Elsevier

Brain and Development

Volume 33, Issue 9, October 2011, Pages 758-769
Brain and Development

Review article
Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy

https://doi.org/10.1016/j.braindev.2011.05.014Get rights and content

Abstract

Objectives

A 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

Case study and review of literature.

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 (below detectable limits), and slightly elevated homocystine (3 μmol/L (0-trace) and homocystinuria (234 μmol/gm creatinine) (0-trace amounts) was suggestive of a disturbance in homocysteine metabolism. Plasma homocysteine measurements (30.7 μmol/L, normal <13.5 μmol/L) confirmed hyperhomocysteinemia. Enzyme assay in skin fibroblasts confirmed severe MTHFR deficiency (patient 0.92, control 13.3 ± 4.6 nmol/mg/h). 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 an 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). At age 9 years, the patient remains severely impaired by vertebral compressive and limb fractures secondary to severe osteoporosis.

Conclusion

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 and phenotype correlations will be explored in the light of available biochemical and molecular genetic data.

Section snippets

Objectives

Several inborn errors of metabolism have now been identified in association with the presentation of severe epilepsy or an epileptic encephalopathy with onset in infancy. Of these conditions, methylene tetrahydrofolate reductase (MTHFR) deficiency is a recessively inherited disorder (MIM #236250) that presents with a non-classical form of homocystinuria. Seizures as a clinical manifestation were noted in the initial case report [1] followed by the recognition of its association with

Longitudinal illustrative case study

A 13 month old female infant presented with symptoms of visual inattention, and developmental delay to the metabolic service at the Children’s Hospital. The infant was born at term to non-consanguineous parents. There were no adverse prenatal or perinatal factors and the delivery proceeded without complications. There were no feeding difficulties noted in early life; however delay in the acquisition of motor milestones was noted in the first year. At presentation, the infant was unable to roll

Results of investigations

Elevated plasma homocysteine (30.7 μmol/L, normal <13.5 μmol/L) was confirmed through a separate assay for total homocysteine. The diagnosis of severe MTHFR deficiency was confirmed by assay of the enzyme activity in cultured skin fibroblasts (DS Rosenblatt, McGill University) MTHFR activity in the patient was low at 0.92 nmol/mg/h (reference range 13.3 ± 4.6). Molecular genetic studies revealed the patient to be a compound heterozygote for two different pathogenic mutations (R52Q and the

Evolution of epilepsy

The progression of her epilepsy has been punctuated by the re-emergence of multiple seizure types; atypical absences, complex partial seizures with secondary generalization, atonic drop attacks, multifocal myoclonic, and most recently nocturnal axial tonic seizures. She has had multiple hospitalizations for control of bouts of status epilepticus. At age 7 years and 9 months she was admitted with non-convulsive status, requiring high dose intravenous midazolam infusion. The seizures switched over

Discussion

MTHFR deficiency is an inborn error of metabolism where the manifestations are usually restricted to the nervous system at initial presentation. It is a disorder of remethylation that is characterized biochemically by homocysteine accumulation and hypomethioninemia in blood and body fluids. MTHFR generates the methyl donor 5-methyltetrahydrofolate through the irreversible reduction of 5,10-methylenetetrahydrofolate. The reconversion of homocysteine to methionine is effected through this one

The enzyme

MTHFR is an FAD (flavin adenine dinucleotide) linked oxidoreductase, composed of 656 amino acids, and is a 74.6 kDa protein. The gene coding for the enzyme is located at the chromosome 1p36.3 locus. Human cDNA for MTHFR enzyme was isolated using porcine cDNA sequences for the MTHFR enzyme, with predicted amino acid sequences that bear strong cross species homology [8]. The human enzyme is a flavoprotein with two identical subunits consisting of a N terminal catalytic domain which binds NADPH,

Presentation and natural history of epilepsy

A wide variation in seizure phenotype is well documented through the present report and a summary of other reports in the literature (Table 1). The phenotypic features of severe MTHFR appear to vary according to age and severity of enzyme deficiency and can be divided into infantile, late infantile and juvenile/late onset types (Table 2).

The infantile presentation is characterized by generalized hypotonia, lethargy, feeding difficulties and recurrent apneas. The onset of epilepsy is

Neuropathology of severe MTHFR deficiency

Post mortem studies [13], [14], [15] have been reported documenting the pathological changes in this disorder. The cardiovascular system principally the aorta, medium sized vessels, as well as the cerebral vasculature on histopathology, shows a number of changes that include; thickening of the media, intimal hyperplasia and swollen endothelial cells, fragmentation and disruption of elastic lamella. The brain shows significant atrophy, ventriculomegaly, accompanied by a significant reduction in

Linking MTHFR deficiency to neuropathology and epileptogenesis

While homocysteine is formed in all tissues, its detoxification occurs only in the liver/kidney through the transsulfuration pathway. So in other tissues such as the blood vessels and the brain, remethylation is the only alternative available. With significant reduction in MTHFR activity homocysteine cannot be remethylated to methionine, hence accumulates within the nervous system.

Homocysteine elevation is accompanied by low levels of methionine and SAM. Its links to neurotoxicity are being

MTHFR deficiency-Angelman syndrome, a link?

In the illustrative case as well as in other previously reported cases the similarities in phenotype between Angelman syndrome and MTHFR deficiency appear, both are known to present with seizures, happy affect, ataxia, and absent speech [25], [26]. It is conceivable that the methylation defects may provide a common denominator between MTHFR deficiency and Angelman syndrome, another aspect that needs further investigation.

Therapeutic aspects

The treatment goals are based on detoxification by reducing Hcy levels through the use of the compound betaine. Treatment is usually begun with 100 mg/kg with increments up to 20 g/day. This treatment renders patients hypermethioninemic. While hepatic levels of betaine-homocysteine methyltransferase are effective in reducing peripheral Hcy levels, brain BHMT levels are low [27]. In this context, the reported experience by Strauss et al. suggests that early and high dose betaine started at birth

Prevention

Early diagnosis of MTHFR deficiency based on clinical indications is critical, as newborn screening programs may not identify hypomethioninemia.

Animal models

A MTHFR knockout mouse has been generated through targeted deletion of MTHFR gene with resulting hyperhomocysteinemia [30]. Homozygotes generated are poor survivors with 10 times higher elevations in Hcy levels (33.1 μmol/L) compared to wild type mice (3.2 μmol/L), with tremor, motor and gait abnormalities and a 25% mortality by postnatal week 5. Pathological changes target cerebellum, however the cerebral cortex is reported to retain normal architecture. Other models have utilized direct

Summary

In summary, MTHFR deficiency is primarily associated with widespread changes in the CNS and blood vessels, and a variable clinical phenotype. Genotype and phenotype correlations are related to degree of enzyme deficiency. Epileptic phenotype is also variable with mild to severe presentations. Severe deficiencies present early and can evolve into a chronic epileptic encephalopathy. Early diagnosis and treatment with betaine seems promising.

Acknowledgements

The authors wish to acknowledge the kind permission of the parents and the help of our colleagues Simon Levin MD, FRCPC, Sandrine De Ribaupierre MD, in the management of the patient. We are also indebted to Kevin Strauss, MD, Clinic For Special Children, Strasburg, PA, USA for sharing his experience with us.

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