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]

Contents

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]

Electroencephalography (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 definitive 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 four to five 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.

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

Research and 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.

Related Research Articles

<span class="mw-page-title-main">Epilepsy</span> Group of neurological disorders causing seizures

Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. An epileptic seizure is the clinical manifestation of an abnormal, excessive, and synchronized electrical discharge in the brain cells called neurons. The occurrence of two or more unprovoked seizures defines epilepsy. The occurrence of just one seizure may warrant the definition in a more clinical usage where recurrence may be able to be prejudged. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical activity in the brain. These episodes can result in physical injuries, either directly such as broken bones or through causing accidents. In epilepsy, seizures tend to recur and may have no detectable underlying cause. Isolated seizures that are provoked by a specific cause such as poisoning are not deemed to represent epilepsy. People with epilepsy may be treated differently in various areas of the world and experience varying degrees of social stigma due to the alarming nature of their symptoms.

Landau–Kleffner syndrome (LKS)—also called infantile acquired aphasia, acquired epileptic aphasia or aphasia with convulsive disorder—is a rare childhood neurological syndrome.

Epileptic spasms is an uncommon-to-rare epileptic disorder in infants, children and adults. One of the other names of the disorder, West syndrome, is in memory of the English physician, William James West (1793–1848), who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West (1840–1860). Other names for it are "generalized flexion epilepsy", "infantile epileptic encephalopathy", "infantile myoclonic encephalopathy", "jackknife convulsions", "massive myoclonia" and "Salaam spasms". The term "infantile spasms" can be used to describe the specific seizure manifestation in the syndrome, but is also used as a synonym for the syndrome itself. West syndrome in modern usage is the triad of infantile spasms, a pathognomonic EEG pattern, and developmental regression – although the international definition requires only two out of these three elements.

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before one year of age, with six months being the age that seizures, char­ac­ter­ized by prolonged convulsions and triggered by fever, usually begin.

Ohtahara syndrome (OS), also known as early infantile epileptic encephalopathy (EIEE) is a progressive epileptic encephalopathy. The syndrome is outwardly characterized by tonic spasms and partial seizures within the first few months of life, and receives its more elaborate name from the pattern of burst activity on an electroencephalogram (EEG). It is an extremely debilitating progressive neurological disorder, involving intractable seizures and severe intellectual disabilities. No single cause has been identified, although in many cases structural brain damage is present.

<span class="mw-page-title-main">SYNGAP1</span> Protein in Homo sapiens

Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene. SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability, epilepsy, autism and sensory processing deficits.

<span class="mw-page-title-main">CHD2</span> Protein-coding gene in the species Homo sapiens

Chromodomain-helicase-DNA-binding protein 2 is an enzyme that in humans is encoded by the CHD2 gene.

<span class="mw-page-title-main">Pitt–Hopkins syndrome</span> Medical condition

Pitt–Hopkins syndrome (PTHS) is a rare genetic disorder characterized by developmental delay, epilepsy, distinctive facial features, and possible intermittent hyperventilation followed by apnea. Pitt–Hopkins syndrome can be marked by intellectual disabilities as well as problems with socializing. It is part of the clinical spectrum of Rett-like syndromes.

Epilepsy-intellectual disability in females also known as PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9 (EIEE9), is a rare type of epilepsy that affects predominately females and is characterized by clusters of brief seizures, which start in infancy or early childhood, and is occasionally accompanied by varying degrees of cognitive impairment. The striking pattern of onset seizures at a young age, genetic testing and laboratory results, potential developmental delays or developmental regression and associated disorders, eases diagnosis.

<span class="mw-page-title-main">Kohlschütter–Tönz syndrome</span> Medical condition

Kohlschütter–Tönz syndrome (KTS), also called amelo-cerebro-hypohidrotic syndrome, is a rare inherited syndrome characterized by epilepsy, psychomotor delay or regression, intellectual disability, and yellow teeth caused by amelogenesis imperfecta. It is a type A ectodermal dysplasia.

<span class="mw-page-title-main">Mental retardation and microcephaly with pontine and cerebellar hypoplasia</span> Rare X-linked dominant genetic disorder

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An epilepsy syndrome is defined as "a characteristic cluster of clinical and EEG features, often supported by specific etiological findings ."

<span class="mw-page-title-main">Methyl-cpg binding domain protein 5</span> Protein-coding gene in the species Homo sapiens

Methyl-CpG binding domain protein 5 is a protein that in humans is encoded by the MBD5 gene.

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<span class="mw-page-title-main">Severe intellectual disability-progressive spastic diplegia syndrome</span> Medical condition

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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. 1 2 3 4 5 6 7 8 "SYNGAP1-Related Epilepsy". Epilepsy Foundation. Retrieved 2021-12-29.
  4. 1 2 "SYNGAP1 Gene Mutation". www.kennedykrieger.org. Retrieved 2021-12-29.
  5. 1 2 3 4 5 6 7 8 "SYNGAP1-Related Disorder". Child Neurology Foundation. Retrieved 2022-12-30.
  6. ↑ "SYNGAP1-related intellectual disability". MedlinePlus. US National Library of Medicine. 4 August 2020. Retrieved 9 August 2020.
  7. 1 2 3 4 5 6 Holder JL, Hamdan FF, Michaud JL (21 February 2019). "SYNGAP1-Related Intellectual Disability". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A (eds.). GeneReviews® (Review). Seattle (WA): University of Washington, Seattle. PMID   30789692. Bookshelf ID NBK537721. Retrieved 2 April 2024– via National Library of Medicine.
  8. 1 2 3 4 5 6 7 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 D, Kenny A, Eley S, McKechanie AG, Stanfield AC (June 2022). "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 . PMC   9164368 . PMID   35655128.
  10. 1 2 3 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): 511–522. 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. 1 2 3 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): 385–394. doi:10.1002/humu.22248. PMID   23161826. S2CID   11397001.
  14. 1 2 3 4 5 6 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): 2231–2237. 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. ↑ Fitzgerald TW, Gerety SS, Jones WD, Van Kogelenberg M, King DA, McRae J, et al. (Deciphering Developmental Disorders Study) (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. 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): 825–830. 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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