Hyperhomocysteinemia: a trigger for complement-mediated TMA?

Area of Science:

• Nephrology
• Genetics
• Hematology

Background:

• Thrombotic microangiopathy (TMA) is a serious condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage.
• Malignant hypertension and acute kidney failure are critical indicators that warrant immediate investigation for underlying causes like TMA.

Observation:

• A 34-year-old man presented with severe hypertension, visual disturbances, and acute kidney failure, diagnosed as TMA.
• Biochemical analysis revealed significantly elevated homocysteine levels and normal complement activity.
• Kidney biopsy confirmed TMA with intimal edema, arteriolar thrombi, and tubulointerstitial damage.

Findings:

• Genetic testing identified a homozygous MTHFR gene polymorphism (c.665C>T) as the cause of severe hyperhomocysteinemia.
• Mutations in complement genes (Factor H and Factor B) were also detected, categorized as possibly pathogenic.
• This is the first reported case of TMA associated with severe hyperhomocysteinemia due to an MTHFR defect, distinct from cobalamin C deficiency.

Implications:

• The case suggests that endothelial damage from hyperhomocysteinemia and hypertension may trigger TMA in individuals with underlying complement pathway genetic predispositions.
• Highlights the critical need for thorough diagnostic evaluation, including genetic testing, for patients presenting with TMA.
• Expands the understanding of genetic factors contributing to TMA pathogenesis beyond known complement regulatory gene mutations.