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

Brief Title

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

Official Title

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

Brief Summary


      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.


      To learn more about propionic acidemia and the genes that might contribute to it.


      People at least 2 years old with PA who can travel to the clinic

      Some unaffected family members


      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.

Detailed Description

      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

      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, 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.

Study Type


Primary Outcome

Natural history to asess long term complications of Propionic Acidemia


Metabolic Disease

Study Arms / Comparison Groups

 Affected Patients with Propionic Acidemia
Description:  Patients with Propionic Acidemia, standard adult, parental permission


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

November 29, 2016

Completion Date

August 31, 2036

Primary Completion Date

August 31, 2036

Eligibility Criteria


          -  Patients 2 years of age or older, of any gender and ethnicity, with propionic acidemia
             are eligible to enroll in this protocol. Patients diagnosis will be confirmed based on
             biochemical and/or molecular and enzymatic testing. Participants of any gender and
             ethnicity over 1 month of age are eligible to enroll remotely for collection of
             outside records and natural history data. They will be eligible to enroll in the full
             study for in-person evaluation at 2 years of age.

          -  Unaffected family members over 1 month of age, of any ethnicity or race, may be
             included in the study as household controls for microbiome studies and/or for genetic
             analysis. Studies in unaffected family members may include collection of medical and
             family history; if necessary completion of physical examination; drawing of blood for
             research purposes include testing of DNA; collection of stool samples for microbiome
             studies; collection of dietary history using pen- and- paper or electronic food diary
             and questionnaires; collection of saliva for metabolite and DNA analysis. In some
             unaffected family members without a known familial cause of propionic acidemia, exome
             sequencing or genome sequencing could be performed. Unaffected family members will not
             receive direct benefit from taking part in the study.

          -  If a participant becomes pregnant while on study, the participant can remain on study.
             The only way to learn more about the critical biological differences in those who
             affected with propionic acidemia who are pregnant is to continue to follow pregnant
             women on study.

        However, no tests or procedures that are greater then minimal risk will be performed.
        Affected subjects who are pregnant may undergo procedures as part of their clinical care,
        including blood draws, genetic studies, and consultations, according to the clinical
        judgement of the clinical team. However, pregnant participants will be excluded from
        procedures such as organ tissue collection, stable isotope studies, GFR testing, and brain
        or cardiac MRI until the pregnancy is concluded.

          -  Healthy volunteers may be eligible to participate in the study if they are between 12
             40 years of age, must meet specific BMI criteria (similar to affected individuals

          -  Patients with propionic acidemia over 1 month of age, of any gender and ethnicity,
             undergoing a transplantation surgery at Children s Hospital of Pittsburgh, are
             eligible to participate in the tissue collection arm of the study.


          -  The PI/AI may decline to enroll a patient because of poor metabolic control, lack of a
             primary metabolic/genetics physician, and intercurrent infection are exclusion
             criteria for this protocol, the likelihood that an acutely ill or poorly controlled
             patient will enroll will be minimized.

          -  A subset of participants may be enrolled in the tissue collection part of the study
             only (i.e. if they are too sick to travel). We can may also arrange limited remote
             consultation with our research team and NIH consultants, the participants referring
             physician and the participant/their legal guardian through the telephone or an NIH
             supported telehealth platform for participants who are unable to safely travel to NIH.
             This would not replace a study visit but would be used when travel isn t possible due
             to extenuating circumstances (e.g. pandemic). Participants would be encouraged to
             follow-up for a more thorough in-person evaluation when they are able to travel to

          -  For the healthy volunteers, they will be excluded if they have halitosis, cavities,
             dental or gingival problems, respiratory diseases (for example, asthma or recent
             history of COVID19), use tobacco products (for example, cigarette smoking or chewing
             tobacco), or use electronic nicotine delivery systems (for example, use of
             e-cigarettes or vaping devices), as this may interfere with accurate measurement of
             their volatile organic compounds. NIH staff and their family members

        will be eligible to participate in the healthy volunteer portion of the study.




8 Months - 100 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers


Charles P Venditti, M.D., (301) 496-6213, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Human Genome Research Institute (NHGRI)

Study Sponsor

Charles P Venditti, M.D., Principal Investigator, National Human Genome Research Institute (NHGRI)

Verification Date

May 26, 2021