Clinical and Laboratory Study of Methylmalonic Acidemia
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.
- Organic Acidemia
- Methylmalonic Acidemia
- Inborn Errors of Metabolism
- Eligible Ages
- Over 2 Years
- Eligible Genders
- Accepts Healthy Volunteers
Patients of any gender, ethnicity, and age over 2 years of age with methylmalonic acidemia and cobalamin disorder are eligible to enroll in this protocol at the NIH Clinical Center. Affected individuals under the age of 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 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 type of MMA.
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, and 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 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. 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 this disorders in pregnant participants. 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, DEXA, X-rays 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 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 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 Type
- Observational Model
- Time Perspective
|Methylmalonic Acidemia||Individuals with methylmalonic acidemia|
Children's National and nearby locations
- NCT ID
- National Human Genome Research Institute (NHGRI)
Study ContactJennifer Sloan, Ph.D.
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 who have increased methylmalonic acid and/or homocysteine in the blood caused by urine or by mutation(s)in recently identified (ACSF3) and unknown genes.
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.