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.

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Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with cb1A, cb1B 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 (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class - cobalamin C (cb1C), D and F - and are also heterogenous, clinically and biochemically. The genetic disorders underlying cb1E and cb1G 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, ophthalmologic 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 MMA 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 Acid Association. All patients will be evaluated at the NIH clinical center. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.

• Amino Acid Metabolism
• Inborn Errors

• Levy HL, Albers S. Genetic screening of newborns. Annu Rev Genomics Hum Genet. 2000;1:139-77. Review.
• Chace DH, Kalas TA, Naylor EW. The application of tandem mass spectrometry to neonatal screening for inherited disorders of intermediary metabolism. Annu Rev Genomics Hum Genet. 2002;3:17-45. Epub 2002 Apr 15. Review.
• Bobik TA, Rasche ME. Identification of the human methylmalonyl-CoA racemase gene based on the analysis of prokaryotic gene arrangements. Implications for decoding the human genome. J Biol Chem. 2001 Oct 5;276(40):37194-8. Epub 2001 Jul 31.

• INCLUSION CRITERIA:

Patients of any gender and ethnicity age 2 and older are eligible to enroll in this protocol. 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.

EXCLUSION CRITERIA:

Patients will be excluded if they cannot travel to the NIH because of their medical condition or are less than 2 years of age. 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 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.