Plasma Homocysteine Levels, Methelene TetraHydroFolate Reductase (MTHFR) Polymorphism, and the Risk of Thromboembolism in Children: A Single Institution Experience

Introduction: Hyperhomocystenemia (HHcy) has been identified as a moderate risk factor for thrombosis in adults. A polymorphism in the folate-metabolizing enzyme Methelene TetraHydroFolate Reductase (MTHFR) has been implicated in causing a mild to moderate elevation in homocysteine (Hcy). Data on the role of HHcy and MTHFR polymorphism in pediatric thromboembolism (TE) are sparse. We reviewed, in our series of 125 patients, the role of elevated Hcy and MTHFR C677T polymorphism as a risk factor for TE in children.

Materials and Methods: Inpatient and outpatient clinic charts of patients with documented TE, followed at the Hemostasis and Thrombosis Center at Children’s Hospital of Michigan were reviewed for demographic data, Hcy level and the presence of the MTHFR C677T polymorphism. Hcy levels were recorded at the time of diagnosis. Normal Hcy levels were defined both as per the standard laboratory normal range and established age-specific normal ranges available from literature. The 97.5% value was taken as the upper normal range. The data were thus analyzed separately with both stratifications.

Results: A total of 171 patient charts were reviewed from January 1989 to June 2008. Hcy and MTHFR data were available on 125 patients. Thus, a total of 125 patients with a documented venous and/or arterial TE (60 venous and 45 arterial) were analyzed. 61 were females and 64 males. Mean age of presentation was 14 years (range of 1 day to 30 years).

When no age segregation was done, normal Hcy plasma concentration was taken as 4 – 12 μmol/L for all ages. Elevated Hcy (>12 μmol/L) was seen in a total of 8 patients (6.5 %), out of which 5 had CT genotype and 3 had the CC genotype. None of these patients were homozygous (TT) for the MTHFR polymorphism (Table 1).

When the HHcy was analyzed by stratifying normal Hcy ranges based on age (Table 2), total of 15 patients (12%) were found to have elevated Hcy. Six patients had CT genotype and 9 patients had CC genotype. Again, none of the homozygote for MTHFR polymorphism had an elevated Hcy even after stratifying by age.

Seven patients were homozygous with TT genotype, 49 patients had the CT genotype and the reminder 69 had normal CC genotype. The median homocysteine levels in these three groups were 5.7 μmol/L (4.3 – 8.5); 6 μmol/L (3–49.1) and 6.5 μmol/L (1.2 – 19.1) respectively (Table 3). Of the 6 patients with CT genotype and elevated homocysteine, 3 patients had end stage renal disease and the corresponding homocysteine levels were 18.3 μmol/L, 18.8 μmol/L and 49.1 μmol/L.

Conclusions:

1. HHcy was a risk factor in 8 out of 125 patients (6.5%) when the normal range was based on standard laboratory normal range and in 15 out of 125 (15%) when age stratified normal ranges were used. There was no difference in the median Hcy levels in patients with CC, CT or TT genotype for MTHFR polymorphism.

2. Our data suggest that MTHFR polymorphism is not associated with elevation in Hcy and is not a risk factor in pediatric TE. Thus, genetic testing for MTHFR C677T polymorphism in pediatric patients with TE may not be justified at this time.