Acidemia, Methylmalonic

National Organization for Rare Disorders, Inc.

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Disorder Subdivisions

  • None

General Discussion

The methylmalonic acidemias are organic acidemias caused by an enzymatic defect in the metabolism of four amino acids (methionine, threonine, isoleucine and valine). This results in an abnormally high level of acid in the blood (academia) and body tissues. In the acute form, drowsiness, coma, and seizures may occur. Mental retardation is a long-term consequence. The disorder may be caused by a deficiency of one or more of the enzymes methylmalonyl CoA mutase, methylmalonyl racemase, or adenosylcobalamin synthetic enzymes. Excretion of methylmalonate, a product of amino acid metabolism, in the urine is abnormally high and therefore is a marker of the disorder. All known organic acidemias are inherited as autosomal recessive traits.


The onset of the Methylmalonic Acidemias usually occurs during the first few months of life although onset to late childhoods has been described. Symptoms may include lethargy, failure to thrive, recurrent vomiting, acidosis, dehydration, respiratory distress, diminished muscle tone, developmental retardation, seizures and/or an enlarged liver.

Laboratory findings include an abnormally high amount of methylmalonic acid in the blood and urine. Metabolic acidosis also occurs. Elevated levels of ketone bodies such as acetone in the blood (ketonemia) or in the urine (ketonuria) may develop. An elevated level of ammonia in the blood (hyperammonemia) may also be present. Excessive levels of the amino acid, glycine in the blood (hyperglycinemia) and in the urine (hyperglycinuria) is found. The concentration of white blood cells, blood platelets and red blood cells may be lower than normal. Low blood sugar (hypoglycemia) may also occur.


Researchers at the University of Calgary and McGill University in Canada announced in December 2002 that they had identified genes that underlie two severe forms of methylmalonic academia. This discovery should make possible DNA testing for carriers and prenatal diagnosis, which is important because treatment can be started during pregnancy.

All known organic acidemias are inherited as autosomal recessive traits. Human traits including the classic genetic diseases are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. On average, 50 percent of their children will be carriers of the disease but will not show symptoms of the disorder, while 25 percent will receive a normal copy of the gene from each parent. These risks are the same for each pregnancy.

Affected Populations

The Methylmalonic Acidemias occur at a rate of 1 in 50,000 to 1 in 100,000 live births.


Methylmalonic Acidemias can usually be diagnosed before birth (prenatally) by measuring the concentration of methylmalonic acid in amniotic fluid or activity of the deficient enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]). During amniocentesis, a sample of fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta. The disorder can be identified at birth through expanded newborn screening with tandem mass spectrometry.

In most affected infants, the disorder is diagnosed or confirmed in the first weeks of life, based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests. Laboratory studies (assays) are typically conducted on certain white blood cells (leukocytes) or cultured skin cells (fibroblasts) to confirm deficient activity of the deficient enzyme. Additional laboratory studies may reveal excessive levels of acids and increased accumulations of ketone bodies in bodily tissues and fluids (ketoacidosis), increased levels of glycine in the blood and urine (hyperglycinemia and hyperglycinuria), high levels of ammonia in the blood (hyperammonemia), and/or decreased levels of circulating platelets and white blood cells (thrombocytopenia and neutropenia).

Standard Therapies


The diet of children with Methylmalonic Acidemias must be carefully controlled. Treatment includes a low-protein diet and avoidance of the amino acids isoleucine, valine, threonine and methionine. To assure a balanced diet, certain medical foods must be fed to affected children. Massive doses of vitamin B12 are indicated in the B12-responsive variants. In the disorders of cobalamin metabolism, administration of intramuscular and/or oral hydroxycobalamin may correct the defect and restore normal metabolism.

Genetic counseling is recommended for the families of children with Methylmalonic Acidemias.

Investigational Therapies

The National Center for Research Resources is sponsoring a study at the Mt. Sinai Medical Center in New York City, entitled Diagnostic and Screening Study of Genetic Disorders. One purpose of this study is to develop and evaluate novel methods for the treatment of metabolic disorders. Methylmalonic acidemia is one of the disorders in which the investigators are interested, and they are recruiting participants.

For further information, please contact:

Dr. Judith P. Willner, Study Chair

Mount Sinai School of Medicine,

New York, NY 10029

Tel: (212) 241-6947

Information on current clinical trials is posted on the Internet at All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010


For information about clinical trials sponsored by private sources, contact:



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Varvogli L, Repetto GM, Waisbren SE, Levy HL. High cognitive outcome in an adolescent with mut(-) methylmalonic acidemia. Am J Med Genet. 2000;96:192-95.

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van der Meer SB, Poggi F, Spada M, et al. Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr. 1994;125:903-08.

Dobson CM, Wai T, Leclerc D, et al. Identification of the gene responsible for the cblB complementation group of vitamin B(12)-dependent methylmalonic aciduria. Hum Mol Genet. 2002 Dec 15;11(26):3361-9.


McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 251000; Last Update: 11/17/1999.

eMedicine - Methylmalonic Acidemia : Article by Olaf A Bodamer, MD

Methylmalonic acidemia - Genetics Home Reference

Supporting Organizations

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building
176 Nantwich Road
Crewe, CW2 6BG
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Tel: 4408452412173
Fax: 4408452412174
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Genetic and Rare Diseases (GARD) Information Center

PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
Website: //

NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison
Bldg 31, Rm 9A06
Bethesda, MD 20892-2560
Tel: (301)496-3583
Website: //

Organic Acidaemias UK

5, Saxon Road
Middlesex, TW15 1QL
United Kingdom
Tel: 4401784245989
Website: //

Organic Acidemia Association

9040 Duluth Street
Golden Valley, MN 55427
Tel: (763)559-1797
Fax: (763)694-0017
Website: //

Taking Action Against Language Disorders for Kids (TALK)

22980 Donna Lane
Bend, OR 97701
Tel: (541)389-0004
Fax: (503)389-0004

The Arc

1825 K Street NW, Suite 1200
Washington, DC 20006
Tel: (202)534-3700
Fax: (202)534-3731
Tel: (800)433-5255
Website: //

For a Complete Report

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