Clinical and Laboratory Study of Methylmalonic Acidemia

April 10, 2024 updated by: National Human Genome Research Institute (NHGRI)

Clinical and Basic Investigations of Methylmalonic Acidemia (MMA) and Related Disorders

Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with cblA, cblB and mut classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current treatment protocol outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered transport and intracellular metabolism of vitamin B12 produces a distinct group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class (cblC, cblD, cblF, cblJ and cblX) and are also heterogenous, clinically and biochemically. The genetic disorders underlying cblE and cblG feature an isolated impairment of the activity of methionine synthase, a critical enzyme involved in the conversion of homocysteine to methionine and these disorders feature (hyper)homocysteinemia. Lastly, a group of patients can have increased methylmalonic acid and/or homocysteine in the blood or urine caused by variant(s)in recently identified (ACSF3) and unknown genes.

In this protocol, we will clinically evaluate patients with methylmalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions will last up to 4-5 days and involve urine collection, blood drawing, ophthalmological examination, radiological procedures, MRI/MRS, skin biopsies in some, and developmental testing. In a subset of patients who have or will receive renal, hepato- or hepato-renal transplants or have an unusual variant or clinical course and have MMA, a lumbar puncture to examine CSF metabolites will be performed. In this small group of patients, CSF metabolite monitoring may be used to adjust therapy.

The study objectives will be to further delineate the spectrum of phenotypes and characterize the natural history of these enzymopathies, query for genotype/enzymatic/phenotype correlations, search for new genetic causes of methylmalonic acidemia and/or homocysteinemia, identify new disease biomarkers and define clinical outcome parameters for future clinical trials.

The population will consist of participants previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association, Homocystinuria Network America and other national and international support groups. Most participants will be evaluated only at the NIH Clinical Center. However, if the NIH team decides that a patient under the age of 2 years is a candidate subject for this research protocol, that patient may enroll at the Children s National Medical Center (CNMC) site, pending approval by Dr Chapman, the Principal Investigator of the CNMC location Individuals may also enroll in the tissue collection only part of the study at the UPMC Children s Hospital of Pittsburgh or share medical history and clinical data via telemedicine visits remotely. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.

Study Overview

Status

Recruiting

Conditions

Detailed Description

Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with mut, cblA, and cblB classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered transport and intracellular metabolism of vitamin B12 produces a distinct group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class (cblC, cblD, cblF, cblJ and cblX) and are also heterogeneous, clinically and biochemically. The genetic disorders underlying cblE and cblG feature an isolated impairment of the activity of methionine synthase, a critical enzyme involved in the conversion of homocysteine to methionine and these disorders feature (hyper)homocysteinemia. Lastly, a group of patients can have increased methylmalonic acid and/or homocysteine and/or malonic acid in the blood or urine caused by variant(s) in recently identified (ACSF3) and unknown genes.

In this protocol, we will clinically evaluate patients with methylmalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions and outpatient evaluations will last up to 4-5 days and involve urine collection, blood drawing, ophthalmological examination, radiological procedures, MRI/MRS, skin biopsies in some, and developmental testing.

The study objectives will be to further delineate the spectrum of phenotypes and characterize the natural history of these enzymopathies, query for genotype/enzymatic/phenotype correlations, search for new genetic causes of methylmalonic acidemia and/or homocysteinemia, identify new disease biomarkers and define clinical outcome parameters for future clinical trials. The population will consist of participants previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association, Homocystinuria Network America and other national and international support groups. Most participants will be evaluated only at the NIH Clinical Center. However, if the NIH team decides that a patient under the age of 2 years is a candidate subject for this research protocol, that patient may enroll at the Children s National Medical Center (CNMC) site, pending approval by Dr. Chapman, the Principal Investigator of the CNMC location. Individuals may also enroll in the tissue collection only part of the study at the UPMC Children s Hospital of Pittsburgh or share medical history and clinical data via telemedicine visits remotely. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.

