Medicine:SYNGAP1-related intellectual disability

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Short description: Medical condition

SYNGAP1-related intellectual disability is a monogenetic developmental and epileptic encephalopathy that affects the central nervous system.[1][2] Symptoms include intellectual disability, epilepsy, autism, sensory processing deficits, hypotonia and unstable gait.[3][4][5]

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.[6] Penetrance is 100%. Mild to severe intellectual or developmental disability is present in the majority of patients.[7] Epilepsy is present in the majority of cases, with approximately 80-98% of patients affected by seizures.[8] Truncal hypotonia and clumsy or ataxic gait are typical.[5] Behavioral and sleep problems are also common.[9][10] Approximately 50% of patients receive a diagnosis of autism spectrum disorder.[8] Some patients have significant feeding issues.[11][7] Constipation has also been reported.[12] Some patients experience strabismus.[5]

Cause

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.[10]

The majority of mutations are considered de novo, however cases of inheritance from both somatic mosaic and germ-line mosaic parents have been reported.[13]

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.[13][7]

EEG monitoring frequently shows generalized epilepsy, predominantly in the occipital regions.[13] Seizure onset usually occurs around 2 years of age.[14] MRI is usually normal.[4][15][7]

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.[8][16][14]

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, Vagus nerve stimulation, or the ketogenic diet in some cases.[5][14] Approximately half of patients have seizures that are pharmacoresistant.[3][10] 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:[14][18][5]

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][7]

Epidemiology

SYNGAP1 encephalopathy is estimated to comprise approximately 0.7- 2% of all cases of intellectual disability[19][20][21] with over one million people expected to be affected worldwide.[22][23] The Syngap Research Fund, a US patient advocacy group, reviewed all the studies that support these estimates. SRF pointed to a more recent study by Lopez-Riviera et al. that predicts an incidence per 100,000 births of 6.107.[24]

History

Although the SynGAP protein was first identified in 1998,[25] SYNGAP1 mutations were not found to be responsible for cases of intellectual disability until 2009.[26]

On October 1, 2021, the first ICD-10 Code for SYNGAP1-related disorders became effective.

  • F78.A1 is a billable/specific ICD-10-CM code that can be used to indicate a diagnosis for reimbursement purposes.
  • The 2023 edition of ICD-10-CM F78.A1 became effective on October 1, 2022.
  • This is the American ICD-10-CM version of F78.A1 - other international versions of ICD-10 F78.A1 may differ.

On August 11, 2021, SYNGAP1-related Disorders was included in the Social Security Administration list of diseases for Compassionate Use.

Research & potential therapies

The use of antisense oligonucleotides to up-regulate the expression of SynGAP protein is currently being researched.[27] The use of statins to address the downstream impacts of loss of SynGAP function on the Ras signaling pathway is also being studied.[28]

Three patient registry efforts are run by third parties and currently gathering patient data:

  1. The Ciitizen SYNGAP1 Registry, established in collaboration with the SynGAP Research Fund
  2. The Simons Searchlight Study supported by the Simons Foundation
  3. The SYNGAP1 Registry supported by the SYNGAP1 Foundation in partnership with the National Organization of Rare Disorders

There are multiple academic labs publicly working on potential therapies for SYNGAP1:

A number of companies have also demonstrated interest in SYNGAP1. Stoke Therapeutics has a published patent for SYNGAP1, Praxis Precision Medicines and Q-State Biosciences have listed SYNGAP1 on their treatment pipelines.

