Schaaf-Yang syndrome

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Schaaf-Yang syndrome
Other namesSYS, Prader-Willi-like syndrome, PWLS, Arthrogryposis, distal, with hypopituitarism, mental retardation, and facial anomalies, Chitayat-Hall syndrome [1]
Person with Schaaf-Yang syndrome.webp
Person showing facial features of SYS, such as: Trigonocephaly and tooth malposition. Also limb contractures can be seen.
Specialty Neurology, Medical genetics, Endocrinology

Schaaf-Yang syndrome is a rare genetic disorder that is caused by a heterozygous mutation in a paternal-expressed gene MAGEL2. [2] Main signs of this disorder are: Intellectual disability/Developmental Delay, autism spectrum disorder, hypogonadism, hypotonia in infancy with feeding problems and distal arthrogryposis. [3] Facial features are: short noses, dense eyebrows and protruding jaw. [4]

Contents

Symptoms

Symptoms of this disease are: [5]

Very frequent

Frequent

Occasional

Cause

The cause of this disease are mutation in a gene MAGEL2 which is located on chromosome 15(15q11.2) and that gene is expressed from paternal chromosome 15 and methylated on maternal chromosome 15. [6] [7] The MAGEL2 is a part of regulatory complex MUST,which consist of MAGEL2-USP7-TRIM27. [8] [9] This complex regulates WASH complex which function is to promotes endosomal actin polymerization. [10] 50% of people with SYS inherited mutation from their father and remainder are de novo mutation (which means that mutation is new and none of the parents have it). [7] [11]

MAGEL2-regulated WASH complex is important for the regulated secretion in the hypothalamus. [12] MAGEL2 mutation causes decreased secretion of hormones, such as: oxytocin, AVP, somatostatin, thyrotropin-releasing hormone and decreased growth hormone and luteinizing hormone. [13] [14] Loss of that protein also showed neuronal activity loss in the hypothalamus and hippocampus of mice by disruptions of neuronal activity and changes in the synaptic excitation/inhibition balance through AMPA receptor trafficking defects. [15] [16]

Diagnosis

SYS can be suspected by symptoms and subsequently can be diagnosed by genetic testing. [17]

Treatment

SYS doesn't have a cure. [7] Although symptomatic management is available, It might be effective but it still doesn't alleviate overall impact of SYS, which leaves caregivers unsatisfied. [18]

Prognosis

Life expectancy of person with SYS can be reduced due to fatal complication. [7] Survival into adulthood is possible and oldest patient with SYS is 36 years olds (at the time of article's publication). [19]

History

The first mention of SYS-like symptoms was described by Chitayat et al. (1990). [20] Although the name was coined by Christian P Schaaf and Yaping Yang, who described SYS in details in 2013. [21]

Prevalence

The prevalnce of SYS is < 1/1,000,000. [22] [19] Currently, it is estimated that about 250 people are diagnosed with SYS. [23]

