CLINICAL TRIALS FOR PEDIATRIC SPINAL MUSCULAR ATROPHY

University Of Texas Sw Med Ctr/Dallas, Dallas TX

Investigators

Linked publications & trials

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease of the anterior horn cell of the spinal cord; this disease is attributable to mutations in the 5q11 site which includes the SMN (survival motor neuron), the neuronal apoptosis inhibitory gene (NAIP), p 44, and a gene identified by its homology in the mouse H4F5. The disease appears to be caused by deletions/mutations in the SMN gene and modified by mutations in the other 3 genes. Perhaps the most significant development in the past year for families with this disorder is the development of a mouse model using transgenic techniques. The mouse has a phenotype similar to infantile SMA and has defective SMN protein. Therefore, the investigator suggests that in vitro manipulation of motor neurons from these mice may reveal compounds that are capable of upregulating or modifying the SMNc gene to produce more protein or more normal protein. Thus, the investigators argue, a clinical trial organization must be formed so that the clinicians may be ready for soon-to-be-discovered scientific advances. The specific aims of this application are therefore to 1) organize a multicenter clinical consortium of investigators for children with SMA; 2) to devise reliable methods to measure strength, motor function, lung function and quality of life in children with SMA and to determine which of those measures might be the most reliable and sensitive to change, and 3) to determine whether administration of creatine to children with SMA improves muscle strength, motor function or lung volumes. Primary endpoints for the study are the Quantitative Muscle Test, the GMFM (gross motor function tool), pulmonary function tests and the Quality of Life survey. The study will be performed at University of Texas Southwestern Medical Center, which will also be the coordinating center, University of Cincinnati Hospital, Shriners Hospital, Portland, Oregon, Medical College of Virginia, and Hennepin County Medical Center in Minneapolis, MN. Overall the disease frequency of SMA is 8 per 1000,000 live births, but the disease appears to have at least 3 different presentations with 3 differing outcomes. Patients with the infantile form are deceased in the newborn period, and thus the investigators propose to study children with types 2 and 3 disease. In 1986, three of the investigators began the first multicenter collaborative effort to study SMA patients in a prospective fashion. Children < 18 years of age were enrolled in the study, and subjects underwent quantitative muscle testing (QMT) to calculate a total muscle score (TMS), measurement of forced vital capacity (FVC) and measurement of ht or ht index and weight. Seventy-three patients over 4 years of age were seen at least 3 times, and controls were enrolled. Patients were grouped according to functional assessment during the study: non-sitter, sitter and walker. A change in function was defined as moving from one function group to another during the study. In this study, the muscle strength as measured by QMT did not decrease during the observation period of 2-6 years in SMA patients. Indeed, for patients under age 15, there was a significant increase in QMT. In contrast, the investigators were able to document loss of function such as ambulating or sitting ability despite this lack of loss of strength. In addition, no SMA patient gained function.