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

Further Study Details: 

Expected Total Enrollment:  600

Inborn errors of metabolism comprise a heterogeneous group of genetic disorders that collectively are relatively common in the population. Many are associated with significant childhood morbidity and mortality as well as substantial health care utilization. Modern newborn screening methodologies that utilize tandem mass spectrometry (MS/MS) have allowed the diagnosis of presymptomatic, affected patients with various metabolic disorders. However, limited progress has been made to develop new treatments, in part because the natural histories of the disease states are not fully understood. One group of inborn errors, the hereditary methylmalonic acidemias (MMA), appears prototypical in this regard as patients can now be diagnosed via increased propionylcarnitine on newborn screening.

Methylmalonic acidemia is heterogeneous, clinically and biochemically. Several different complementation groups exist. The isolated methylmalonyl-CoA mutase deficiency disorders, defined by the cblA, cblB, cblH, and mut complementation classes, share a common defect in the activity of the adenosylcobalamin-dependent enzyme, methylmalonyl-CoA mutase. Affected patients exhibit extreme elevations of methylmalonic acid in all tissues and body fluids and are metabolically fragile. No definitive treatment exists, although some patients have benefited from liver, kidney, and combined hepato-renal transplantation. Among the complications of isolated MMA, the high incidence of mental retardation and propensity toward basal ganglia infarctions of the brain, growth problems, and renal disease stand out as areas that require epidemiological definition, clinical characterization and scientific analysis.

The cobalamin deficiency disorders, cobalamin C (cblC), cobalamin D (cblD), and cobalamin F (cblF) all exhibit a combined deficiency of the two vitamin B12-dependent enzymes, methylmalonyl-CoA mutase and methionine synthase. The pathophysiological features of these disorders are likely related to an impaired transsulfuration cycle, since the patients have hyperhomocyst(e)inemia in body fluids and tissues with concomitant hypomethioninemia. There is great clinical heterogeneity in these disorders, with presentations ranging from crisis in the neonatal period, to reversible dementia in adolescence. Patients suffer from multi-organ system involvement and would greatly benefit from prospective clinical characterization and scientific investigation, especially since the underlying genetic defects remain unknown.

Two other cobalamin disorders, cobalamin E (cblE) and cobalamin G (cblG), affect only the transmethylation pathway. These defects reside in methionine synthase reductase (cblE) or methionine synthase (cblG). Careful characterization of patients with these extremely rare inborn errors will help delineate the basis of the clinical heterogeneity seen in the combined defects.

In this protocol, we will clinically evaluate patients with methymalonic acidemia and cobalamin 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 inpatient admissions will last 4-5 days and occur every year. They will involve urine collection, blood drawing, ophthalmologic examination, radiological procedures, skin biopsies, 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.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
MMA patients of any gender and ethnicity age 2-70 years 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.

Maryland
      National Human Genome Research Institute (NHGRI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  040127; 04-HG-0127
Record last reviewed:  December 2, 2004
Last Updated:  January 28, 2005
Record first received:  February 18, 2004
ClinicalTrials.gov Identifier:  NCT00078078
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08