Spinal Muscular Atrophy (SMA) is the leading genetic cause of death in infancy. It is a devastating disease that leads to progressive loss of those nerve cells that control our muscle bulk and movement. Patients develop increasing weakness in all muscles, eventually including those needed for breathing. In more than half of patients, SMA starts in infancy and typically leads to death within the first 2 years of life. In others, the disease begins in childhood and leads to significant disability.

SMA is caused by a defect in the "Survival of Motor Neurons" (SMN1) gene. Researchers are hopeful to find a cure, because nature has provided humans with a second gene, almost an identical copy of the SMN1 gene. Normally, the second gene does not contribute much, but researchers think that its function can be increased by medications.

To find out whether these medications help patients with SMA, we have to conduct clinical trials. Here, we propose to prepare for clinical trials. We will invite SMA patients to join our research effort. We will examine them regularly to better understand their disease. The visits will include questions, physical exam, blood drawing, and sometimes X-rays and a skin biopsy. We will use modern computer methods to process the information. While we are doing this, we will plan a clinical trial. Once the clinical trial begins, we will offer SMA patients participation if they meet the criteria for that trial.

We will make sure that the participants' privacy is maintained and that the study risks are as low as possible.

Identifying an effective SMA treatment is very important because there is currently none. Clinical trials are the only way to decide whether a new treatment works in SMA patients or not.

Spinal Muscular Atrophy (SMA) is one of the most devastating neurological diseases of childhood. Affected infants and children suffer from progressive muscle weakness caused by degeneration of lower motor neurons in the spinal cord and brainstem. Clinically, four phenotypes are distinguished within the continuous spectrum of disease severity based on the age of onset and the highest motor milestone ever achieved. SMA is caused by homozygous deletion of the survival motor neuron-1 (SMN1) gene. A related gene, SMN2, produces low levels of full-length SMN protein due to inefficient splicing. There is an inverse correlation between SMN copy number and disease severity, presumably mediated by levels of full length SMN protein. Therefore, increasing the amount of full-length SMN protein is a promising treatment strategy. Several drugs targeting splicing efficiency have resulted in increased SMN protein in preclinical assays and are now awaiting clinical testing.

With the future objective to conduct clinical trials in SMA, the proposed project has 3 specific aims: 1) To establish a web-based database that will serve to enroll the patient population and that will facilitate timely recruitment for future clinical trials; (2) to plan for clinical trials by a) developing reliable outcome measures, and (b) establishing the infrastructure needed to carry out efficient clinical trials, (c) convening meetings of preclinical and clinical researchers involved in SMA drug development to select candidate drugs, and (3) to characterize the patient population from a clinical and molecular point of view.

We have established a Pediatric Neuromuscular Clinical Research Network (PNCR) to evaluate patients at three sites: New York, Boston and Philadelphia. Data management (including fully web-based data repository) and statistical analyses will be carried out at the University of Rochester by the "Muscle Study Group Data Center", which is a group experienced in clinical trials of neuromuscular disease. We will characterize the patient population using selected outcome measures, standardized among sites. The clinical trial planning phase will focus on developing the necessary infrastructure between sites, critically evaluating candidate outcome measures, obtaining pilot data using those outcome measures, and establishing their reliability. In parallel to the proposed study we will work closely with the preclinical units of the Columbia University SMA research center to identify and prioritize candidate drugs for future clinical trials. Finally, based on the observational data from the proposed study, and discussions among the network's clinical experts we will develop efficient phase I/II clinical trial designs to test candidate drugs. This clinical research is timely and relevant, because laboratory research has identified candidate drugs for SMA. There is currently no effective treatment for this devastating disease. All activities of the Network will conform to established regulations that govern clinical research and patient privacy (HIPAA).

Inclusion Criteria

• Clinical diagnosis of Spinal Muscular Atrophy
• Genetic diagnosis of SMN gene deletion
• Parents or if applicable subjects must give informed consent
• must be capable of complying with the study procedures
• Female subjects of child-bearing potential must agree to undergo pregnancy test prior to radiological studies
• Diagnosis of SMA before age 19 years

Exclusion Criteria:

• Unstable medical condition precluding participation
• Significant respiratory compromise that would interfere with safe travel to site of evaluation. (The clinical site PI decides when air travel is not recommended and when the patient's location is not within a reasonably safe driving distance (upper limit 150-250 miles)