Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) with 
homocystinuria can result in early demise or later-onset neurological 
impairment, including developmental delay, motor dysfunction, and seizures. We 
previously characterized BALB/c Mthfr (-/-)mice as a model for this disorder and 
have recently backcrossed the disrupted allele onto the C57Bl/6 background to 
examine the variable phenotypes in MTHFR deficiency. Compared with BALB/c Mthfr 
(-/-)mice, C57Bl/6 Mthfr (-/-)mice have enhanced survival rates (81% vs 26.5%). 
Four-day-old BALB/c mutant pups had lower body, brain, and spleen weights 
relative to their wild-type counterparts compared with C57Bl/6 mutants. Pregnant 
BALB/c Mthfr (+/-)mice had increased resorptions and embryonic delays compared 
with wild-type littermates, whereas these outcomes in C57Bl/6 c Mthfr (+/-)mice 
were similar to those of wild-type C57Bl/6 mice. BALB/c-mutant pups had altered 
hematological profiles (higher hematocrit, hemoglobin, and white blood cell 
counts, with lower platelet counts) compared with C57Bl/6 mutants. Mutants of 
both strains had similar degrees of hepatic steatosis, hepatic activity of 
betaine:homocysteine methyltransferase, and altered cerebellar histology. 
Electroretinograms (ERG) in C57Bl/6 Mthfr (-/-)mice revealed decreased amplitude 
of scotopic and photopic waves in 6-week-old mice, with normalized ERGs at 
13 weeks. Plasma homocysteine was modestly higher in C57Bl/6 compared with 
BALB/c mice. Our results emphasize the variable presentation of MTHFR deficiency 
in different genetic backgrounds and suggest that plasma homocysteine is not a 
predictor of severity. In addition, our novel findings of decreased spleen 
weights, thrombocytopenia, and impaired retinal function warrant investigation 
in patients with severe MTHFR deficiency or other forms of homocystinuria.