O. Braissant¹, D. Ballhausen², L. Bonafé², O. Boulat¹

¹Laboratoire de Chimie Clinique / CHUV CH 1011 Lausanne, ²Division de Pédiatrie Moléculaire / CHUV CH 1011 Lausanne

Methylmalonic CoA mutase deficiency results in methylmalonic acidemia / aciduria (MA). In MA, methylmalonate (MMA) and propionate are mainly produced in the liver from Isoleucine, Leucine, Threonine, and odd-chain fatty acids resulting in life-threatening metabolic crisis. The experience of liver transplantation in Methylmalonic CoA mutase deficient patients shows a high incidence of peri-/post-operative brain damage. The limitation of the flux of organic acids across the blood-brain-barrier has been demonstrated to be a risk factor for neurodegeneration in some organic acidemias. Brain intracellular accumulation of MMA, not necessarily reflected through MMA concentrations in CSF, plasma or urine, could thus trigger a cascade of reactions leading to brain damage. We present the MMA concentrations in plasma, urine and CSF in a 10-years-old girl with MA who received a combined liver-kidney transplantation. Despite a strong reduction of plasma and urine MMA after transplantation, MMA remained high in CSF. This suggests that brain damage after liver transplantation in MA may occur because of ongoing autonomous synthesis of MMA in CNS. To get insight in brain MMA metabolism, we analyzed the expression of methylmalonyl-CoA-mutase (MCM), the key enzyme of this metabolic pathway, within the adult rat brain by in situ hybridization. MCM was found expressed in the whole rat brain in neurons, but was absent from glial cells. This finding supports the hypothesis that autonomous MMA production is possible in the brain, which could be the determining prognostic factor in liver transplanted patients. Further studies are needed to provide evidence on the presence of this pathway and to understand the mechanisms leading to neurotoxicity in methylmalonic aciduria.