Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia

Overview

Background: People s bodies need to break down food into the chemicals. These chemicals are used for energy and growth. Some people cannot process all chemicals very well. Too much of some chemicals can cause diseases. One of these diseases is called propionic acidemia (PA). People with PA can have problems with growth, learning heart, abdomen, and other organs. Researchers want to better understand how these problems happen. Objective: To learn more about propionic acidemia and the genes that might contribute to it. Eligibility: People at least 2 years old with PA who can travel to the clinic Some unaffected family members Design: Participants will have a 3 to 5-day hospital visit every year or every few years. Family members may have just 1 visit. During the family member visit, they may have: Medical history Physical exam Samples of blood and urine Questions about diet and a food diary Doctors and nurses may do additional studies: Samples of saliva, skin and stool Fluid from a gastronomy tube, if participants have one Dental and eye evaluations A kidney test - a small amount of dye will be injected and blood will be collected. Consultations with specialists A test of calories needed at rest. A clear plastic tent is placed over the participant to measure breathing. Stable isotope study. Participants will take a nonradioactive substance then blow into a bag. Photos taken of the face and body with underwear on Ultrasound of the abdomen Heart tests Hand x-ray Brain scan Participants may have other tests if study doctors recommend them. They will get the results of standard medical tests and genetic tests.

Propionic acidemia (PA) is one of the most common inborn errors of organic acid metabolism. Although this disorder is now routinely detected in the immediate neonatal period on the US newborn screen, clinical outcomes are poor despite timely and aggressive medical intervention. Worldwide, the incidence of PA varies widely. The estimated live-birth incidence of PA is 1:243,000 in the US, 1:166,000 in Italy and 1:250,000 in Germany. Affected patients are medically fragile and can suffer from complications such as failure to thrive, intellectual disability, basal ganglia strokes, seizures, cardiomyopathy, cardiac arrhythmias, pancreatitis, impaired gut motility, osteoporosis and hematological complications. The frequency of these complications in the US patients and their precipitants remain poorly understood. Furthermore, current treatment outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Specific treatments include dietary modification to reduce propiogenic precursor load, levocarnitine to facilitate excretion of propionate, and oral antibiotics to suppress propionogenic gut flora. More recently, solid organ transplantation (liver and/or kidney) has been used to treat PA patients experiencing frequent and severe episodes of metabolic instability. However, optimal transplant strategy and post-transplant management have not been delineated. Several survey-based and retrospective studies describing the natural history of propionic acidemia have been published in the last decade. While these publications added to our understanding of the clinical course of this disease, these studies have not systematically focused on the US population using prospective analysis and reflect largely European experience, where many developed countries do not routinely screen for PA using newborn screen. Thus, the benefits of newborn screening on the PA outcomes require further clarification. Under proposed NIH protocol, we will prospectively evaluate patients with propionic acidemia with special emphasis on the US population. Typical inpatient admissions and outpatient evaluations will last up to 4-5 days and may involve blood drawing, urine collection, stool collections, genomic studies, ophthalmological examination, cardiology evaluation, radiological procedures, brain and cardiac MRI/MRS, dietary assessment and neurobehavioral evaluation. In some patient s skin biopsies will be pursued. The study objectives will be to describe the natural history of propionic acidemia in the US patients by delineating the spectrum of phenotypes and querying for genotype, enzymology, microbiome, and phenotype correlations. The population will consist of patients previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov, Organic Acidemia Association and Propionic Acidemia Foundation. Patients will be evaluated at the NIH Clinical Center or via telehealth platforms supported by NIH. Outcome measures will largely be descriptive and encompass correlations between clinical, microbiological, biochemical and molecular parameters.