Untangling the Pathogenesis of the Ultra-Rare Neuromuscular Disease, Triosephosphate Isomerase Deficiency


Translational Research

Poster Number: M255


Tracey Myers, BS, University of Pittsburgh, Michael Palladino, PhD, University of Pittsburgh

Triosephosphate isomerase deficiency (TPI Df) is an ultra-rare form of glycolytic enzymopathy and is the most severe disease in its class. TPI catalyzes the 5th step of glycolysis and is critical for obtaining full energetic yield. In TPI Df, mutations in the TPI1 gene result in very low levels of TPI protein, which manifests as a very severe clinical syndrome. Patients typically present with anemia in the neonatal period and develop neuromuscular symptoms such as hypotonia, generalized spasticity, and tremor before the age of 2. Neuromuscular symptoms progress quickly, and most die from respiratory failure before the age of 6. Often, disease diagnosis is delayed or missed altogether as TPI Df is not traditionally screened for in cases of neonatal anemia. Due to the rare nature of the disease and the pediatric patient population, there have been few opportunities to create a cohesive outline of how different biological systems are affected by the disease. This lack of knowledge about disease pathogenesis factors into the total absence of treatment options for these patients aside from supportive care. With a better understanding of how the disease progresses, early points of intervention may be identified. Indeed, it is likely that early intervention is crucial for preventing a severe disease course, but crucial timepoints have not yet been identified. A murine model of the disease has been developed and this work summarizes findings in this model. Thorough investigations into brain pathology, function of the neuromuscular junction, and disease manifestations in all 3 types of muscle (smooth, cardiac and skeletal) have been performed across a time course. These findings can help guide the development of novel therapeutics and assist in clinical management of TPI Df patients by providing a timeline of dysfunction.