Is the cerebellum affected by 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

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

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.

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.

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

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.

Learn more about the gene associated with CASK-related intellectual disability

• CASK

This condition is inherited in an X-linked pattern

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

Genetic Testing Information

• Genetic Testing Registry: Mental retardation and microcephaly with pontine and cerebellar hypoplasia
  

Patient Support and Advocacy Resources

• Disease InfoSearch
• National Organization for Rare Disorders (NORD)

Research Studies from ClinicalTrials.gov

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• FG SYNDROME 4
• MENTAL RETARDATION AND MICROCEPHALY WITH PONTINE AND CEREBELLAR HYPOPLASIA

Scientific Articles on PubMed

• PubMed

• 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. Citation on PubMed or Free article on PubMed Central
• 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. Citation on PubMed or Free article on PubMed Central
• 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. Citation on PubMed
• Hsueh YP. Calcium/calmodulin-dependent serine protein kinase and mental retardation. Ann Neurol. 2009 Oct;66(4):438-43. doi: 10.1002/ana.21755. Citation on PubMed
• Moog U, Kutsche K, Kortum 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, Schluter 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. Citation on PubMed
• Moog U, Kutsche K. CASK Disorders. 2013 Nov 26 [updated 2020 May 21]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK169825/ Citation on PubMed
• 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. Citation on PubMed
• 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. Citation on PubMed or Free article on PubMed Central

Related Health Topics

• Brain Malformations
• Cerebellar Disorders
• Developmental Disabilities
• Eye Movement Disorders
• Genetic Disorders
• Optic Nerve Disorders

MEDICAL ENCYCLOPEDIA

• Brain Structures (Image)
• Genetics
• Hearing loss - infants
• Intellectual disability
• Microcephaly
• Nystagmus
• Strabismus

Understanding Genetics

• What is the prognosis of a genetic condition?
• How can gene variants affect health and development?
• What does it mean if a disorder seems to run in my family?
• What are the different ways a genetic condition can be inherited?
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