References

  1. ↑ "Entry - #615547 - SCHAAF-YANG SYNDROME; SHFYNG - OMIM".
  2. ↑ Schaaf, Christian P.; Gonzalez-Garay, Manuel L.; Xia, Fan; Potocki, Lorraine; Gripp, Karen W.; Zhang, Baili; Peters, Brock A.; McElwain, Mark A.; Drmanac, Radoje; Beaudet, Arthur L.; Caskey, C. Thomas; Yang, Yaping (November 2013). "Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism". Nature Genetics. 45 (11): 1405–1408. doi:10.1038/ng.2776. ISSN   1546-1718. PMC   3819162 . PMID   24076603.
  3. ↑ McCarthy, John; Lupo, Philip J.; Kovar, Erin; Rech, Megan; Bostwick, Bret; Scott, Daryl; Kraft, Katerina; Roscioli, Tony; Charrow, Joel; Schrier Vergano, Samantha A.; Lose, Edward; Smiegel, Robert; Lacassie, Yves; Schaaf, Christian P. (2018). "Schaaf-Yang syndrome overview: Report of 78 individuals". American Journal of Medical Genetics Part A. 176 (12): 2564–2574. doi:10.1002/ajmg.a.40650. ISSN   1552-4833. PMC   6585857 . PMID   30302899.
  4. ↑ Fountain, Michael D.; Aten, Emmelien; Cho, Megan T.; Juusola, Jane; Walkiewicz, Magdalena A.; Ray, Joseph W.; Xia, Fan; Yang, Yaping; Graham, Brett H.; Bacino, Carlos A.; Potocki, Lorraine; Haeringen, Arie van; Ruivenkamp, Claudia A. L.; Mancias, Pedro; Northrup, Hope (2017-01-01). "The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families". Genetics in Medicine. 19 (1): 45–52. doi:10.1038/gim.2016.53. ISSN   1098-3600. PMC   5116288 . PMID   27195816.
  5. ↑ "Orphanet: Clinical signs and symptoms". www.orpha.net. Retrieved 2025-03-01.
  6. ↑ GeneCards Human Gene Database. "MAGEL2 Gene - GeneCards | MAGL2 Protein | MAGL2 Antibody". www.genecards.org. Archived from the original on 2022-12-03. Retrieved 2025-03-01.
  7. 1 2 3 4 Schaaf, Christian P.; Marbach, Felix (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Schaaf-Yang Syndrome", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   33570896 , retrieved 2025-03-01
  8. ↑ Gee, Rebecca R. Florke; Chen, Helen; Lee, Anna K.; Daly, Christina A.; Wilander, Benjamin A.; Tacer, Klementina Fon; Potts, Patrick Ryan (2020-11-20). "Emerging roles of the MAGE protein family in stress response pathways". Journal of Biological Chemistry. 295 (47): 16121–16155. doi: 10.1074/jbc.REV120.008029 . ISSN   0021-9258. PMC   7681028 . PMID   32921631.
  9. ↑ Hao, Yi-Heng; Doyle, Jennifer M.; Ramanathan, Saumya; Gomez, Timothy S.; Jia, Da; Xu, Ming; Chen, Zhijian J.; Billadeau, Daniel D.; Rosen, Michael K.; Potts, Patrick Ryan (2013-02-28). "Regulation of WASH-Dependent Actin Polymerization and Protein Trafficking by Ubiquitination". Cell. 152 (5): 1051–1064. doi:10.1016/j.cell.2013.01.051. ISSN   0092-8674. PMC   3640276 . PMID   23452853.
  10. ↑ Schubert, Tim; Schaaf, Christian P. (2025). "MAGEL2 (patho-)physiology and Schaaf–Yang syndrome". Developmental Medicine & Child Neurology. 67 (1): 35–48. doi:10.1111/dmcn.16018. ISSN   1469-8749. PMC   11625468 . PMID   38950199.
  11. ↑ "https://www.cancer.gov/publications/dictionaries/cancer-terms/def/de-novo-mutation". www.cancer.gov. 2011-02-02. Retrieved 2025-03-01.{{cite web}}: External link in |title= (help)
  12. ↑ Hoyos Sanchez, Maria Camila; Bayat, Tara; Gee, Rebecca R. Florke; Fon Tacer, Klementina (January 2023). "Hormonal Imbalances in Prader–Willi and Schaaf–Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals". International Journal of Molecular Sciences. 24 (17): 13109. doi: 10.3390/ijms241713109 . ISSN   1422-0067. PMC   10487939 . PMID   37685915.
