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Common mutations at the homocysteine metabolism pathway and pediatric stroke
1Pediatric Molecular Genetics and Pediatric Neurology, Department of Ankara University, Ankara, Turkey. nejat_akar@hotmail.com
Insights
Factor V (FV) 1691 A and prothrombin (PT) 20210 A mutations are significant risk factors for ischemic stroke in Turkish children. Routine genetic analysis for these mutations is recommended for pediatric stroke patients.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Hyperhomocysteinemia, linked to homocysteine metabolism gene mutations, may increase thrombosis risk.
- Conflicting data exist on homocysteine metabolism mutations and stroke risk, with limited reports in pediatric acute stroke.
- This study investigates the role of these mutations in Turkish children with ischemic stroke.
Purpose of the Study:
- To determine the association between specific gene mutations and ischemic stroke in Turkish children.
- To evaluate the prevalence of methylene tetrahydrofolate reductase (MTHFR), methylene tetrahydrofolate dehydrogenase (MTHFD), and methionine synthase reductase (MTRR) mutations.
- To assess the contribution of Factor V (FV) 1691 A and prothrombin (PT) 20210 A mutations to pediatric ischemic stroke.
Main Methods:
- Clinical diagnosis and MRI-verified cerebral infarct in 46 pediatric patients (<18 years).
- Genotyping for MTHFR 677 C-T, MTHFR 1298 A-C, MTHFD 1958 G-A, and MTRR 66 A-G mutations.
- Analysis of FV 1691 A and PT 20210 A mutations in patients and 68 healthy controls.
Main Results:
- No significant difference in MTHFR, MTHFD, or MTRR allele distribution between patients and controls.
- FV 1691 A mutation found in 26.0% of patients, conferring a 6.4-fold increased risk of cerebral infarct.
- PT 20210 A mutation identified in 16.6% of patients; 4.2% carried both FV 1691 A and PT 20210 A mutations.
Conclusions:
- FV 1691 A and PT 20210 A mutations are significant risk factors for ischemic stroke in Turkish children.
- These mutations should be included in routine genetic analysis for pediatric stroke patients.
- Homocysteine metabolism gene mutations (MTHFR, MTHFD, MTRR) did not show a significant association in this cohort.
Abstract:
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. 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. We aimed to study the role of these mutations in Turkish children with ischemic stroke. Forty-six patients having cerebral infarct were clinically diagnosed, and the infarction verified with magnetic resonance imaging of the brain was included in the study. All patients were below the age of 18 (10 months to 18 years). Sixty-eight controls, consecutively selected among healthy unrelated subjects from the same geographic area of Turkey without personal and family history of thrombosis, stroke or Behest's disease, were included. Genotyping for the common mutations was carried out by the methods described previously. There was no difference between the pediatric stroke patients and controls for the distribution of methylene tetrahydrofolate reductase (MTHFR) 677 C-T, MTHFR 1298 A-C, methylene tetrahydrofolate dehydrogenase (MTHFD) 1958 G-A and methionine synthase reductase (MTRR) 66 A-G alleles. There was no risk for double gene alterations (MTHFR 677 C-T vs. 1298 A-C) after individuals with FV 1691 A mutation is excluded. Twelve of the 46 patients were found to carry FV 1691 A mutation (26.0%), one being homozygote. The cerebral infarct risk for FV 1691 A was found to be 6.4 (CI 95% 1.7-23.0). Eight of the 46 patients were found to carry PT 20210 A mutation (16.6%). Two of the FV 1691 A heterozygous patients carried PT 20210 A mutation at the same time (4.2%). As a conclusion, we can say that FV 1691 A and PT 20210 A mutations are important and must be included to the routine analysis of pediatric stroke patients.