Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin

Cobalamin C (cblC) defects result in decreased activity of both methylmalon yl-CoA mutase and N-5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase), with subsequent methylmalonic aciduria and homocyst inuria. Patients typically show failure to thrive, developmental delay and megaloblastic anaemia. Vitamin therapy has been B-12 beneficial in some cas es. We report a now 4-year-old Hispanic girl with cblC disease documented b y complementation analysis, with progressive neurological deterioration and worsening head MRI changes while on intramuscular hydroxocobalamin begun a t age 3 weeks. Oral carnitine and folic acid were added at age 1 year. Bloo d levels of methylmalonic acid were reduced to treatment ranges. In the abs ence of acute metabolic crises, she developed microcephaly, progressive hyp otonia and decreased interactiveness. Funduscopic examination was normal at age 13 months. At age 19 months, she developed nystagmus, and darkly pigme nted fundi and sclerotic retinal vessels were observed on examination. Her neonatal head MRI was normal. By age 1 year, the MRI showed diffuse white-m atter loss, with secondary third and lateral ventricle enlargement, a thin corpus callosum, and normal basal ganglia. At age 15 months, progression of the white-matter loss, as well as hyperintense globi pallidi, were present . Interval progression of both grey- and white-matter loss was seen at age 27 months. We therefore caution that progressive neurological deterioration and head MRI abnormalities may still occur in cblC disease, despite early initiation of hydroxocobalamin therapy and improvement in toxic metabolite concentrations in physiological fluids.