  13. ↑ Schubert, Tim; Schaaf, Christian P. (2025). "MAGEL2 (patho-)physiology and Schaaf–Yang syndrome". Developmental Medicine & Child Neurology. 67 (1): 35–48. doi:10.1111/dmcn.16018. ISSN   1469-8749. PMC   11625468 . PMID   38950199.
  14. ↑ Chen, Helen; Victor, A. Kaitlyn; Klein, Jonathon; Tacer, Klementina Fon; Tai, Derek J. C.; Esch, Celine de; Nuttle, Alexander; Temirov, Jamshid; Burnett, Lisa C.; Rosenbaum, Michael; Zhang, Yiying; Ding, Li; Moresco, James J.; Diedrich, Jolene K.; Yates, John R. (2020-09-03). "Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production". JCI Insight. 5 (17). doi:10.1172/jci.insight.138576. ISSN   0021-9738. PMC   7526459 . PMID   32879135.
  15. ↑ Temkin, Paul; Morishita, Wade; Goswami, Debanjan; Arendt, Kristin; Chen, Lu; Malenka, Robert (2017-04-05). "The Retromer Supports AMPA Receptor Trafficking During LTP". Neuron. 94 (1): 74–82.e5. doi:10.1016/j.neuron.2017.03.020. ISSN   0896-6273. PMID   28384478.
  16. ↑ Ates, Tayfun; Oncul, Merve; Dilsiz, Pelin; Topcu, Iskalen Cansu; Civas, Cihan Civan; Alp, Muhammed Ikbal; Aklan, Iltan; Ates Oz, Edanur; Yavuz, Yavuz; Yilmaz, Bayram; Sayar Atasoy, Nilufer; Atasoy, Deniz (2019-01-01). "Inactivation of Magel2 suppresses oxytocin neurons through synaptic excitation-inhibition imbalance". Neurobiology of Disease. 121: 58–64. doi:10.1016/j.nbd.2018.09.017. ISSN   0969-9961. PMID   30240706.
  17. ↑ "About SYS". www.fpwr.org. Retrieved 2025-03-01.
  18. ↑ Dötsch, Laura; Matesevac, Lisa; Strong, Theresa V.; Schaaf, Christian P. (2023). "Caregiver-based perception of disease burden in Schaaf-Yang syndrome". Molecular Genetics & Genomic Medicine. 11 (12): e2262. doi:10.1002/mgg3.2262. ISSN   2324-9269. PMC   10724517 . PMID   37533374.
  19. 1 2 Marbach, Felix; Elgizouli, Magdeldin; Rech, Megan; Beygo, Jasmin; Erger, Florian; Velmans, Clara; Stumpel, Constance T. R. M.; Stegmann, Alexander P. A.; Beck-Wödl, Stefanie; Gillessen-Kaesbach, Gabriele; Horsthemke, Bernhard; Schaaf, Christian P.; Kuechler, Alma (2020-10-19). "The adult phenotype of Schaaf-Yang syndrome". Orphanet Journal of Rare Diseases. 15 (1): 294. doi: 10.1186/s13023-020-01557-8 . ISSN   1750-1172. PMC   7574436 . PMID   33076953.
  20. ↑ Chitayat, David; Hall, Judith G.; Couch, Robert M.; Phang, Min S.; Baldwin, Virginia J. (1990). "Syndrome of mental retardation, facial anomalies, hypopituitarism, and distal arthrogryposis in sibs". American Journal of Medical Genetics. 37 (1): 65–70. doi:10.1002/ajmg.1320370116. ISSN   1096-8628. PMID   2240046.
  21. ↑ Schaaf, Christian P.; Gonzalez-Garay, Manuel L.; Xia, Fan; Potocki, Lorraine; Gripp, Karen W.; Zhang, Baili; Peters, Brock A.; McElwain, Mark A.; Drmanac, Radoje; Beaudet, Arthur L.; Caskey, C. Thomas; Yang, Yaping (November 2013). "Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism". Nature Genetics. 45 (11): 1405–1408. doi:10.1038/ng.2776. ISSN   1546-1718. PMC   3819162 . PMID   24076603.
  22. ↑ "Orphanet: Schaaf-Yang syndrome". www.orpha.net. Retrieved 2025-03-01.
  23. ↑ "Advancing research into Schaaf-Yang syndrome, a rare disease that causes intellectual disability and congenital malformations". Current events. Retrieved 2025-03-01.
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