SYNGAP1-related intellectual disability

SYNGAP1-related intellectual disability is a monogenetic developmental and epileptic encephalopathy that affects the central nervous system.[1] Symptoms include intellectual disability, epilepsy, autism, sensory processing deficits, hypotonia and unstable gait.

Signs and symptoms

The first signs of SYNGAP1-related encephalopathy are typically gross motor delays in infancy followed by developmental delays, seizure onset and language impairment.[2] Penetrance is 100%. Mild to severe intellectual or developmental disability is present in the majority of patients.[3] Epilepsy is present in almost all cases, with approximately 94-98% of patients affected by seizures.[4] Truncal hypotonia and clumsy gait are typical. Behavioral and sleep problems are also common.[5] Approximately 50% of patients receive a diagnosis of autism spectrum disorder. [4] Some patients have significant feeding issues.[3]

Cause and pathophysiology

SYNGAP1 encephalopathy is an autosomal dominant genetic disorder caused by haploinsufficiency of the SynGAP protein, usually due to the presence of a heterozygous protein-truncating loss-of-function variation on the SYNGAP1 gene. Missense variations, which may result in either a loss or a change-of-function can also result in the disorder. These pathogenic variations disrupt early cognitive development, particularly in the hippocampus and cortex.[5]

The majority of mutations are considered de novo, however cases of inheritance from both somatic mosaic and germ-line mosaic parents have been reported.[6]

Diagnosis

Diagnosis is based on genetic testing, with the recommended testing approach being Chromosomal Microarray Analysis followed by an Intellectual Disability multigene panel or Whole Exome Sequencing. A diagnosis is established following the identification of a heterozygous pathogenic (or likely pathogenic) point mutation of the SYNGAP1 gene (present in approximately 89% of patients), a micro deletion of chromosome 6 incorporating SYNGAP1 (approximately 11% of patients), or a balanced translocation disrupting SYNGAP1.[6][3]

EEG monitoring frequently shows generalized epilepsy, predominantly in the occipital regions.[6] MRI is usually normal.[3]

Seizure types

SYNGAP1-related encephalopathy can result in a specific seizure type, characterized by eyelid myoclonia followed by an atonic drop. Reflex seizures are also seen, often triggered by eating and photosensitivity.[4][7]

Differential diagnosis

Treatment

There is currently no cure or causative treatment. Epilepsy may be controlled by the use of one or more anti-epileptic drugs, however approximately half of patients have seizures that are pharmacoresistant.[5] Patients with significant feeding issues may require the use of a gastrostomy tube. Communication may be supported with the use of an Augmentative and Alternative Communication device. Patients with significant mobility or gait issues may require the use of wheelchairs, adaptive strollers or Ankle Foot Orthoses.

Supportive treatments can include:[8]

Prognosis

Despite the common mechanism of haploinsufficiency, there is distinct phenotypic variability amongst patients. Although one third of patients are non-verbal, others can communicate with single words, while others can speak conversationally using 4-5 word sentences.[3]

Epidemiology

SYNGAP1 encephalopathy is estimated to comprise approximately 0.7- 1% of all cases of intellectual disability[9][10] with over one million people expected to be affected worldwide.[11][12]

History

Although the SynGAP protein was first identified in 1998[13], SYNGAP1 mutations were not found to be responsible for cases of intellectual disability until 2009.[14]

Research

The use of antisense oligonucleotides to upregulate the expression of SynGAP protein is currently being researched.[15] The use of statins to address the downstream impacts of loss of SynGAP function on the Ras signaling pathway is also being studied.[16]

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gollark: `pcall` returns `true`/`false` as its first return value.
gollark: You're pcalling it.
gollark: unlegal.
gollark: With plethora, yes.

