Homocystinuria due to methylenetetrahydrofolate reductase mutation, clinical features, follow-up, treatment and thrombotic risk: a two case series.

Abstract

Homocystinuria due to methylenetetrahydrofolate reductase (MTHFR) deficiency is an inherited metabolic disease which leads to an accumulation of homocysteine in the blood and has been implicated in the occurrence
of atherosclerotic disease and thromboembolic events in young adults.
However, the neurologic manifestations of homocystinuria are numerous
and not attributable solely to an atherosclerotic/thrombotic mechanism.
We describe the cases of two siblings whose diagnosis was established
in adulthood.
A 37 year-old male, with a history of mental retardation, psychiatric disease
and femoral-popliteal venous thrombosis developed, at the age of 34, encephalopathy, spastic tetraparesis and hyperreflexia. He was diagnosed
with homocystinuria based on severe hyperhomocystinemia and MTHFR
gene mutations. Partial clinical and laboratory remission were observed
with folic acid, cobalamin, pyridoxine and restrictive diet.
His sister, age 33, with a history of mild cognitive impairment and epilepsy
was studied and the same genetic mutations were identified. Her homocysteine levels remained high despite being under the same treatment as her brother, and she developed persecutory paranoid delusions, spastic
paraparesis, hyperreflexia and altered proprioceptive sensitivity.
In both cases the neuro-axis study showed patterns of diffuse leucoencephalopathy. Only with the introduction of betaine was an adequate metabolic and clinical control achieved. Despite marked reduction of homocysteinemia, the index case died of massive pulmonary thromboembolism.
Homocystinuria must be considered in young adults with psychiatric and
pyramidal symptoms. Despite being recognized as a hypercoagulability
syndrome, there is insufficient clinical evidence to establish therapeutic
guidelines with regards to anticoagulation in homocystinuria.