Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy
Abstract number :
3.305
Submission category :
11. Human Genetics
Year :
2010
Submission ID :
13317
Source :
www.aesnet.org
Presentation date :
12/3/2010 12:00:00 AM
Published date :
Dec 2, 2010, 06:00 AM
Authors :
Asuri Prasad, C. Rupar and C. Prasad
Rationale: A rare recessively inherited defect leading to deficiency of the enzyme 5, 10-methylenetetrahydrofolate reductase (MTHFR) underlies one form of hyperhomocysteinemia. We describe the association of severe MTHFR deficiency and neurological manifestations with particular attention to neurodevelopment and evolution of epileptic seizures. Methods: Longitudinal Case Study over 10 years and literature review Results: A 9 year old female infant born to Caucasian non-consanguineous parents presented with infantile spasms and developmental regression in the first year. The biochemical profile of low plasma methionine (undetectable), and high homocysteine (117 moles/gm creatinine) suggested hyperhomocysteinemia. Enzyme assay in skin fibroblasts confirmed severe MTHFR deficiency (patient 0.92, control 13.3 /-4.6 nmole/mg/hr). Molecular genetic studies identified compound heterozygosity for 2 variant polymorphisms (c.677C>T, and c. 1298A>C) and a splicing mutation (c.1348 1G>A). This is a novel mutation that removes a splice site at the end of exon 7 resulting in a premature stop codon that truncates the protein losing exons 8-11. CSF neurotransmitter analysis showed extremely low level of 5-methyl tetrahydrofolate of <5 (40-128 nmol/L).The course of epilepsy has been characterized by progression to severe epileptic encephalopathy. Periventricular white matter change consistent with demyelination is seen on MR imaging. Treatment protocols include; oral betaine, supplementation with methionine, folic acid, and 5-methyltetrahydrofolate with questionable benefit. Epileptic seizures remain pharmacoresistant to antiepileptic medications singly and in combinations. Frequent bouts of status epilepticus have led to multiple hospitalizations, and neurosurgical interventions (corpus callosotomy, vagal nerve stimulation). Conclusions: Severe MTHFR deficiency is an important diagnostic consideration in infantile epileptic encephalopathies. Early diagnosis and specific treatment interventions are possible. Further research is needed into effective treatment of epilepsy and prevention of complications in this disorder. Genotype phenotype correlations will be explored in the light of available biochemical and molecular genetic data
Genetics