Methylmalonic Acidemia

Author: roberta trapani
Date: 09/03/2013



A metabolic disorder resulting from an enzyme deficiency and characterized by the presence of excessive amounts of methylmalonic acid in the urine; it can be congenital (genetic causes) or acquired (nutritional causes) because of a severe alimentary deficiency of vitamin B12 . methylmalonic acidemia

Methylmalonic acid :



This condition occurs in an estimated 1 in 50,000 to 100,000 people. About 1 in 25,000 - 48,000 babies are born with this condition. Medline Plus,methylmalonic acidema, 2013 However, the actual rate may be higher, because a newborn may die before the condition is ever diagnosed. Methylmalonic acidemia affects boys and girls equally.


The effects of methylmalonic acidemia, which usually appear in early infancy, vary from mild to life-threatening. Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delay, excessive tiredness (lethargy), an enlarged liver (hepatomegaly), and failure to gain weight and grow at the expected rate. Genetics Home Reference, Methymalonic acidemia,2011


Exams and Tests :

Testing for methylmalonic acidemia is often done as part of a newborn screening exam. The U.S. Department of Health and Human Services recommends screening for this condition at birth because early detection and treatment has been shown to be beneficial.

Tests that may be done to diagnose this condition include: Genetics Home Reference, Methylmalonic acidemia, 2011

Ammonia test

Blood gases

Complete blood count

CT scan or MRI of the brain

Electrolyte levels

• Genetic testing

Methylmalonic acid blood test

Plasma amino acid test


Genetic causes : Methylmalonic acidemia ( MMA ), also called methylmalonic aciduria, is an autosomal recessive metabolic disorder in which the body is unable to process certain proteins and fats (lipids) properly. It is a classical type of organic acidemia . Methylmalonic acidemia
The defective gene is located on an autosome , and two copies of the gene—one from each parent—must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder. PubMed 2013,Methylmalonic acidemia

Mutations in the MUT , MMAA , MMAB , MMADHC , and MCEE genes cause methylmalonic acidemia. The long term effects of methylmalonic acidemia depend on which gene is mutated and the severity of the mutation.
About 60 percent of methylmalonic acidemia cases are caused by mutations in the MUT gene. This gene provides instructions for making an enzyme called methylmalonyl CoA mutase . This enzyme works with vitamin B12 (also called cobalamin) to break down several protein building blocks (amino acids), certain lipids, and cholesterol. Mutations in the MUT gene alter the enzyme's structure or reduce the amount of the enzyme, which prevents these molecules from being broken down properly. As a result, a substance called methylmalonyl CoA and other potentially toxic compounds can accumulate in the body's organs and tissues, causing the signs and symptoms of methylmalonic acidemia.
Mutations in the MUT gene that prevent the production of any functional enzyme result in a form of the condition designated mut0 . Mut0 is the most severe form of methylmalonic acidemia and has the poorest outcome. Mutations that change the structure of methylmalonyl CoA mutase but do not eliminate its activity cause a form of the condition designated mut- . The mut- form is typically less severe, with more variable symptoms than the mut0 form.

Some cases of methylmalonic acidemia are caused by mutations in the MMAA , MMAB , or MMADHC gene. Recent studies have identified the involvement of an accessory protein called MMAA , which interacts with methylmalonyl-CoA mutase ( MCM ) to prevent MCM's inactivation or acts as a chaperone to promote regeneration of inactivated enzyme. Proteins produced from the MMAA , MMAB , and MMADHC genes are needed for the proper function of methylmalonyl CoA mutase. Mutations that affect proteins produced from these three genes can impair the activity of methylmalonyl CoA mutase, leading to methylmalonic acidemia.
A few other cases of methylmalonic acidemia are caused by mutations in the MCEE gene. This gene provides instructions for producing an enzyme called methylmalonyl CoA epimerase . Like methylmalonyl CoA mutase, this enzyme also plays a role in the breakdown of amino acids, certain lipids, and cholesterol. Disruption in the function of methylmalonyl CoA epimerase leads to a mild form of methylmalonic acidemia. Genetics Home Reference, Methylmalonic acidemia, 2011


The following are the known genotypes responsible for methylmalonic acidemia :

DatabasecblA typecblB typecblC typecblD typecblF typemut type

MMAA and MMAB Aminoacids Percentage

MUT, MMACHC, MMADHC and LMBRD1 Aminoacids Percentage

It is likely that mutations in other, unidentified genes also cause methylmalonic academia.

