Glucose metabolism and pancreatic defects in spinal muscular atrophy

Objective: Spinal muscular atrophy (SMA) is the number 1 genetic killer of young children. It is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although SMA is primarily a motor neuron disease, metabolism abnormalities such as metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia, and hyperglycemia have been reported in SMA patients. We thus initiated an in-depth analysis of glucose metabolism in SMA. Methods: Glucose metabolism and pancreas development were investigated in the Smn2B/- intermediate SMA mouse model and type I SMA patients. Results: Here, we demonstrate in an SMA mouse model a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon-producing a cells at the expense of insulin-producing beta cells. These SMA mice display fasting hyperglycemia, hyperglucagonemia, and glucose resistance. We demonstrate similar abnormalities in pancreatic islets from deceased children with the severe infantile form of SMA in association with supportive evidence of glucose intolerance in at least a subset of such children. Interpretation: Our results indicate that defects in glucose metabolism may play an important contributory role in SMA pathogenesis. ANN NEUROL 2012;72:256268.