NHGRI logo

The Clinical and Basic Investigations of Methylmalonic Acidemia study will evaluate patients with MMA and related disorders to learn more about the genetic causes of the various types of these inherited metabolic disorders and the medical complications associated with them.

Goals of the Study

People with Methylmalonic Acidemia (MMA) and cobalamin disorders may have difficulty with growth and development, neurological problems such as strokes, seizures and low muscle tone, kidney problems, poor vision, and metabolic instability causing them to become seriously ill, sometimes with little warning. There is no cure for any type of MMA, but special diets, vitamin therapies and in some patients, organ transplantation, are used for treatment.

This study will evaluate patients with MMA and cobalamin disorders to learn more about the genetic causes of these inherited metabolic disorders and the medical complications associated with them. People with MMA may have difficulty with growth and development, neurological problems such as strokes, seizures and low muscle tone, kidney problems, poor vision, and metabolic instability causing them to become seriously ill, sometimes with little warning. There is no cure for any genetic MMA syndrome, but special diets, medication and vitamin therapies are used for treatment.

The study seeks to learn more about the genetic causes of the various types of these inherited metabolic disorders and the medical complications associated with them by clinically evaluating patients with methymalonic acidemia and cobalamin (vitamin B12) metabolic defects. By better understanding the complications, we may gain insight into what causes them. This knowledge may help guide the development of new therapies and provide more precise ways to assess how effective current medical regimens are working.

What are we not trying to do?

  1. We are not testing any new medication or procedure to treat or cure MMA.
  2. At the National Institutes of Health, we are interested in research. Although we are happy to provide advice for people enrolled in our study, we are not able to "take over" the long-term care of a person with MMA
  3. To enroll in our study, a person needs a confirmed diagnosis of MMA. We are not able to provide a "first time" diagnosis or regular metabolic care.

Eligibility and Enrollment

To enroll in our study, a person must:

  1. Be between 2 and 70 years of age.
  2. Be able to travel to and be admitted to the NIH Clinical Center in Bethesda, Maryland for 4 to 5 days each year for 5 to 10 years.
  3. Have a diagnosis of mut, cblA, cblB, cblC, cblD, or cblF type MMA based on complementation status determination in cultured fibroblasts and/or genetic testing. We are also interested in evaluating patients with elevated homocysteine due to cblE and cblG deficiencies. Some patients who have not yet had these laboratory tests will be admitted to the protocol based upon metabolic parameters, such as MMA and/or homocysteine levels in the blood and/or urine, and clinical history. Dr. Venditti will determine patient eligibility when definitive testing has not been performed.

There are some reasons that may prevent you from joining the study. Patients will be excluded if they cannot travel to the NIH because of their medical condition or are less than 2 years of age. Other criteria that may lead to exclusion include: sub-optimal metabolic control as determined by Dr. Venditti's review of the laboratory data; residing in a hospital; any patient who requires dialysis once or more/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.

To participate in the study, patients will be admitted to the National Institutes of Health (NIH) Clinical Center for 4 to 5 days every year for 5 to 10 years and undergo the following tests and procedures:

  • A complete medical history, physical examination and eye examination.
  • Consultations from dentists and specialists for the nervous system, rehabilitation, digestive tract, endocrine and kidney, as needed.
  • A 24-hour urine collection to examine for methylmalonic acid, other acids, sugar and proteins to measure kidney function.
  • Blood tests to assess liver and thyroid function, blood counts and blood chemistries, methylmalonic acid levels, and for genetic tests and basic research studies.
  • In some patients, a blood test to measure growth hormone production as needed. A very small amount of blood is collected overnight (every 20 to 30 minutes from 8:00 p.m. to 8:00 a.m.) through an intravenous catheter (plastic tube placed in a vein). The total amount of blood drawn is approximately one tablespoon. Patients who have stopped growing or whose weight does not permit collection of one 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) if not already performed or if there is a need to repeat.
    • 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 the size of a pencil eraser 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 abdomen (kidneys, liver, spleen etc).
  • 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.
  • Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) of the brain. This is non-invasive but some patients may require sedation.

To enroll in the MMA study, contact Jennifer Sloan or Dr. Venditti for more information.

What is involved in the study?