Nutritional causes : Methylmalonyl CoA requires vitamin B12 to form succinyl-CoA. When the amount of B12 is insufficient for the conversion of cofactor methylmalonyl-CoA into succinyl-CoA, the buildup of unused methylmalonyl-CoA eventually leads to methylmalonic acidemia. This diagnosis is often used as an indicator of vitamin B12 deficiency in serum. Cobalamin (Vitamin B12) plays also an essential role in the synthesis of methionine (Met) from homocysteine (Hcy). Vitamin B(12) is an organometallic compound with important metabolic derivatives that act as cofactors of certain enzymes, which have been grouped into three subfamilies depending on their cofactors. Among them, methylmalonyl-CoA mutase (MCM) has been extensively studied. This enzyme catalyzes the reversible isomerization of L-methylmalonyl-CoA to succinyl-CoA using adenosylcobalamin (AdoCbl) as a cofactor participating in the generation of radicals that allow isomerization of the substrate. PubMed 2012,Methylmalonic acidemia


Long-term complications can include feeding problems, intellectual disability, chronic kidney disease, and inflammation of the pancreas (pancreatitis). Without treatment, this disorder can lead to coma and death in some cases. Genetics Home Reference, Methymalonic acidemia, 2011


Treatment consists of cobalamin and carnitine supplements and a low-protein diet. The child's diet must be carefully controlled.
If supplements do not help, the doctor may also recommend a diet that avoids substances called isoleucine , threonine , methionine , and valine .
Liver or kidney transplantation (or both) have been shown to help some patients. These transplants provide the body with new cells that help breakdown methylmalonic acid normally.

Health Guide, Methylmalonic acidemia,2013

Therapy :
Infants and children with methylmalonic acidemia ( MMA ) are at increased risk for metabolic decompensation particularly during episodes of increased catabolism (eg. intercurrent infections, trauma, surgery, psychosocial stress). During these episodes, provide treatment that is swift and directed towards reversing catabolism and promoting anabolism:

• Limit protein catabolism during acute metabolic crises. Stop usual protein intake and intravenously administer generous fluid and glucose (4-8 mg/kg/min, depending on age) if necessary. Cessation of protein intake should last for no longer than 24 hours.
• Continue medication and increase carnitine intake to 200-300 mg/kg/d intravenously if necessary.
• Provide appropriate treatment of concurrent illnesses (eg. infections).
• Provide early reintroduction of protein intake (within 1-2 d after onset of acute decompensation).
• Consider hemodialysis or hemofiltration for persistent hyperammonemia and/or metabolic acidosis.

MedScape, Methylmalonic acidemia, 2011

Clinical Trial about Methylmalonic Acidemia
Clinical analysis of organic acidemia in neonates from neonatal intensive care units , 2012 May


To study the clinical features of organic acidemia in neonates admitted to the intensive care unit.
The clinical features of neonates from 15 neonatal intensive care units of Henan Province, who were diagnosed with congenital organic acidemia by gaschromatography-mass spectrometry (GC-MS) between June 2008 and August 2011 were retrospectively reviewed.
Fifty neonates of 287 high risk neonates were confirmed as having or highly suspected to have inborn errors of metabolism. Of the 50 cases, 32 cases were diagnosed with organic acidemia disease, including 28 cases of methylmalonic acidemia, 2 cases of propionic acidemia, 1 case of maple syrup urine disease and 1 case of isovaleric acldemla. In most cases, disease onset occurred in the first week after birth in most of cases (75%). Neonates whose symptoms occurred immediately after or within a few hours of birth presented with serious conditions. Clinical manifestations were various and mainly related to neurologic, respiratory and gastrointestinal symptoms such as poor response, coma, drowsiness, abnormal muscle tone, convulsions, polypnea, dyspnea, milk refusal, diarrhea and jaundice. Initial symptoms were non-specific and included dyspnea, poor response, milk refusal, lethargy and seizures.

Methylmalonic acidemia is a common inherited metabolic disease in the neonatal period. Clinical manifestations of organic acid metabolism abnormalities in neonates are atypical and early onset is associated with more serious conditions.

PubMed ,Clinical analysis of organic acidemia in neonates from neonatal intensive care units, May 2012

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