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
