Novel Homozygous MTHFR Variant Causing Homocystinuria: Subtle Phenotypic Clues in Carriers

Homocystinuria is a rare metabolic disorder characterized by elevated homocysteine levels due to defects in methionine metabolism.

We present a 17-year-old male with tall stature, intellectual disability, and skeletal abnormalities. Elevated plasma homocysteine levels 199.95 μmol/L were noted, which increased to 225.04 μmol/L following pyridoxine therapy, indicating nonresponsiveness. Genetic analysis revealed a novel homozygous missense variant in exon 12 of the MTHFR gene (p.Lys625Thr). Notably, the carrier father exhibited an increased arm span-to-height ratio and raised serum homocysteine level 25.78 μmol/L, a subtle phenotypic and biochemical trait absent in the carrier mother. Management included a low-methionine diet, vitamin supplementation, and initiation of betaine therapy.

This case underscores the importance of genetic testing and individualized management in homocystinuria, especially with novel mutations. The observed subtle phenotypic feature in the carrier father highlights the need for comprehensive family evaluations.