Early-onset combined methylmalonic aciduria and homocystinuria: Neuroradiologic findings

BACKGROUND AND PURPOSE: Combined methylmalonic aciduria and homocystinuria (MMA-HC) is caused by impaired hepatic conversion of dietary cobalamin to m ethylcobalamin and adenosylcobalamin, resulting in decreased activity of me thylmalonyl-CoA mutase and methionine synthase. Patients with the early-ons et variety present within 12 months of age with severe neurologic, hematolo gic, and gastrointestinal abnormalities. We describe the neuroradiologic fe atures of early-onset MMA-HC and discuss related pathophysiological mechani sms. METHODS: Twelve infants with hypotonia, failure to thrive, poor feeding, an d hematologic abnormalities were diagnosed with MMA-HC on the basis of a ty pical plasmatic and urinary metabolic profile and enzyme activity in fibrob lastic cultures. Complementation studies were performed in two cases, and y ielded a CMC result. MR imaging was performed at presentation in four cases and later in the others. All patients showed prompt biochemical improvemen t with intramuscular hydroxocobalamin administration, and most had moderate neurologic improvement. RESULTS: Diffuse supratentorial white matter edema and dysmyelination was t he typical MR picture at presentation, whereas white matter bulk loss chara cterized later stages of the disease. Nucleocapsular areas of gliosis were an additional finding in one case. One patient had tetraventricular hydroce phalus at presentation. CONCLUSION: White matter damage is probably caused by reduced methyl group availability and nonphysiological fatty acids toxicity, whereas focal glios is results from homocysteine-induced toxicity to the endothelium, Hydroceph alus may result from diffuse intracranial extracerebral arterial stiffness, known as reduced arterial pulsation hydrocephalus. MR imaging features at presentation and at follow-up are nonspecific.