Autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations: a report of 8 cases and literature review

WANG Xiao-Le; TIAN Ya-Nan; CHEN Chen; PENG Jing

doi:10.7499/j.issn.1008-8830.2301054

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Chinese Journal of Contemporary Pediatrics ›› 2023, Vol. 25 ›› Issue (5) : 489-496. DOI: 10.7499/j.issn.1008-8830.2301054

CLINICAL RESEARCH

Autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations: a report of 8 cases and literature review

WANG Xiao-Le¹, TIAN Ya-Nan², CHEN Chen¹, PENG Jing^1,3

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Abstract

Objective To summarize the clinical phenotype and genetic characteristics of children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations. Methods A retrospective analysis was performed on the medical data of 8 children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations who were diagnosed and treated in the Department of Pediatrics, Xiangya Hospital of Central South University. Results The mean age of onset was 9 months for the 8 children. All children had moderate-to-severe developmental delay (especially delayed language development), among whom 7 children also had seizures. Among these 8 children, 7 had novel heterozygous mutations (3 with frameshift mutations, 2 with nonsense mutations, and 2 with missense mutations) and 1 had 6p21.3 microdeletion. According to the literature review, there were 48 Chinese children with mental retardation caused by SYNGAP1 gene mutations (including the children in this study), among whom 40 had seizures, and the mean age of onset of seizures was 31.4 months. Frameshift mutations (15/48, 31%) and nonsense mutations (19/48, 40%) were relatively common in these children. In terms of treatment, among the 33 children with a history of epileptic medication, 28 (28/33, 85%) showed response to valproic acid antiepileptic treatment and 16 (16/33, 48%) achieved complete seizure control after valproic acid monotherapy or combined therapy. Conclusions Children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations tend to have an early age of onset, and most of them are accompanied by seizures. These children mainly have frameshift and nonsense mutations. Valproic acid is effective for the treatment of seizures in most children.

Key words

Mental retardation / SYNGAP1 gene / Developmental retardation / Epilepsy / Child

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WANG Xiao-Le, TIAN Ya-Nan, CHEN Chen, PENG Jing. Autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations: a report of 8 cases and literature review[J]. Chinese Journal of Contemporary Pediatrics. 2023, 25(5): 489-496 https://doi.org/10.7499/j.issn.1008-8830.2301054

