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

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:

- Patients 2 years of age and older are eligible to enroll in this study.

- Patients with biochemical, molecular or enzymatic evidence of propionic acidemia of
any gender and ethnicity are eligible to enroll in this protocol.

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

EXCLUSION CRITERIA:

- Patients will be excluded if they cannot travel to the NIH because of their medical
condition.

- Pregnant patients are eligible to participate in the study. However, they may not take
part in some tests, for example stable isotope studies.

- The principal investigator may decline to enroll a patient for other reasons. Other
criteria that may lead to exclusion include, for example, residing in a hospital,
suboptimal metabolic control as determined by Dr. Venditti's review of the laboratory
data, any patient who requires dialysis once or more in a week and weighs less than 40
kg, any patient who is being treated for an intercurrent infection with antibiotics or
has evidence of an acute infection, and any patient who does not have a regular/local
metabolic, genetic or endocrine physician and/or a family physician, pediatrician, or
internist.