Patient-specific cellular models for Spinal Muscular Atrophy with progressive Myoclonic Epilepsy: from pathogenesis to therapeutics development for a neglected neurological disorder

Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME) is a neurodegenerative disorder. Symptoms occur at the age of 3-5 years and consist of gait disturbances and motor deficits, progressive severe tetraparesis in about 2-3 years. Epileptic seizures, mainly as PME, resistant to conventional anti-convulsant drugs, often follow or accompany the motor regression. Symptoms invariably worsen resulting in severe disability, leaving the affected children in a totally dependent tetraparetic and apallic vegetative state for several months or years, before death for intercurrent infections and/or respiratory paralysis. No therapy is available. Muscle weakness is the consequence of the selective death of motor neuron, the nervous cells which transmit the order for muscle contraction but the reason for this selectivity is unknown. The genetic defect underlining SMA-PME impairs the synthesis of an enzyme, which is necessary to metabolize the ceramide, a lipid whose accumulation results toxic for the cell. A major hurdle in the investigation of rare diseases is the paucity of reliable models. In SMA-PME, for example, animal models are not available and cell lines from affected patients have not been established. To overcome these limits, this project will explore how induced pluripotent stem cell lines (iPSCs) derived from SMA-PME fibroblasts can serve as a disease model. The iPSCs meet the defining criteria originally proposed for human embryonic stem cells, except that they are not derived from embryos. We can reprogram these cells and differentiate them into motor neurons (targeted in SMA-PME) generating a model to study mechanisms and test novel drugs. Since the genetic defect in SMA-PME is the same observed in another severe infantile condition, Farber disease, our study might result beneficial even for Farber's patients. The development of models will broad our comprehension of these disorders and might lead to the development of effective therapies.