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Mental retardation and microcephaly with pontine and cerebellar hypoplasia

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Intellectual disability and microcephaly with pontine and cerebellar hypoplasia
Other namesX-linked intellectual disability - microcephaly - pontocerebellar hypoplasia[1]
This condition is inherited in an X-linked dominant manner.
SpecialtyMedical genetics Edit this on Wikidata

Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) – also known as mental retardation, X-linked, syndromic, Najm type (MRXSNA); X-linked intellectual deficit, Najm type; intellectual developmental disorder, X-linked, syndromic, Najm type; X-linked intellectual disability–microcephaly–pontocerebellar hypoplasia syndrome; and by variations of these terms – is a rare X-linked dominant genetic disorder of infants characterised by intellectual disability and pontocerebellar hypoplasia. It usually affects females; many males die before birth or not long after.[2]

The disorder is associated with a mutation in the CASK gene.[3] As with the vast majority of genetic disorders, there is no known cure to MICPCH.[citation needed]

The following values seem to be aberrant in children with CASK gene defects: lactate, pyruvate, 2-ketoglutarate, adipic acid and suberic acid, which seems to backup the proposal that CASK affects mitochondrial function.[4] It is also speculated that phosphoinositide 3-kinase in the inositol metabolism is impacted in the disease, causing folic acid metabolization problems.[citation needed]

Signs and symptoms

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The symptoms of MICPCH include progressive microcephaly, hypotonia, intellectual disability, possible optic atrophy, motor disabilities, brainstem/cerebellar hypoplasia (PCH), and, in forty percent of cases, epilepsy.[5][6] Development of gross motor skills, such as sitting, standing, and walking, is severely delayed, along with restricted fine motor skills. Some affected individuals can walk with assistance, but most MICPCH patients rely on wheelchairs.[5] Additional features include disrupted sleep; sensorineural hearing loss, feeding difficulties; and gastrointestinal problems, including constipation and gastroesophageal reflux.

MICPCH in males may occur with or without severe epileptic encephalopathy (Ohtahara syndrome, West syndrome, or early myoclonic epilepsy) in addition to severe-to-profound developmental delay. When seizures are present, they occur early and may be intractable.[7] Prognosis is poor for males with this condition.[8] The differences in phenotype between girls and boys arise simply due to the fact that in boys there is only one X-chromosome and hence one CASK gene. This results in males with MICPCH having no functioning CASK protein present in their brains whilst females will have approximately 50% of healthy levels.

Infantile/epileptic spasms appears to be a prevalent seizure type within individuals suffering from MICPCH.[9] It appears that females are more likely to have late onset epileptic spasms whilst males are prone to early onset spasms (infantile spasms).[9]

Cause

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MICPCH is caused by pathogenic variants in the CASK gene. This gene provides instructions for making calcium/calmodulin dependent serine protein kinase (CASK), a protein that is essential for brain function. CASK, being a multidomain protein, is found to interact with multiple molecules including neurexin,[10] syndecan[11] and Mint1,[12] playing an important synaptic function, and also possibly plays a role in cell proliferation and cell polarization.[13][14] In addition, CASK is now thought to be involved in neurotransmission.[15] CASK is widely expressed in the brain and its full role in brain function is still not clear.

Diagnosis

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MICPCH is diagnosed following an MRI displaying pontocerebellar hypoplasia and positive genetic testing for a pathogenic or likely-pathogenic mutation of the CASK gene. Initial testing tends to occur following a diagnosis of microcephaly in the first year of life. A diagnostic ICD-10 code has been assigned to MICPCH: Q04.3.

Inheritance

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The CASK gene is located on the X chromosome and are therefore inherited in an X-linked manner. Nearly all known pathogenic mutations are de novo, rather than being inherited from an affected mother or father. A broader spectrum of phenotypes are being diagnosed, with cases of inheritance noted.[16] Risk to the family members of a proband with a CASK disorder depends on the phenotype (i.e., MICPCH or XLID ± nystagmus) in the proband.[17]

Treatment

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MICPH has no specific treatment and no cure. Antiseizure medications (ASMs) are used to manage seizures; however, in most cases, control is partial or transient. Commonly used ASMs include valproic acid, clobazam, vigabatrin and Levetiracetam. There is no data for the efficacy and safety of ASMs in MICPCH. Currently, there are no specifically approved therapeutics for the symptoms of MICPCH. Medications to control GI and sleep disturbances are often prescribed and children are given feeding tubes to ensure adequate fluids and nourishment. Therapies, including physical, occupational and speech therapy are recommended.

