This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease characterized by diffuse weakness and muscular atrophy. It is one of the most common neuromuscular conditions, and a leading cause of hereditary infant mortality. Patients most frequently present in infancy and early childhood, but the clinical spectrum of onset and severity is broad, ranging from the infant with congenital joint contractures and ventilator dependence to adult onset of proximal muscle weakness. This clinical heterogeneity increases the inherent challenges in clinical trial design for the evaluation of promising new therapies. Our work and that of others have demonstrated that SMA is a progressive motor neuron disease, as reflected by loss of function as well as maximum compound motor action potential amplitudes and motor unit number estimates in a distally innervated hand muscle over time. Disease progression can occur rapidly in SMA type 1 infants prior to reaching a stable albeit significantly weak endpoint, while patients with SMA types 2 and 3 often demonstrate a more slowly progressive course, with stable function preserved over many years. As an important prelude to this current proposal, pilot studies at the University of Utah have established stability of functional outcome measures over at least a six month time period in a cohort of non-ambulatory sitters and ambulatory SMA type 2 and 3 children. The primary objective of this protocol is to assess the safety, tolerability, and efficacy of a combined regimen of oral VPA and carnitine in SMA patients 2-17 years of age.Secondary objectives are to refine electrophysiological and clinical techniques to help us better follow the course of patients with SMA, particularly as it relates to the primary disease process causing weakness, motor neuron dysfunction and loss. These include: 1) clinical assessments which will help accurately assess functional motor outcome and strength of patients, 2) electrophysiologic techniques to study and follow the course of motor neuron loss, and 3) investigation of genetic mechanisms which influence the severity of phenotype.We hypothesize that treatment with VPA increases expression of SMN protein via up-regulation of SMN2 gene expression, resulting in the rescue of motor neurons and allowing re-innervation.
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