Project 1- Longitudinal Study

Baylor College Of Medicine, Houston TX

Investigators

Abstract

ABSTRACT – PROJECT 1 (LONGITUDINAL STUDY OF ORGANIC ACIDEMIAS) In the past two decades, expanded newborn screening has transformed the diagnosis and management of organic acidemias. Organic acidemias are inborn errors of metabolism that are due to enzymatic defects in amino acid catabolism associated with life-threatening metabolic decompensations. The introduction of expanded newborn screening for these disorders has facilitated diagnoses through the detection of diagnostic metabolites in blood spots from newborns. As a result of prompt diagnosis and better management, including optimization of nutritional management, new medications, and/or liver transplantation, individuals with organic acidemias are surviving into adulthood. This improved survival has led to the discovery of long-term complications, such as renal and cardiac complications, that were previously unknown or poorly characterized. Moreover, the increased availability of genetic testing has expanded the phenotype of organic acidemias to include milder forms that were previously under-recognized. In addition to organ transplantation, there are now a growing number of new therapeutics under pre-clinical investigation and in phase 1/2 clinical trials for organic acidemias. This growing number of potential therapeutics highlights important gaps in our knowledge of the natural history of organic acidemias and importance of better natural history data to improve clinical trial readiness. Furthermore, it highlights the need for genotype-phenotype correlations as genotype often predicts severity and could inform the timing of interventions, and impact clinical trial results. As the earliest cohort of newborn screened individuals enters adulthood, the ROAR consortium prospective, multi-site longitudinal study is well-timed to fill this gap in knowledge about the natural history of five organic acidemias (methylmalonic acidemia due to methylmalonyl- CoA mutase deficiency, propionic acidemia, isovaleric acidemia, glutaric aciduria type 1, and cobalamin C disease). We have assembled a team to accomplish this goal with the following aims: 1) Establish age- and diagnosis-based frequency of acute metabolic decompensations for each organic acidemia, 2) Define the incidence and progression of renal disease in organic acidemias and understand genotype-phenotype correlations, aggravating/alleviating factors, and responses to therapy, 3) Identify the frequency and spectrum of feeding difficulties and gastrointestinal complications in each organic acidemia and assess the response of these complications to routine clinical interventions, 4) Characterize neurodevelopmental outcomes in organic acidemias and the effects of genotype, metabolic decompensations, and other clinical factors on neurocognitive development and striatal brain injury, and 5) Determine the frequency, rationale for and success of solid organ transplantation in methylmalonic and propionic acidemias. The data generated from this first, multi-site, natural history study solely focused on organic acidemias in the U.S. will impact patient management and anticipatory guidance and play a critical role in clinical trial readiness as the field prepares for the emergence of new therapies for these disorders.