References

1 Ellis CA, Petrovski S, Berkovic SF. Epilepsy genetics: clinical impacts and biological insights[J]. Lancet Neurol, 2020, 19(1): 93-100. PMID: 31494011. DOI: 10.1016/S1474-4422(19)30269-8.
2 Hamdan FF, Gauthier J, Spiegelman D, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation[J]. N Engl J Med, 2009, 360(6): 599-605. PMID: 19196676. PMCID: PMC2925262. DOI: 10.1056/NEJMoa0805392.
3 Dressler A, Trimmel-Schwahofer P, Reithofer E, et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome—comparison with various standard antiepileptic drug regimen[J]. Epilepsy Res, 2015, 109: 81-89. PMID: 25524846. DOI: 10.1016/j.eplepsyres.2014.10.014.
4 Wang Y, Lv Y, Li Z, et al. Phenotype and genotype analyses of Chinese patients with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations[J]. Front Genet, 2022, 13: 957915. PMID: 36583017. PMCID: PMC9792850. DOI: 10.3389/fgene.2022.957915.
5 Niu Y, Gong P, Jiao X, et al. Genetic and phenotypic spectrum of Chinese patients with epilepsy and photosensitivity[J]. Front Neurol, 2022, 13: 907228. PMID: 36034301. PMCID: PMC9416002. DOI: 10.3389/fneur.2022.907228.
6 田小娟, 方方, 丁昌红, 等. SYNGAP1基因相关儿童癫痫临床特点和基因分析[J]. 中华儿科杂志, 2021, 59(12): 1059-1064. PMID: 34856666. DOI: 10.3760/cma.j.cn112140-20210430-00369.
7 Zhang H, Yang L, Duan J, et al. Phenotypes in children with SYNGAP1 encephalopathy in China[J]. Front Neurosci, 2021, 15: 761473. PMID: 34924933. PMCID: PMC8678593. DOI: 10.3389/fnins.2021.761473.
8 张会婷. SYNGAP1脑病相关临床特点及遗传学特征[D]. 沈阳: 中国医科大学, 2022.
9 田杨, 彭炳蔚, 栗金亮, 等. SYNGAP1基因变异致癫痫伴认知发育障碍3例临床分析[J]. 临床儿科杂志, 2020, 38(8): 571-574. DOI: 10.3969/j.issn.1000-3606.2020.08.003.
10 高在芬, 律玉强, 张开慧, 等. 一例SYNGAP1基因变异所致精神发育迟滞5型[J]. 中华医学遗传学杂志, 2020, 37(6): 661-664. PMID: 32472547. DOI: 10.3760/cma.j.issn.1003-9406.2020.06.016.
11 陆静, 张仪, 韩聪, 等. 一例智力障碍患儿的SYNGAP1基因新突变[J]. 中华医学遗传学杂志, 2019, 36(7): 716-719. PMID: 31302919. DOI: 10.3760/cma.j.issn.1003-9406.2019.07.015.
12 Pei Y, Li W, Du L, et al. Novel mutation of SYNGAP1 associated with autosomal dominant mental retardation 5 in a Chinese patient[J]. Fetal Pediatr Pathol, 2018, 37(6): 400-403. PMID: 30572772. DOI: 10.1080/15513815.2018.1497113.
13 Gamache TR, Araki Y, Huganir RL. Twenty years of SynGAP research: from synapses to cognition[J]. J Neurosci, 2020, 40(8): 1596-1605. PMID: 32075947. PMCID: PMC7046327. DOI: 10.1523/JNEUROSCI.0420-19.2020.
14 Araki Y, Zeng M, Zhang M, et al. Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP[J]. Neuron, 2015, 85(1): 173-189. PMID: 25569349. PMCID: PMC4428669. DOI: 10.1016/j.neuron.2014.12.023.
15 Llamosas N, Arora V, Vij R, et al. SYNGAP1 controls the maturation of dendrites, synaptic function, and network activity in developing human neurons[J]. J Neurosci, 2020, 40(41): 7980-7994. PMID: 32887745. PMCID: PMC7548701. DOI: 10.1523/JNEUROSCI.1367-20.2020.
16 Mignot C, von Stülpnagel C, Nava C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy[J]. J Med Genet, 2016, 53(8): 511-522. PMID: 26989088. DOI: 10.1136/jmedgenet-2015-103451.
17 Berryer MH, Hamdan FF, Klitten LL, et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency[J]. Hum Mutat, 2013, 34(2): 385-394. PMID: 23161826. DOI: 10.1002/humu.22248.
18 Jr Holder JL, Hamdan FF, Michaud JL. SYNGAP1-Related Intellectual Disability[M]//AdamMP, MirzaaGM, PagonRA, alet. GeneReviews?[Internet]. Seattle (WA): University of Washington, Seattle, 1993-2023.
19 Vlaskamp DRM, Shaw BJ, Burgess R, et al. SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy[J]. Neurology, 2019, 92(2): e96-e107. PMID: 30541864. PMCID: PMC6340340. DOI: 10.1212/WNL.0000000000006729.
20 Lo Barco T, Kaminska A, Solazzi R, et al. SYNGAP1-DEE: a visual sensitive epilepsy[J]. Clin Neurophysiol, 2021, 132(4): 841-850. PMID: 33639450. DOI: 10.1016/j.clinph.2021.01.014.
21 Cirignotta F, Marcacci G, Lugaresi E. Epileptic seizures precipitated by eating[J]. Epilepsia, 1977, 18(4): 445-449. PMID: 412665. DOI: 10.1111/j.1528-1157.1977.tb04990.x.
22 Roche Martínez A, Alonso Colmenero MI, Gomes Pereira A, et al. Reflex seizures in Rett syndrome[J]. Epileptic Disord, 2011, 13(4): 389-393. PMID: 22258043. DOI: 10.1684/epd.2011.0475.
23 von Stülpnagel C, Hartlieb T, Borggr?fe I, et al. 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[J]. Seizure, 2019, 65: 131-137. PMID: 30685520. DOI: 10.1016/j.seizure.2018.12.020.
24 Lo Barco T, De Gaetano L, Santangelo E, et al. SYNGAP1-related developmental and epileptic encephalopathy: the impact on daily life[J]. Epilepsy Behav, 2022, 127: 108500. PMID: 34954508. DOI: 10.1016/j.yebeh.2021.108500.
25 Agarwal M, Johnston MV, Stafstrom CE. SYNGAP1 mutations: clinical, genetic, and pathophysiological features[J]. Int J Dev Neurosci, 2019, 78: 65-76. PMID: 31454529. DOI: 10.1016/j.ijdevneu.2019.08.003.
26 Parker MJ, Fryer AE, Shears DJ, et al. De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability[J]. Am J Med Genet A, 2015, 167A(10): 2231-2237. PMID: 26079862. PMCID: PMC4744742. DOI: 10.1002/ajmg.a.37189.
27 Writzl K, Knegt AC. 6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment[J]. Am J Med Genet A, 2013, 161A(7): 1682-1685. PMID: 23687080. DOI: 10.1002/ajmg.a.35930.
28 Zollino M, Gurrieri F, Orteschi D, et al. Integrated analysis of clinical signs and literature data for the diagnosis and therapy of a previously undescribed 6p21.3 deletion syndrome[J]. Eur J Hum Genet, 2011, 19(2): 239-242. PMID: 21119708. PMCID: PMC3025798. DOI: 10.1038/ejhg.2010.172.
29 von Stülpnagel C, Funke C, Haberl C, et al. SYNGAP1 mutation in focal and generalized epilepsy: a literature overview and a case report with special aspects of the EEG[J]. Neuropediatrics, 2015, 46(4): 287-291. PMID: 26110312. DOI: 10.1055/s-0035-1554098.
30 Kuchenbuch M, D'Onofrio G, Chemaly N, et al. Add-on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy[J]. Epilepsia Open, 2020, 5(3): 496-500. PMID: 32913957. PMCID: PMC7469777. DOI: 10.1002/epi4.12411.
31 Sullivan BJ, Ammanuel S, Kipnis PA, et al. Low-dose perampanel rescues cortical gamma dysregulation associated with parvalbumin interneuron GluA2 upregulation in epileptic Syngap1+/- mice[J]. Biol Psychiatry, 2020, 87(9): 829-842. PMID: 32107006. PMCID: PMC7166168. DOI: 10.1016/j.biopsych.2019.12.025.