Study Type

Observational

Enrollment (Estimated)

2275

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • Recruiting
        • National Institutes of Health Clinical Center
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15224
        • Recruiting
        • UPMC Children's Hospital of Pittsburgh
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 month and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Individuals with methylmalonic acidemia

Description

  • INCLUSION CRITERIA:

Patients of any gender, ethnicity, and over 1 month of age with biochemical or genetic diagnosis of methylmalonic acidemia or cobalamin disorders are eligible to enroll in this protocol. The primary reason for expanding enrollment to young children is because individuals with cobalamin C deficiency (cblC) develop a maculopathy often in utero or early infancy yet the natural history of the disease progression in these early years has not been well defined. Our colleagues at the National Eye Institute have documented the retinal findings in the largest cohort of individuals with cblC and have developed an expertise in this disorder. A recent report suggests that early treatment may significantly improve the retinal disease and will be the focus of a future clinical trial at the NIH Clinical Center requiring a need for more natural history data from birth to early childhood. Children ages 1 month to 2 years or under 12 kg will be reviewed by the Pediatric Consult Service prior to scheduling and if approved will be evaluated in the outpatient clinic for limited evaluations blood draw, eye exam, consults. Affected infants that are not approved by the Pediatric Consult Service or are not stable enough to travel may enroll remotely by telemedicine to include in natural history data collection, such as medical history and laboratory result sharing and interpretation, molecular genetic testing, genetic counseling, nutrition consult with dietary food log analysis, neurocognitive assessments. Affected individuals of any of the other disorders under study, younger than 2 years may be evaluated at Children s National Medical Center (CNMC) as part of an evolving agreement in the Translational Program in Pediatrics, if they are deemed eligible for participation by the NIH team and the CNMC team. Patients will be diagnosed based on a determination of MMA and homocysteine levels in plasma and urine. Most will have their complementation class known or pending. Molecular genetic analyses to determine mutations will be expected to have been performed prior to acceptance into the study. Some patients who have not yet had these laboratory tests will be admitted to the protocol based upon metabolic parameters and clinical history. This latter category of patients might include individuals with a suspected genetic but unknown type of MMA.

EXCLUSION CRITERIA:

The PI/AI may decline to enroll a patient for reasons such as being medically unstable, residing in a hospital, sub-optimal metabolic control or for any concerns arising after review of the laboratory and clinical data; any patient who requires dialysis once or more/week and weighs <40 kg; any patient who is being treated for an intercurrent infection with antibiotics or has evidence of an acute infection and has metabolic symptoms; any patient who does not have a regular/local metabolic, genetic or endocrine physician and/or a family physician, pediatrician, or internist; any patient who may be metabolically unstable but not acutely ill; and any patient or family who may not be able to institute recommendations for appropriate testing and care before visiting the NIH. Each family may be contacted by the NIH team prior to a pending admission to confirm that the patient is metabolically stable and ready to visit the NIH in a state of relative health, with an adequate supply of special formulas, medications, supplements, and if needed, medical equipment such as feeding pumps and replacement parts for feeding tubes. A subset of participants will be enrolled in the tissue collection part of the study only (i.e. if they are too sick to travel).

Pregnant women may be eligible to enroll in the study if they are affected with methylmalonic acidemia or a cobalamin disorder or are family members of an affected subject. Pregnant women are not excluded because it is important to learn more about the effects of these disorders in pregnant participants and the fetus. This research involves no more than minimal risk to the fetus. Affected subjects who are pregnant or become pregnant during their participation on the study will not be withdrawn, but will be excluded from some procedures until the pregnancy is concluded. 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. Pregnant participants will be excluded from some procedures such as stable isotope, GFR testing, and MRI until the pregnancy is concluded.

Patients with methylmalonic acidemia or cobalamin disorders of any age, gender and ethnicity, undergoing a transplantation surgery at UPMC Children s Hospital of Pittsburgh, are eligible to participate in the tissue collection arm of the study. Pregnant women will be excluded from tissue collection at the UPMC Children s Hospital of Pittsburgh.

For the healthy volunteers, eligibility criteria include individuals that are age 18 and over.

Exclusion criteria include: women who are pregnant, individuals being treated with antibiotics, individuals with kidney or liver disease, individuals on a special diet such as a high protein diet or taking protein supplements and individuals with severe claustrophobia or other anxiety disorders.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Methylmalonic Acidemia
Individuals with methylmalonic acidemia

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Natural history to assess long term complications of disease
Time Frame: ongoing
assessing the complications of MMA during a week long evaluation with imaging, labs and consultations
ongoing

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Human Genome Research Institute (NHGRI)

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 7, 2004

Study Registration Dates

First Submitted

February 18, 2004

First Submitted That Met QC Criteria

February 18, 2004

First Posted (Estimated)

February 19, 2004

Study Record Updates

Last Update Posted (Actual)

April 11, 2024

Last Update Submitted That Met QC Criteria

April 10, 2024

Last Verified

March 11, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 040127
  • 04-HG-0127

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

.Study is observational natural history study that is ongoing with no defined endpoints.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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