Neural and non-neural contributions to phenotype in human SMA type 1

Massachusetts General Hospital, Boston MA

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Abstract

Spinal Muscular Atrophy (SMA) remains a leading cause of premature death in infancy and childhood, in spite of proactive care interventions and emerging therapies poised to change the landscape in the years ahead. Untreated, most infants with SMA type I develop generalized muscle weakness, bulbar symptoms, and respiratory insufficiency in early infancy, resulting in death or ventilator-dependence by two years of age. Studies in a variety of model systems indicate a selective vulnerability of motor neurons. Severe motor disability and premature death in SMA type I infants has been primarily attributed to the consequences of motor neuron degeneration. However, recent studies in SMA animal models indicate additional systemic defects that remain of uncertain relevance in humans with SMA, including defects: 1) at the neuromuscular junction and in muscle development, 2) in cardiac development and function, 3) in glucose metabolism and pancreatic function, 4) in hepatic function and metabolism, and 5) in the function of the spleen and lymphatic system. Here we propose to systematically investigate whether SMA type I infants at the time of death demonstrate similar abnormalities, in what cells and tissues, and to what degree. Our preliminary findings indicate abnormalities in systemic and central nervous system tissues that may contribute to overall disease burden and endophenotypes in children with infantile onset SMA and underscore a need for further studies. We propose to methodically study tissues from an autopsy cohort of 13 infants and children with confirmed homozygous deletion of SMN1, with confirmed presence of 2, and only 2, SMN2 copies, and clinical features consistent with SMA type I. We propose to examine both neural and non-neural autopsy tissues and correlate the observed findings with relevant pre-mortem and peri-mortem clinical and/or laboratory features. Tissues from SMA patients will be compared with age- and sex-matched tissues from normal pediatric patients obtained from existing biobanks. By systematically examining these tissue samples and reviewing observed abnormalities in the context of detailed clinical phenotypes, our project will address the following outstanding questions: 1) characterize central nervous system tissues obtained from SMA type I patients, and 2) perform a systematic review of peripheral tissue/organs in human SMA type I cases and compare to age- and sex-matched control tissues. This project will provide critical additive insights regarding the contribution of extra motoneuronal involvement in SMA.