Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia
Natural History, Physiology, Microbiome and Biochemistry Studies of Propionic Acidemia
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
 [Kolker, Cazorla, et al 2015; Leonard et al 2003]. Worldwide, the incidence of PA varies
 widely. The estimated live-birth incidence of PA is 1:105,000-130,000 in the US [Chace et al
 2001; Couce et al 2011], 1:166,000 in Italy [Dionisi-Vici et al 2002] and 1:250,000 in
 Germany [Schulze et al 2003]. 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, and
 hematological complications. The frequency of these complications in the US patients and
 their precipitants remain undefined. 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 propiogenic gut
 flora. More recently, solid organ transplantation (liver and/or kidney) has been used to
 treat PA patients. However, optimal transplant strategy and posttransplant

 management are incompletely understood.

 Several survey-based and retrospective studies describing the natural history of propionic
 acidemia have been published in the last decade [Baumgartner et al 2014; Kolker, Cazorla, et
 al 2015; Kolker, Valayannopoulos, et al 2015; Kraus et al 2012; Nizon et al 2013; Pena &
 Burton 2012; Pena, Franks, et al 2012]. While these publications added to our understanding
 of the clinical course of this disease, the 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 [Grunert et al 2012].

 Under proposed NIH protocol, we will prospectively evaluate patients with propionic acidemia
 with special emphasis on the US population. Routine inpatient admissions and outpatient
 evaluations will last 4-5 days and 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 patients 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. Outcome measures will largely be descriptive
 and encompass correlations between clinical, microbiological, biochemical and molecular
 parameters.
-  INCLUSION CRITERIA:

 -  Participants of any gender or ethnicity over 1 month of age are eligible to enroll
 remotely for collection of outside records and natural history data

 -  Participants of any gender or ethnicity over 2 years of age are eligible to enroll in
 the full study for remote or on-site evaluation

 -  Participants with biochemical, molecular or enzymatic evidence of propionic acidemia.

 -  Participants with suspected genetic but unknown types of propionic acidemia may also
 be invited to participate.

 EXCLUSION CRITERIA:

 -  Pregnant patients are eligible to participate in the study. However, they may not take
 part in some procedures such as tissue collection, stable isotope, GFR testing, and
 brain or cardiac MRI until the pregnancy is concluded.

 -  The principal investigator may decline to enroll a patient for reasons such as being
 medically unstable, residing in a hospital, on dialysis, sub-optimal metabolic
 control, being treat for an infection, or for any concerns arising after reviewing the
 patient s medical records.