Prognosis

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Males with CASK-null variants are unlikely to live past infancy. It is believed this is due to thinning of the brain stem which leads to central respiratory failure, airway infection, and pneumonia.[7][8] The prognosis for females is variable and not fully described. Fatality in teens and early adult hood has occurred. Early onset of regular therapies and intensive therapies has been known to aid development.[18]

History

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The CASK protein was first identified in 1996.[19] The human CASK gene was first described as a candidate locus for X-linked optic atrophy in 1998.[20] The first patient was described in literature in 2007[21] and an association between a CASK gene mutation and MICPCH confirmed in 2008.[22][23]

Support

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In the United States, the non-profit organization Project CASK is activating research, engaging affected families, and funding cutting-edge science to develop treatments and a cure for CASK gene disorders.

The non-profit organisation CASK Research UK provides family support and research grants into MICPCH and its associated conditions.

See also

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References

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  1. ^ "X-linked intellectual disability, Najm type | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 18 July 2019.
  2. ^ Online Mendelian Inheritance in Man (OMIM): 300749
  3. ^ Burglen, L.; Chantot-Bastaraud, S.; Garel, C.; Milh, M.; Touraine, R.; Zanni, G.; Petit, F.; Afenjar, A.; Goizet, C.; Barresi, S.; Coussement, A. L.; Ioos, C.; Lazaro, L.; Joriot, S.; Desguerre, I.; Lacombe, D.; Des Portes, V.; Bertini, E.; Siffroi, J. P.; Billette De Villemeur, T.; Rodriguez, D. (2012). "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 Journal of Rare Diseases. 7 (18): 18. doi:10.1186/1750-1172-7-18. PMC 3351739. PMID 22452838.
  4. ^ Mukherjee K, Slawson JB, Christmann BL, Griffith LC (2014). "Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry". Front Mol Neurosci. 7: 58. doi:10.3389/fnmol.2014.00058. PMC 4075472. PMID 25071438.
  5. ^ a b Moog, Ute; Kutsche, Kerstin (1993), Adam, Margaret P.; Everman, David B.; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "CASK Disorders", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID 24278995, retrieved 2022-11-07
  6. ^ Burglen, Lydie; Chantot-Bastaraud, Sandra; Garel, Catherine; Milh, Mathieu; Touraine, Renaud; Zanni, Ginevra; Petit, Florence; Afenjar, Alexandra; Goizet, Cyril; Barresi, Sabina; Coussement, Aurélie; Ioos, Christine; Lazaro, Leila; Joriot, Sylvie; Desguerre, Isabelle (2012-03-27). "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 Journal of Rare Diseases. 7: 18. doi:10.1186/1750-1172-7-18. ISSN 1750-1172. PMC 3351739. PMID 22452838.
  7. ^ a b Moog, Ute; Bierhals, Tatjana; Brand, Kristina; Bautsch, Jan; Biskup, Saskia; Brune, Thomas; Denecke, Jonas; de Die-Smulders, Christine E; Evers, Christina; Hempel, Maja; Henneke, Marco; Yntema, Helger; Menten, Björn; Pietz, Joachim; Pfundt, Rolph (2015-04-12). "Phenotypic and molecular insights into CASK-related disorders in males". Orphanet Journal of Rare Diseases. 10: 44. doi:10.1186/s13023-015-0256-3. ISSN 1750-1172. PMC 4449965. PMID 25886057.
  8. ^ a b Mukherjee, Konark; Patel, Paras A.; Rajan, Deepa S.; LaConte, Leslie E. W.; Srivastava, Sarika (2020-07-21). "Survival of a male patient harboring CASK Arg27Ter mutation to adolescence". Molecular Genetics & Genomic Medicine. 8 (10): e1426. doi:10.1002/mgg3.1426. ISSN 2324-9269. PMC 7549553. PMID 32696595.
  9. ^ a b Nakajiri, Tomoshi; Kobayashi, Katsuhiro; Okamoto, Nobuhiko; Oka, Makio; Miya, Fuyuki; Kosaki, Kenjiro; Yoshinaga, Harumi (October 2015). "Late-onset epileptic spasms in a female patient with a CASK mutation". Brain & Development. 37 (9): 919–923. doi:10.1016/j.braindev.2015.02.007. ISSN 1872-7131. PMID 25765806. S2CID 35591581.
  10. ^ Hata, Y; Butz, S; Sudhof, TC (1996-04-15). "CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins". The Journal of Neuroscience. 16 (8): 2488–2494. doi:10.1523/JNEUROSCI.16-08-02488.1996. ISSN 0270-6474. PMC 6578772. PMID 8786425.