References

  1. ↑ "SYNGAP1-related non-syndromic intellectual disability - About the Disease - Genetic and Rare Diseases Information Center" (in en). https://rarediseases.info.nih.gov/diseases/12558/syngap1-related-non-syndromic-intellectual-disability. 
  2. ↑ "SYNGAP1: Mind the Gap" (in English). Frontiers in Cellular Neuroscience 10: 32. 2016. doi:10.3389/fncel.2016.00032. PMID 26912996. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 "SYNGAP1-Related Epilepsy" (in en). https://www.epilepsy.com/learn/epilepsy-due-specific-causes/genetic-causes-epilepsy/specific-genetic-epilepsies/syngap1-related-epilepsy. 
  4. ↑ 4.0 4.1 "SYNGAP1 Gene Mutation" (in en). https://www.kennedykrieger.org/patient-care/conditions/syngap1-gene-mutation. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 "SYNGAP1-Related Disorder". https://www.childneurologyfoundation.org/disorder/syngap1-related-disorder/. 
  6. ↑ "SYNGAP1-related intellectual disability". MedlinePlus. US National Library of Medicine. 4 August 2020. https://ghr.nlm.nih.gov/condition/syngap1-related-intellectual-disability. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 SYNGAP1-Related Intellectual Disability (Review). Seattle (WA): University of Washington, Seattle. 1993. http://www.ncbi.nlm.nih.gov/books/NBK537721/. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 "SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy". Neurology 92 (2): e96–e107. January 2019. doi:10.1212/WNL.0000000000006729. PMID 30541864. 
  9. ↑ "Clinical and behavioural features of SYNGAP1-related intellectual disability: a parent and caregiver description". Journal of Neurodevelopmental Disorders 14 (1): 34. June 2022. doi:10.1186/s11689-022-09437-x. PMID 35655128. 
  10. ↑ 10.0 10.1 10.2 "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy". Journal of Medical Genetics 53 (8): 511–522. August 2016. doi:10.1136/jmedgenet-2015-103451. PMID 26989088. https://hal.sorbonne-universite.fr/hal-01302596/file/Mignot_2016_Genetic_and.pdf. 
  11. ↑ "Intellectual disability, autosomal dominant 5 - NIH Genetic Testing Registry (GTR) - NCBI". https://www.ncbi.nlm.nih.gov/gtr/conditions/C2675473/?_ga=2.14057527.1840357920.1672434435-388263976.1672434434. 
  12. ↑ "Simons Searchlight | SYNGAP1" (in en-US). https://www.simonssearchlight.org/research/what-we-study/syngap1/. 
  13. ↑ 13.0 13.1 13.2 "Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency". Human Mutation 34 (2): 385–394. February 2013. doi:10.1002/humu.22248. PMID 23161826. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Philadelphia, The Children's Hospital of (2020-05-12). "SYNGAP1-Related Disorders" (in en). https://www.chop.edu/conditions-diseases/syngap1-related-disorders. 
  15. ↑ "SYNGAP1-related NSID" (in en-US). https://rarediseases.org/rare-diseases/syngap1-related-nsid/. 
  16. ↑ "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" (in English). Seizure 65: 131–137. February 2019. doi:10.1016/j.seizure.2018.12.020. PMID 30685520. 
  17. ↑ "De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability". American Journal of Medical Genetics. Part A 167A (10): 2231–2237. October 2015. doi:10.1002/ajmg.a.37189. PMID 26079862. 
  18. ↑ "SYNGAP1-related NSID" (in en-US). https://rarediseases.org/rare-diseases/syngap1-related-nsid/. 
  19. ↑ "SYNGAP1-related intellectual disability: MedlinePlus Genetics" (in en). https://medlineplus.gov/genetics/condition/syngap1-related-intellectual-disability/. 
  20. ↑ "Large-scale discovery of novel genetic causes of developmental disorders". Nature 519 (7542): 223–228. March 2015. doi:10.1038/nature14135. PMID 25533962. Bibcode: 2015Natur.519..223T. 
  21. ↑ "Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1". Nature Genetics 45 (7): 825–830. July 2013. doi:10.1038/ng.2646. PMID 23708187. 
  22. ↑ "De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism". Biological Psychiatry. Genes, Autism, and Associated Phenotypes 69 (9): 898–901. May 2011. doi:10.1016/j.biopsych.2010.11.015. PMID 21237447. 
  23. ↑ "Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder". American Journal of Human Genetics 101 (3): 369–390. September 2017. doi:10.1016/j.ajhg.2017.07.016. PMID 28867142. 
  24. ↑ "A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants". Brain 143 (4): 1099–1105. April 2020. doi:10.1093/brain/awaa051. PMID 32168371. 
  25. ↑ "Twenty Years of SynGAP Research: From Synapses to Cognition". The Journal of Neuroscience 40 (8): 1596–1605. February 2020. doi:10.1523/JNEUROSCI.0420-19.2020. PMID 32075947. 
  26. ↑ "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation". The New England Journal of Medicine 360 (6): 599–605. February 2009. doi:10.1056/NEJMoa0805392. PMID 19196676. 
  27. ↑ "Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression". Nature Communications 11 (1): 3501. July 2020. doi:10.1038/s41467-020-17093-9. PMID 32647108. Bibcode: 2020NatCo..11.3501L. 
  28. ↑ "Positive Short-Term Effect of Low-Dose Rosuvastatin in a Patient with SYNGAP1-Associated Epilepsy". Neuropediatrics 50 (4): 266–267. August 2019. doi:10.1055/s-0039-1681066. PMID 30875700. 

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