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.

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 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.

Genetic Testing Information

• Genetic Testing Registry: Syndromic X-linked intellectual disability Najm type

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• FG SYNDROME 4; FGS4
• INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA; MICPCH

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, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. 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