REGULAR ARTICLECommon Mutations at the Homocysteine Metabolism Pathway and Pediatric Stroke
Introduction
The incidence rate of cerebral infarction in children has been reported to be 1.2 cases per 100,000 children per year [1]. Although several causes or potential risk factors exist for the occurrence of stroke in children, in about one-third of these patients, no obvious cause or underlying disorder can be diagnosed. Inherited gene defects related to the coagulation system have been reported as risk factors for ischemic stroke [2], [3]. These gene defects include G–A transition at nucleotide 1691 in exon 10 of the Factor V gene causing APC resistance and a G–A transition in the 3′ untranslated region of the prothrombin gene at nucleotide position 20210 (G–A), which is associated with increased levels of prothrombin activity [4], [5], [6]. We and others recently reported that FV 1691 A, FV 4070 G and PT 20210 A mutations to be important and independent risk factors for the occurrence of cerebral infarcts in pediatric age range [7], [8], [9], [10], [11].
Methylene tetrahydrofolate reductase (MTHFR), methylene tetrahydrofolate dehydrogenase (MTHFD), methionine synthase (MS), methionine synthase reductase (MTRR), cobalamin coenzyme synthesis and cystathionine β-synthase (CBS) are the enzymes that play a role in homocysteine metabolism. Deficiency of these enzyme activities results in hyperhomocysteinemia and homocystinuria. Heterozygosity and/or homozygosity for mutations at the genes of the enzymes involved in homocysteine metabolism may confer an increased risk for thrombosis by causing hyperhomocysteinemia. Metabolic traffic of homocysteine occurs along two major interchanges that lead either via remethylation to methionine or through irreversible trans-sulfuration, first to cystathionine and then to cysteine [12], [13], [14]. A C–T polymorphism at nucleotide 677 in the MTHFR gene responsible for an alanine to valine substitution results in the synthesis of a thermolabile form of MTHFR that causes increased levels of homocysteine [15]. Although the mutations related to homocysteine metabolism possibly increase the risk of stroke, the data are conflicting, and there are very few reports linking these defects to acute stroke in children including ours to common mutation of MTHFR [7], [8], [10]. No data are available on the rest of these gene defects in the pathogenesis of stroke.
The aim of this study was to evaluate the role of these mutations in Turkish children with ischemic stroke.
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Materials and Methods
Forty-six patients having cerebral infarct were included in the study. All patients were below the age of 18 (10 months to 18 years). All were clinically diagnosed, and the infarction was verified with magnetic resonance imaging (MRI) of the brain. Of these patients, there were one protein C deficiency (PC), two with systemic lupus erythematosus (SLE), one with cystic fibrosis (CF), two with infection, one with sickle cell syndrome (SS), one with moya moya disease, two homozygous Beta
Results
Genotype distribution of MTHFR 677 C–T, MTHFR 1298 A–C, MTHFD 1958 G–A, MTRR 66 A–G and FV 1691 G–A are given in Table 1. Risk assessment of double gene alterations (MTHFR 677 C–T vs. 1298 A–C) after FV 1691A mutation is excluded, and is given in Table 2. Possible effect of these two mutations on FV 1691 G/A alteration is given in Table 3. Our data revealed that neither of the risk alleles of the homocysteine metabolism-related genes alone increased the risk for the occurrence of stroke.
Discussion
Hyperhomocysteinemia is a known risk factor for cerebrovascular, peripheral vascular, coronary heart disease and thrombosis [13], [14]. Heterozygosity and/or homozygosity for mutations in the enzymes involved in homocysteine metabolism may confer an increased risk for thrombosis by causing hyperhomocysteinemia. A common mutation in MTHFR 677 C–T has been shown to cause increased plasma homocysteine levels, thus, causing a predisposition to thrombosis [15].
Previous studies on the effect of MTHFR
Acknowledgements
This study was supported by Ankara University Research Fund and Duygu Ozel was supported by Turkish Scientific and Research Council.
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