SYNGAP1 and Methylenetetrahydrofolate in Cerebrospinal Fluid: Cognitive Development after Oral Folate (5-Methyltetrahydrofolate) Supplementation in a 5-Year-Old Girl

Abstract

Synaptic Ras GTPase-activating protein 1 (SYNGAP1), also called Ras-GAP 1 or RASA5, is a cerebral protein with a role in brain synaptic function. Its expression affects the development, structure, function, and plasticity of neurons. Mutations in the gene cause a neurodevelopment disorder termed mental retardation-type 5, also called SYNGAP1 syndrome. This syndrome can cause many neurological symptoms including pharmaco-resistant epilepsy, intellectual disability, language delay, and autism spectrum disorder. The syndrome naturally evolves as epileptic encephalopathy with handicap and low intellectual level. A treatment to control epilepsy, limit any decrease in social capacities, and improve intellectual development is really a challenging goal for these patients. The etiologic investigation performed in a 5-year-old girl with early epileptic absence seizures (onset at 6 months) and psychomotor delay (language) revealed a low methylenetetrahydrofolate level in cerebrospinal fluid in a lumbar puncture, confirmed by a second one (35 nmol/L and 50 nmol/L vs. 60–100 nmol/L normal), associated with normal blood and erythrocyte folate levels. Hyperhomocysteinemia, de vivo disease, and other metabolic syndromes were excluded by metabolic analysis. No genetic disorders (like methylenetetrahydrofolate reductase and methenyltetrahydrofolate synthetase) with folate metabolism were found. The physical examination showed only a minor kinetic ataxia. An oral folate (5-methyltetrahydrofolate) supplementation was started with oral vitamin therapy. The child showed good progress in language with this new treatment; epilepsy was well balanced with only one antiepileptic drug. The SYNGAP1 mutation was identified in this patient's genetic analysis. Since the start of folate supplementation/vitamin therapy, the patient's neurologic development has improved. To our knowledge, no association between these two pathologies has been linked and no patient with this SYNGAP1 mutation has ever showed much intellectual progress. Low cerebral methylenetetrahydrofolate levels could be associated with SYNGAP1 mutations. One of the hypotheses is the link of folate metabolism with epigenetic changes including methylation process. One inborn metabolic activity in folate metabolism may be associated with SYNGAP1 disease with epigenetic repercussions. Further studies should assess the link of SYNGAP1 and methyltetrahydrofolate and the evolution of SYNGAP1 patients with oral folate supplementation or vitamin therapy.

Keywords

pediatric neurology - SYNGAP1 - 5MTHF - neurotransmitters - vitamin therapy

Authors' Contributions

V.H. and B.C. conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript.

V.H. and B.C. collected data, performed the initial analyses, and reviewed and revised the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable to all aspects of the work.

Publication History

Received: 04 July 2021

Accepted: 08 October 2021

Article published online:
07 December 2021

• References

• 1 Hamdan FF, Gauthier J, Rouleau GA, Michaud JL. [De novo mutations in SYNGAP1 associated with non-syndromic mental retardation]. Med Sci (Paris) 2010; 26 (02) 133-135
• 2 Agarwal M, Johnston MV, Stafstrom CE. SYNGAP1 mutations: clinical, genetic, and pathophysiological features. Int J Dev Neurosci 2019; 78: 65-76
• 3 Vlaskamp DRM, Shaw BJ, Burgess R. et al. SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy. Neurology 2019; 92 (02) e96-e107 [Erratum in: Neurology. 2019 Nov 12;93(20):908. PMID: 30541864; PMCID: PMC6340340]
• 4 Jeyabalan N, Clement JP. SYNGAP1: mind the gap. Front Cell Neurosci 2016; 10: 32 DOI: 10.3389/fncel.2016.00032.
• 5 Mitchell ES, Conus N, Kaput J. B vitamin polymorphisms and behavior: evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci Biobehav Rev 2014; 47: 307-320
• 6 Zou M, Sun C, Liang S. et al. Fisher discriminant analysis for classification of autism spectrum disorders based on folate-related metabolism markers. J Nutr Biochem 2019; 64: 25-31
• 7 Vlachos GS, Scarmeas N. Dietary interventions in mild cognitive impairment and dementia. Dialogues Clin Neurosci 2019; 21 (01) 69-82
• 8 Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T. Inherited disorders of neurotransmitters: classification and practical approaches for diagnosis and treatment. Neuropediatrics 2019; 50 (01) 2-14
• 9 Gales A, Masingue M, Millecamps S. et al. Adolescence/adult onset MTHFR deficiency may manifest as isolated and treatable distinct neuro-psychiatric syndromes. Orphanet J Rare Dis 2018; 13 (01) 29
• 10 Pearl PL, Wallis DD, Gibson KM. Pediatric neurotransmitter diseases. Curr Neurol Neurosci Rep 2004; 4 (02) 147-152
• 11 Werner FM, Coveñas R. Classical neurotransmitters and neuropeptides involved in generalized epilepsy in a multi-neurotransmitter system: how to improve the antiepileptic effect?. Epilepsy Behav 2017; 71 (Pt B): 124-129
• 12 Horvath GA, Demos M, Shyr C. et al. Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: a potential treatment target?. Mol Genet Metab 2016; 117 (01) 42-48
• 13 Surtees R. Inborn errors of neurotransmitter receptors. J Inherit Metab Dis 1999; 22 (04) 374-380
• 14 Bhargava S, Tyagi SC. Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review. Mol Cell Biochem 2014; 387 (1-2): 55-61
• 15 Vidmar Golja M, Šmid A, Karas Kuželički N, Trontelj J, Geršak K, Mlinarič-Raščan I. Folate insufficiency due to MTHFR deficiency is bypassed by 5-methyltetrahydrofolate. J Clin Med 2020; 9 (09) 2836
• 16 Loots JM, Kramer S, Brennan MJ. The effect of folates on the reflex activity in the isolated hemisected frog spinal cord. J Neural Transm (Vienna) 1982; 54 (3-4): 239-249