Clinical and Laboratory Study of Methylmalonic Acidemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )
ClinicalTrials.gov Identifier:
NCT00078078
First received: February 18, 2004
Last updated: May 14, 2014
Last verified: May 2014
  Purpose

This study will evaluate patients with methylmalonic acidemia (MMA) to learn more about the genetic causes of the various types of this inherited metabolic disorder and the medical complications associated with it. People with MMA may have problems with learning and development and kidney malfunctioning. They can become seriously ill, sometimes with little warning. There is no cure for any MMA, but special diets and vitamin therapies are used for treatment.

Patients between 2 and 70 years of age with MMA may be eligible for this study. Participants are admitted to the NIH Clinical Center for 4-5 days each year for 5-10 years for the following tests and procedures:

  • Medical history, physical examination, eye examination
  • Consultations from dentists and specialists in the nervous system, digestive tract, endocrine, and kidney, as needed.
  • 24-hour urine collection to examine for methylmalonic acid, other acids, sugar, and proteins for measuring kidney function.
  • Blood test to assess liver and thyroid function, blood counts and blood chemistries, methylmalonic acid levels, and for genetic tests and basic research studies.
  • Blood test to measure growth hormone production. For this test, a very small amount of blood is collected overnight (every 20-30 minutes from 8:00 PM to 8:00 AM) through an intravenous catheter (plastic tube placed in a vein). The total amount of blood drawn is approximately 1 tablespoon. Patients who have stopped growing or whose weight does not permit collection of 1 tablespoon of blood do not undergo this procedure.
  • Frequent blood pressure measurements, including overnight monitoring
  • Skin biopsy for cell culture (cells to grow in the laboratory for future testing). For this procedure, an area of skin is numbed with an anesthetic such as lidocaine. A 4-mm diameter circular area is then removed using a sharp punch and scissors. The wound is dressed and usually heals within a week.
  • Photographs of the face and body (wearing underwear) to help track growth and appearance.
  • Ultrasound of the kidneys
  • Hand x-ray to determine bone age
  • Dual energy x-ray absorptionometry (DEXA) scan to assess bone density. For the DEXA scan, the patient lies still on a table while the spine and hip are scanned using a small amount of radiation.

Any patient who becomes seriously ill during the evaluation may be cared for at the NIH or transferred to another hospital if it is deemed advisable.


Condition
Amino Acid Metabolism
Inborn Errors

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: Clinical and Basic Investigations of Methylmalonic Acidemia (MMA) and Related Disorders

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 1000
Study Start Date: February 2004
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 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. Rarely, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered intracellular metabolism of vitamin B12 produces another group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class cobalamin C (cblC), D and F 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. Lastly, a group of patients who have increased methylmalonic acid and/or homocysteine in the blood caused by mutation(s) in unknown genes exist.

In this protocol, we will clinically evaluate patients with methymalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions will last 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 associated with these enzymopathies, query for genotype/enzymatic/phenotype correlations and search for new genes in rare families that have evidence for an unknown class of methylmalonic acidemia and/or homocysteinemia. The population will consist of patients previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association. Most patients 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. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Patients of any gender, ethnicity, and age are eligible to enroll in this protocol. Affected individuals under the age of 2 years may be clinically 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. 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. Some patients who have not yet had this laboratory test 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 class of MMA. We will also obtain specimens for patients under 2 years old with a suspected diagnosis of combined malonic and methylmalonic aciduria (CMAMMA) for ACSF3 genetic testing because the NIH is the only center offering CLIA certified molecular diagnosis.

EXCLUSION CRITERIA:

Patients will be excluded if they cannot travel to the NIH or CNMC because of their medical condition. The PI may decline to enroll a patient for other reasons. Other criteria that may lead to exclusion include, for example, residing in a hospital, sub-optimal metabolic control as determined by Dr. Venditti s review of the laboratory 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, and any patient who may be metabolically unstable but not acutely ill. Each family may be contacted by Dr. Venditti or a staff member working with him one week prior to a pending inpatient 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00078078

Contacts
Contact: Charles P Venditti, M.D. (301) 496-6213 venditti@mail.nih.gov

Locations
United States, District of Columbia
Childrens National Medical Center Recruiting
Washington, District of Columbia, United States
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Charles P Venditti, M.D. National Human Genome Research Institute (NHGRI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )
ClinicalTrials.gov Identifier: NCT00078078     History of Changes
Other Study ID Numbers: 040127, 04-HG-0127
Study First Received: February 18, 2004
Last Updated: May 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Vitamin B12
Methylmalonic Acidemia
Hyperhomocysteinemia
MMA
Metabolic Disease

Additional relevant MeSH terms:
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases

ClinicalTrials.gov processed this record on July 23, 2014