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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02890342
Recruitment Status : Recruiting
First Posted : September 7, 2016
Last Update Posted : May 27, 2020
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Tracking Information
First Submitted Date September 3, 2016
First Posted Date September 7, 2016
Last Update Posted Date May 27, 2020
Actual Study Start Date November 29, 2016
Estimated Primary Completion Date August 31, 2036   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: March 10, 2020)
Natural history to asess long term complications of Propionic Acidemia [ Time Frame: Ongoing ]
assessing the long term complications of Propionic Acidemia during a week long evaluation with imaging, labs, and consultations.
Original Primary Outcome Measures
 (submitted: September 3, 2016)
The study is non-interventional, prospective [ Time Frame: Study Completion ]
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
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 [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, 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.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population Patients with Propionic Acidemia
  • Metabolic Disease
  • Propionic Acidemia
  • Organic Acidemia
Intervention Not Provided
Study Groups/Cohorts
  • Affected Patients with Propionic Acidemia
    Patients with Propionic Acidemia
  • Unaffected Family Members
    Unaffected family members
Publications * Shchelochkov OA, Manoli I, Sloan JL, Ferry S, Pass A, Van Ryzin C, Myles J, Schoenfeld M, McGuire P, Rosing DR, Levin MD, Kopp JB, Venditti CP. Chronic kidney disease in propionic acidemia. Genet Med. 2019 Dec;21(12):2830-2835. doi: 10.1038/s41436-019-0593-z. Epub 2019 Jun 28.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: April 30, 2020)
Original Estimated Enrollment
 (submitted: September 3, 2016)
Estimated Study Completion Date August 31, 2036
Estimated Primary Completion Date August 31, 2036   (Final data collection date for primary outcome measure)
Eligibility 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.


  • 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.
Sexes Eligible for Study: All
Ages 2 Years to 100 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contact: Susan C Ferry, R.N. (301) 496-6213
Listed Location Countries United States
Removed Location Countries  
Administrative Information
NCT Number NCT02890342
Other Study ID Numbers 160156
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )
Study Sponsor National Human Genome Research Institute (NHGRI)
Collaborators Not Provided
Principal Investigator: Charles P Venditti, M.D. National Human Genome Research Institute (NHGRI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date April 27, 2020