In this study, we will clinically evaluate patients with methymalonic acidemia and cobalamin (vitamin B12) metabolic defects. We will define and characterize a patient population, obtain cells and urine, perform mutation analysis in known genes, and search for the causative genes when the molecular basis of the complementation class is uncertain.

Routine admissions will last 4 to 5 days and occur every year. Some patients may be seen on the outpatient clinic but most will be inpatient admissions. Evaluations will involve urine collection, blood drawing, ophthalmologic examination, radiological procedures such as abdominal ultrasound and brain MRI, and developmental and neurological testing. A skin biopsy will be only performed if it has not been done or there is a need for a repeat study. In a subset of patients who have or will receive kidney, liver or liver kidney transplants or have an unusual variant or clinical course, a lumbar puncture to examine CSF metabolites will be recommended. In this small group of patients, CSF metabolite monitoring may be used to adjust MMA therapy. All testing is optional for the participants.

Financial Considerations

The visits and all testing are free and there is no cost to you, your family or your insurance company for this study.

We will pay for most of your travel expenses. If you live locally (near the NIH) we will give you some money for meals and provide lodging if necessary. If you live further away, we will pay for your transportation to NIH (plane, car mileage, train, etc), lodging, and give you some money for meals. Travel must be arranged by NIH.

Participants in the study do not receive any compensation other than travel and lodging expenses.

Publications

Chandler, R. J. and Venditti, C. P. Genetic and genomic systems to study methylmalonic acidemia. Mol Genet Metab, 86(1-2):34-43. 2005. [PubMed]

Chandler, R. J. and Venditti, C. P. Adenovirus-mediated gene delivery rescues a neonatal lethal murine model of mut(0) methylmalonic acidemia. Hum Gene Ther, 19(1):53-60. 2008. [PubMed]

Chandler, R. J. et al. Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle. BMC Med Genet, 8:64. 2007. [PubMed]

Adams D., Venditti C.P. (February 2008) Disorders of Intracellular Cobalamin Metabolism. GeneReviews at GeneTests: Medical Genetics Information Resource [online database]. Copyright, University of Washington, Seattle, 1997-2008. [PubMed]

Chandler, R. J. et al. Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J, 23(4):1252-61. 2008. [PubMed]

Bassim, C. W. et al. Enamel defects and salivary methylmalonate in methylmalonic acidemia. Oral Dis, 15(3):196-205. 2009. [PubMed]

Carrillo-Carrasco N., Sloan J., Valle D., Hamosh A. and Venditti C.P. Hydroxycobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis, 32:728-731. 2009. [PubMed]

Manoli I, Venditti C.P.: Methylmalonic Acidemia (Sept 2010). GeneReviews at GeneTests: Medical Genetics Information Resource [online database]. Copyright, University of Washington, Seattle, 1997-2010. [PubMed]

Hauser N.S., Manoli, I., Graf J.C., Sloan J., and Venditti C.P. Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations. Am J Clin Nutr, 93(1):47-56. 2011. [PubMed]

Carrillo-Carrasco N., Chandler R.J., and Venditti C.P. Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. J Inherit Metab Dis, July 12, 2011. [PubMed]

Carrillo-Carrasco N. and Venditti C.P. Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology and outcomes. J Inherit Metab Dis, July 12, 2011. [PubMed]

Sloan J.L., Johnston J.J., Manoli I., Chandler R.J., Krause K., Carrillo-Carrasco N., Chandrasekaran S.D., Sysol J.R., O'Brien K., Hauser N.S., Sapp J.C., Dorward H.M., Huizing M., NISC, Barshop B.A., Berry S.A., James P.M., Champaigne N.L., de Lonlay P., Valayannopoulos V., Geschwind M.D., Gavrilov D.K., Nyhan W.L., Biesecker L.G., and Venditti C.P. Exome sequencing identifies ACSF3 as the cause of Combined Malonic and Methylmalonic Aciduria. Nature Genetics, 43(9):883-6. 2011. [PubMed]

MMA Resources

Contact

Charles P. Venditti, M.D., Ph.D.
Charles P. Venditti, M.D., Ph.D.
  • Senior Investigator
  • Medical Genomics and Metabolic Genetics Branch

Last updated: April 20, 2012