References
  1. Jeyabalan, Nallathambi; Clement, James P. (2016). "SYNGAP1: Mind the Gap". Frontiers in Cellular Neuroscience. 10: 32. doi:10.3389/fncel.2016.00032. ISSN 1662-5102. PMC 4753466. PMID 26912996.
  2. "SYNGAP1-related intellectual disability". US National Library of Medicine. 4 August 2020. Retrieved 9 August 2020.
  3. Holder, J. Lloyd; Hamdan, Fadi F.; Michaud, Jacques L. (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "SYNGAP1-Related Intellectual Disability", GeneReviews® (Review), Seattle (WA): University of Washington, Seattle, PMID 30789692
  4. Vlaskamp, Danique R.M.; Shaw, Benjamin J.; Burgess, Rosemary; Mei, Davide; Montomoli, Martino; Xie, Han; Myers, Candace T.; Bennett, Mark F.; XiangWei, Wenshu; Williams, Danielle; Maas, Saskia M. (2018-12-12). "SYNGAP1 encephalopathy". Neurology. 92 (2): e96–e107. doi:10.1212/WNL.0000000000006729. ISSN 0028-3878. PMC 6340340. PMID 30541864.
  5. Mignot, Cyril; Stülpnagel, Celina von; Nava, Caroline; Ville, Dorothée; Sanlaville, Damien; Lesca, Gaetan; Rastetter, Agnès; Gachet, Benoit; Marie, Yannick; Korenke, G. Christoph; Borggraefe, Ingo (2016-08-01). "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy". Journal of Medical Genetics. 53 (8): 511–522. doi:10.1136/jmedgenet-2015-103451. ISSN 0022-2593. PMID 26989088. S2CID 40830735.
  6. Berryer, Martin H.; Hamdan, Fadi F.; Klitten, Laura L.; Møller, Rikke S.; Carmant, Lionel; Schwartzentruber, Jeremy; Patry, Lysanne; Dobrzeniecka, Sylvia; Rochefort, Daniel; Neugnot-Cerioli, Mathilde; Lacaille, Jean-Claude (February 2013). "Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency". Human Mutation. 34 (2): 385–394. doi:10.1002/humu.22248. ISSN 1098-1004. PMID 23161826.
  7. Stülpnagel, Celina von; Hartlieb, Till; Borggräfe, Ingo; Coppola, Antonietta; Gennaro, Elena; Eschermann, Kirsten; Kiwull, Lorenz; Kluger, Felicitas; Krois, Ilona; Møller, Rikke S.; Rössler, Franziska (2019-02-01). "Chewing induced reflex seizures ("eating epilepsy") and eye closure sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: Review of literature and report of 8 cases". Seizure - European Journal of Epilepsy. 65: 131–137. doi:10.1016/j.seizure.2018.12.020. ISSN 1059-1311. PMID 30685520. S2CID 56595032.
  8. "SYNGAP1-related NSID". NORD (National Organization for Rare Disorders). Retrieved 2020-07-24.
  9. Fitzgerald, T. W.; Gerety, S. S.; Jones, W. D.; van Kogelenberg, M.; King, D. A.; McRae, J.; Morley, K. I.; Parthiban, V.; Al-Turki, S.; Ambridge, K.; Barrett, D. M. (March 2015). "Large-scale discovery of novel genetic causes of developmental disorders". Nature. 519 (7542): 223–228. Bibcode:2015Natur.519..223T. doi:10.1038/nature14135. ISSN 1476-4687. PMC 5955210. PMID 25533962.
  10. Carvill, Gemma L.; Heavin, Sinéad B.; Yendle, Simone C.; McMahon, Jacinta M.; O’Roak, Brian J.; Cook, Joseph; Khan, Adiba; Dorschner, Michael O; Weaver, Molly; Calvert, Sophie; Malone, Stephen (July 2013). "Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1". Nature Genetics. 45 (7): 825–830. doi:10.1038/ng.2646. ISSN 1061-4036. PMC 3704157. PMID 23708187.
  11. Hamdan, Fadi F.; Daoud, Hussein; Piton, Amélie; Gauthier, Julie; Dobrzeniecka, Sylvia; Krebs, Marie-Odile; Joober, Ridha; Lacaille, Jean-Claude; Nadeau, Amélie; Milunsky, Jeff M.; Wang, Zhenyuan (2011-05-01). "De Novo SYNGAP1 Mutations in Nonsyndromic Intellectual Disability and Autism". Biological Psychiatry. Genes, Autism, and Associated Phenotypes. 69 (9): 898–901. doi:10.1016/j.biopsych.2010.11.015. ISSN 0006-3223. PMID 21237447. S2CID 11318735.
  12. Krupp, Deidre R.; Barnard, Rebecca A.; Duffourd, Yannis; Evans, Sara A.; Mulqueen, Ryan M.; Bernier, Raphael; Rivière, Jean-Baptiste; Fombonne, Eric; O’Roak, Brian J. (2017-09-07). "Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder". American Journal of Human Genetics. 101 (3): 369–390. doi:10.1016/j.ajhg.2017.07.016. ISSN 0002-9297. PMC 5590950. PMID 28867142.
  13. Gamache, Timothy R.; Araki, Yoichi; Huganir, Richard L. (2020-02-19). "Twenty Years of SynGAP Research: From Synapses to Cognition". Journal of Neuroscience. 40 (8): 1596–1605. doi:10.1523/JNEUROSCI.0420-19.2020. ISSN 0270-6474. PMC 7046327. PMID 32075947.
  14. Hamdan, Fadi F.; Gauthier, Julie; Spiegelman, Dan; Noreau, Anne; Yang, Yan; Pellerin, Stéphanie; Dobrzeniecka, Sylvia; Côté, Mélanie; Perreau-Linck, Elizabeth; Perreault-Linck, Elizabeth; Carmant, Lionel (2009-02-05). "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation". The New England Journal of Medicine. 360 (6): 599–605. doi:10.1056/NEJMoa0805392. ISSN 1533-4406. PMC 2925262. PMID 19196676.
  15. Lim, Kian Huat; Han, Zhou; Jeon, Hyun Yong; Kach, Jacob; Jing, Enxuan; Weyn-Vanhentenryck, Sebastien; Downs, Mikaela; Corrionero, Anna; Oh, Raymond; Scharner, Juergen; Venkatesh, Aditya (2020-07-09). "Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression". Nature Communications. 11 (1): 3501. doi:10.1038/s41467-020-17093-9. ISSN 2041-1723. PMC 7347940. PMID 32647108.
  16. Kluger, Gerhard; von Stülpnagel-Steinbeis, Celina; Arnold, Stephan; Eschermann, Kirsten; Hartlieb, Till (August 2019). "Positive Short-Term Effect of Low-Dose Rosuvastatin in a Patient with SYNGAP1-Associated Epilepsy". Neuropediatrics. 50 (4): 266–267. doi:10.1055/s-0039-1681066. ISSN 1439-1899. PMID 30875700.
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