal AP, Corbett M, Shaw M, Gecz J, Raymond FL, Stratton MR, Schwartz CE, Abidi FE. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes. Eur J Hum Genet. 2010 May;18(5):544-52. doi: 10.1038/ejhg.2009.220. Epub 2009 Dec 23. Erratum in: Eur J Hum Genet. 2010 May;18(5):552. (http://www.ncbi.nlm.nih.gov/pubmed/20029458?dopt=Abstract)
  • Hayashi S, Okamoto N, Chinen Y, Takanashi J, Makita Y, Hata A, Imoto I, Inazawa J. Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Hum Genet. 2012 Jan;131(1):99-110. doi: 10.1007/s00439-011-1047-0. Epub 2011 Jul 7. (http://www.ncbi.nlm.nih.gov/pubmed/21735175?dopt=Abstract)
  • Hsueh YP. Calcium/calmodulin-dependent serine protein kinase and mental retardation. Ann Neurol. 2009 Oct;66(4):438-43. doi: 10.1002/ana.21755. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19847910?dopt=Abstract)
  • Moog U, Kutsche K, Kortüm F, Chilian B, Bierhals T, Apeshiotis N, Balg S, Chassaing N, Coubes C, Das S, Engels H, Van Esch H, Grasshoff U, Heise M, Isidor B, Jarvis J, Koehler U, Martin T, Oehl-Jaschkowitz B, Ortibus E, Pilz DT, Prabhakar P, Rappold G, Rau I, Rettenberger G, Schlüter G, Scott RH, Shoukier M, Wohlleber E, Zirn B, Dobyns WB, Uyanik G. Phenotypic spectrum associated with CASK loss-of-function mutations. J Med Genet. 2011 Nov;48(11):741-51. doi: 10.1136/jmedgenet-2011-100218. Epub 2011 Sep 27. (http://www.ncbi.nlm.nih.gov/pubmed/21954287?dopt=Abstract)
  • Najm J, Horn D, Wimplinger I, Golden JA, Chizhikov VV, Sudi J, Christian SL, Ullmann R, Kuechler A, Haas CA, Flubacher A, Charnas LR, Uyanik G, Frank U, Klopocki E, Dobyns WB, Kutsche K. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet. 2008 Sep;40(9):1065-7. doi: 10.1038/ng.194. (http://www.ncbi.nlm.nih.gov/pubmed/19165920?dopt=Abstract)
  • Watkins RJ, Patil R, Goult BT, Thomas MG, Gottlob I, Shackleton S. A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus. Hum Mol Genet. 2013 May 15;22(10):2105-18. doi: 10.1093/hmg/ddt060. Epub 2013 Feb 12. (http://www.ncbi.nlm.nih.gov/pubmed/23406872?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: March 2014
Published: December 22, 2014