Methylmalonic Acid Accumulation and the Development of Peripheral Neuropathy (IN1-1.010)

Abstract

Objective: This study evaluated the pathophysiology of peripheral neuropathy seen with MMA accumulation both in vivo and in vitro. Background A potential cause of peripheral neuropathy is cobalamin (vitamin B12) deficiency, which leads to accumulation of methylmalonic acid (MMA). The mechanism by which cobalamin deficiency is uncertain, but recent evidence in Parkinson9s Disease and Diabetic Neuropathy clinical studies has implicated MMA. Design/Methods: We performed mouse dorsal root ganglia neuronal and Schwann cell cultures exposed to a dose range of methylmalonic acid or placebo. We examined cellular viability, reactive oxygen species and mitochondrial function in vitro. Complementary in vivo studies with either daily systemic (intraperitoneal), intrathecal or near-nerve MMA or placebo delivery were performed in mice. Electrophysiological, structural and molecular studies were performed for dorsal root ganglia and sciatic nerves after 3 months of exposure to MMA or placebo. Results: There was no impact upon in vitro Schwann cells with exposure to amiodarone. However, MMA was associated with a dose-related somal atrophy of neurons and neuronal loss in vitro. In vivo, MMA had little impact when delivered with localized near-nerve delivery, but led to diffuse development when delivered systemically and dramatic neuropathy when delivered intrathecally. Peripheral neuropathy was associated with gradual loss of motor and sensory nerve potential amplitudes, loss of large and small nerve fibers, and loss of intraepidermal nerve fiber density. Increased reactive oxygen species and mitochondrial dysfunction were detected in the dorsal root ganglia with MMA when delivered intrathecally or systemically. Conclusions: MMA has a direct impact upon the dorsal root ganglia neurons without any observed effect upon Schwann cells. Accumulation of MMA is associated with induction of experimental peripheral axonal neuropathy due to direct effects upon dorsal root ganglia neuronal well being. Supported by: Alberta Heritage Foundation for Medical Research. Disclosure: Dr. Francis has nothing to disclose. Dr. Hohol has nothing to disclose. Dr. Jawad has nothing to disclose. Dr. Ayer has nothing to disclose. Dr. Toth has received personal compensation for activities with Pfizer and Eli Lilly & Company as a speaker. Dr. Toth has received research support from Pfizer Inc, Valeant Pharmaceuticals International and Eli Lilly & Company.