  11. ^ Cohen, Alexandra R.; Wood, Daniel F.; Marfatia, Shirin M.; Walther, Zenta; Chishti, Athar H.; Anderson, James Melvin (1998-07-13). "Human CASK/LIN-2 Binds Syndecan-2 and Protein 4.1 and Localizes to the Basolateral Membrane of Epithelial Cells". The Journal of Cell Biology. 142 (1): 129–138. doi:10.1083/jcb.142.1.129. ISSN 0021-9525. PMC 2133028. PMID 9660868.
  12. ^ Butz, S.; Okamoto, M.; Südhof, T. C. (1998-09-18). "A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain". Cell. 94 (6): 773–782. doi:10.1016/s0092-8674(00)81736-5. ISSN 0092-8674. PMID 9753324. S2CID 12465062.
  13. ^ Caruana, Georgina (2002). "Genetic studies define MAGUK proteins as regulators of epithelial cell polarity". The International Journal of Developmental Biology. 46 (4): 511–518. ISSN 0214-6282. PMID 12141438.
  14. ^ Qi, Jie; Su, Yongyue; Sun, Rongju; Zhang, Fang; Luo, Xiaofeng; Yang, Zongcheng; Luo, Xiangdong (2005-03-11). "CASK inhibits ECV304 cell growth and interacts with Id1". Biochemical and Biophysical Research Communications. 328 (2): 517–521. doi:10.1016/j.bbrc.2005.01.014. ISSN 0006-291X. PMID 15694377.
  15. ^ Mori, Takuma; Kasem, Enas A.; Suzuki-Kouyama, Emi; Cao, Xueshan; Li, Xue; Kurihara, Taiga; Uemura, Takeshi; Yanagawa, Toru; Tabuchi, Katsuhiko (2019). "Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B". Molecular Psychiatry. 24 (7): 1079–1092. doi:10.1038/s41380-018-0338-4. ISSN 1359-4184. PMC 6756202. PMID 30610199.
  16. ^ Dubbs, Holly; Ortiz-Gonzalez, Xilma; Marsh, Eric D. (September 2022). "Pathogenic variants in CASK : Expanding the genotype–phenotype correlations". American Journal of Medical Genetics Part A. 188 (9): 2617–2626. doi:10.1002/ajmg.a.62863. ISSN 1552-4825. PMID 35670295. S2CID 249433609.
  17. ^ Moog, Ute; Kutsche, Kerstin (1993), Adam, Margaret P.; Everman, David B.; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "CASK Disorders", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID 24278995, retrieved 2022-11-07
  18. ^ DeLuca, Stephanie C.; Wallace, Dory A.; Trucks, Mary Rebekah; Mukherjee, Konark (2017-12-19). "A clinical series using intensive neurorehabilitation to promote functional motor and cognitive skills in three girls with CASK mutation". BMC Research Notes. 10 (1): 743. doi:10.1186/s13104-017-3065-z. ISSN 1756-0500. PMC 5735954. PMID 29258560.
  19. ^ Hata, Y; Butz, S; Sudhof, TC (1996-04-15). "CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins". The Journal of Neuroscience. 16 (8): 2488–2494. doi:10.1523/JNEUROSCI.16-08-02488.1996. ISSN 0270-6474. PMC 6578772. PMID 8786425.
  20. ^ Dimitratos, S. D.; Stathakis, D. G.; Nelson, C. A.; Woods, D. F.; Bryant, P. J. (1998-07-15). "The location of human CASK at Xp11.4 identifies this gene as a candidate for X-linked optic atrophy". Genomics. 51 (2): 308–309. doi:10.1006/geno.1998.5404. ISSN 0888-7543. PMID 9722958.
  21. ^ Froyen, Guy; Van Esch, Hilde; Bauters, Marijke; Hollanders, Karen; Frints, Suzanna G. M.; Vermeesch, Joris R.; Devriendt, Koen; Fryns, Jean-Pierre; Marynen, Peter (October 2007). "Detection of genomic copy number changes in patients with idiopathic mental retardation by high-resolution X-array-CGH: important role for increased gene dosage of XLMR genes". Human Mutation. 28 (10): 1034–1042. doi:10.1002/humu.20564. ISSN 1098-1004. PMID 17546640. S2CID 25495518.
  22. ^ Hayashi, Shin; Mizuno, Seiji; Migita, Ohsuke; Okuyama, Torayuki; Makita, Yoshio; Hata, Akira; Imoto, Issei; Inazawa, Johji (2008-08-15). "The CASK gene harbored in a deletion detected by array-CGH as a potential candidate for a gene causative of X-linked dominant mental retardation". American Journal of Medical Genetics. Part A. 146A (16): 2145–2151. doi:10.1002/ajmg.a.32433. ISSN 1552-4833. PMID 18629876. S2CID 33739467.
  23. ^ Najm, Juliane; Horn, Denise; Wimplinger, Isabella; Golden, Jeffrey A.; Chizhikov, Victor V.; Sudi, Jyotsna; Christian, Susan L.; Ullmann, Reinhard; Kuechler, Alma; Haas, Carola A.; Flubacher, Armin; Charnas, Lawrence R.; Uyanik, Gökhan; Frank, Ulrich; Klopocki, Eva (September 2008). "Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum". Nature Genetics. 40 (9): 1065–1067. doi:10.1038/ng.194. ISSN 1061-4036. PMID 19165920.
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