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SYNGAP1-related intellectual disability

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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] Starting in mid 2019 the global patient community took it upon themselves to count reported patients via an effort called they "Syngap Census". As of March 31, 2021 they reported 762 patients.

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. These are the Ciitizen SYNGAP1 Registry, SYNGAP1 (MRD5) Natural History Study and Registry and the Simons Searchlight Study supported by the Simons Foundation.

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". rarediseases.info.nih.gov. Retrieved 2022-12-30.
  2. ^ Jeyabalan N, Clement JP (2016). "SYNGAP1: Mind the Gap". Frontiers in Cellular Neuroscience. 10: 32. doi:10.3389/fncel.2016.00032. PMC 4753466. PMID 26912996.
  3. ^ a b c d e f g h "SYNGAP1-Related Epilepsy". Epilepsy Foundation. Retrieved 2021-12-29.
  4. ^ a b "SYNGAP1 Gene Mutation". www.kennedykrieger.org. Retrieved 2021-12-29.
  5. ^ a b c d e f g h "SYNGAP1-Related Disorder". Child Neurology Foundation. Retrieved 2022-12-30.
  6. ^ "SYNGAP1-related intellectual disability". US National Library of Medicine. 4 August 2020. Retrieved 9 August 2020.{{cite web}}: CS1 maint: url-status (link)
  7. ^ a b c d e f Holder JL, Hamdan FF, Michaud JL (1993). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A (eds.). SYNGAP1-Related Intellectual Disability (Review). Seattle (WA): University of Washington, Seattle. PMID 30789692. {{cite book}}: |work= ignored (help)
  8. ^ a b c d e f g Vlaskamp DR, Shaw BJ, Burgess R, Mei D, Montomoli M, Xie H, et al. (January 2019). "SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy". Neurology. 92 (2): e96–e107. doi:10.1212/WNL.0000000000006729. PMC 6340340. PMID 30541864.
  9. ^ Wright, Damien; Kenny, Aisling; Eley, Sarah; McKechanie, Andrew G.; Stanfield, Andrew C. (2022-06-02). "Clinical and behavioural features of SYNGAP1-related intellectual disability: a parent and caregiver description". Journal of Neurodevelopmental Disorders. 14 (1): 34. doi:10.1186/s11689-022-09437-x. ISSN 1866-1955. PMC 9164368. PMID 35655128.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ a b c Mignot C, von Stülpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, et al. (August 2016). "Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy" (PDF). Journal of Medical Genetics. 53 (8): 511–22. doi:10.1136/jmedgenet-2015-103451. PMID 26989088. S2CID 40830735.
  11. ^ "Intellectual disability, autosomal dominant 5 - NIH Genetic Testing Registry (GTR) - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-30.
  12. ^ "Simons Searchlight | SYNGAP1". www.simonssearchlight.org. Retrieved 2021-07-04.
  13. ^ a b c Berryer MH, Hamdan FF, Klitten LL, Møller RS, Carmant L, Schwartzentruber J, et al. (February 2013). "Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency". Human Mutation. 34 (2): 385–94. doi:10.1002/humu.22248. PMID 23161826. S2CID 11397001.
  14. ^ a b c d e f Philadelphia, The Children's Hospital of (2020-05-12). "SYNGAP1-Related Disorders". www.chop.edu. Retrieved 2021-07-04.
  15. ^ "SYNGAP1-related NSID". NORD (National Organization for Rare Disorders). Retrieved 2022-12-30.
  16. ^ von Stülpnagel C, Hartlieb T, Borggräfe I, Coppola A, Gennaro E, Eschermann K, et al. (February 2019). "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. 65: 131–137. doi:10.1016/j.seizure.2018.12.020. PMID 30685520. S2CID 56595032.
  17. ^ Parker MJ, Fryer AE, Shears DJ, Lachlan KL, McKee SA, Magee AC, et al. (October 2015). "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): 2231–7. doi:10.1002/ajmg.a.37189. PMC 4744742. PMID 26079862.
  18. ^ "SYNGAP1-related NSID". NORD (National Organization for Rare Disorders). Retrieved 2020-07-24.
  19. ^ "SYNGAP1-related intellectual disability: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-12-30.
  20. ^ Deciphering Developmental Disorders Study; et al. (March 2015). "Large-scale discovery of novel genetic causes of developmental disorders". Nature. 519 (7542): 223–8. Bibcode:2015Natur.519..223T. doi:10.1038/nature14135. PMC 5955210. PMID 25533962.
  21. ^ Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, et al. (July 2013). "Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1". Nature Genetics. 45 (7): 825–30. doi:10.1038/ng.2646. PMC 3704157. PMID 23708187.
  22. ^ Hamdan FF, Daoud H, Piton A, Gauthier J, Dobrzeniecka S, Krebs MO, et al. (May 2011). "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. PMID 21237447. S2CID 11318735.
  23. ^ Krupp DR, Barnard RA, Duffourd Y, Evans SA, Mulqueen RM, Bernier R, et al. (September 2017). "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. PMC 5590950. PMID 28867142.
  24. ^ López-Rivera JA, Pérez-Palma E, Symonds J, Lindy AS, McKnight DA, Leu C, et al. (April 2020). "A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants". Brain. 143 (4): 1099–1105. doi:10.1093/brain/awaa051. PMC 7174049. PMID 32168371.
  25. ^ Gamache TR, Araki Y, Huganir RL (February 2020). "Twenty Years of SynGAP Research: From Synapses to Cognition". The Journal of Neuroscience. 40 (8): 1596–1605. doi:10.1523/JNEUROSCI.0420-19.2020. PMC 7046327. PMID 32075947.
  26. ^ Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, et al. (February 2009). "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation". The New England Journal of Medicine. 360 (6): 599–605. doi:10.1056/NEJMoa0805392. PMC 2925262. PMID 19196676.
  27. ^ Lim KH, Han Z, Jeon HY, Kach J, Jing E, Weyn-Vanhentenryck S, et al. (July 2020). "Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression". Nature Communications. 11 (1): 3501. Bibcode:2020NatCo..11.3501L. doi:10.1038/s41467-020-17093-9. PMC 7347940. PMID 32647108.
  28. ^ Kluger G, von Stülpnagel-Steinbeis C, Arnold S, Eschermann K, Hartlieb T (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. PMID 30875700. S2CID 80619705.
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