Review articleMethylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy
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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