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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.

genetic conditions
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1. Introduction

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.

2. Frequency

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.

3. Causes

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.

4. Inheritance

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.

5. Other Names for This Condition

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

References

  1. 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 withCASK mutations: confirmation of a recognizable phenotype and first description ofa male mosaic patient. Orphanet J Rare Dis. 2012 Mar 27;7:18. doi:10.1186/1750-1172-7-18.
  2. 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. CASKmutations are frequent in males and cause X-linked nystagmus and variable XLMRphenotypes. Eur J Hum Genet. 2010 May;18(5):544-52. doi: 10.1038/ejhg.2009.220.
  3. 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 withmental retardation and microcephaly with pontine and cerebellar hypoplasia(MICPCH). Hum Genet. 2012 Jan;131(1):99-110. doi: 10.1007/s00439-011-1047-0.
  4. Hsueh YP. Calcium/calmodulin-dependent serine protein kinase and mentalretardation. Ann Neurol. 2009 Oct;66(4):438-43. doi: 10.1002/ana.21755. Review.
  5. 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 withCASK loss-of-function mutations. J Med Genet. 2011 Nov;48(11):741-51. doi:10.1136/jmedgenet-2011-100218.
  6. Moog U, Kutsche K. CASK Disorders. 2013 Nov 26 [updated 2020 May 21]. In: AdamMP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle;1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK169825/
  7. 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 brainmalformation phenotype with microcephaly and hypoplasia of the brainstem andcerebellum. Nat Genet. 2008 Sep;40(9):1065-7. doi: 10.1038/ng.194.
  8. Watkins RJ, Patil R, Goult BT, Thomas MG, Gottlob I, Shackleton S. A novelinteraction between FRMD7 and CASK: evidence for a causal role in idiopathicinfantile nystagmus. Hum Mol Genet. 2013 May 15;22(10):2105-18. doi:10.1093/hmg/ddt060.
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View Times: 264
Entry Collection: MedlinePlus
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Update Time: 24 Dec 2020
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    Yang, C. CASK-Related Intellectual Disability. Encyclopedia. Available online: https://encyclopedia.pub/entry/5046 (accessed on 04 October 2022).
    Yang C. CASK-Related Intellectual Disability. Encyclopedia. Available at: https://encyclopedia.pub/entry/5046. Accessed October 04, 2022.
    Yang, Catherine. "CASK-Related Intellectual Disability," Encyclopedia, https://encyclopedia.pub/entry/5046 (accessed October 04, 2022).
    Yang, C. (2020, December 24). CASK-Related Intellectual Disability. In Encyclopedia. https://encyclopedia.pub/entry/5046
    Yang, Catherine. ''CASK-Related Intellectual Disability.'' Encyclopedia. Web. 24 December, 2020.
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