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Clinical and Basic Investigations of Methylmalonic Acidemia (MMA) and Related Disorders
MMA General Information
What is methylmalonic acidemia?
Methylmalonic acidemia is an inherited disorder in which the body is unable to
process certain proteins and fats (lipids) properly. People with this disease
can't change, or "metabolize," an enzyme called methymalonyl-coenzyme
A. The result is a buildup of methylmalonic acid in the body.
The effects of methylmalonic acidemia vary from mild to life-threatening. This
condition, which usually appears in early infancy or diagnosed in the first year
of life, is characterized by vomiting, dehydration, weak muscle tone (hypotonia),
and excessive tiredness (lethargy). Without treatment, the disorder can lead to
coma and death in some cases. This condition occurs in 1 in 25,000 to 48,000 people.
What causes methylmalonic acidemia?
Mutations in the MMAA, MMAB, and MUT genes cause methylmalonic acidemia.
About half of methylmalonic acidemia cases are caused by mutations in the MUT
gene. This gene provides instructions for making an enzyme called methylmalonyl
CoA mutase, which is responsible for one step in the breakdown of several amino
acids (the building blocks of proteins), certain lipids, and cholesterol. Mutations
in the MUT gene alter the 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,
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. Mutations that change
the structure of methylmalonyl CoA mutase but do not eliminate its activity
cause a form of the condition designated mut-.
Other cases of methylmalonic acidemia are caused by mutations in the MMAA
or MMAB genes. To function properly, methylmalonyl CoA mutase must
work together with the proteins made by these genes. Mutations that affect either
of these proteins can impair the activity of methylmalonyl CoA mutase, leading
to methylmalonic acidemia.
Other genes that have not yet been identified may also cause methylmalonic
acidemia.
How do people inherit methylmalonic acidemia?
This condition is inherited in an autosomal recessive pattern, which means
two copies of a specific gene in each cell are altered so defective gene must
be inherited from both parents. Most often, the parents of an individual with
an autosomal recessive disorder are carriers of one copy of the altered gene
but do not show signs and symptoms of the disorder. Both boys and girls are
equally affected.
What is the risk of having methylmalonic acidemia if another family member
has it?
Methylmalonic acidemia is inherited in an autosomal recessive manner, meaning
two copies of the gene mutation must be present at a certain location on one
of the 22 pairs of chromosomes for there to be observable symptoms of the disease
in a particular individual. At conception, each sibling of an affected individual
has a 25 percent chance of being affected, a 50 percent chance of being an asymptomatic
carrier, and a 25 percent chance of being unaffected and not a carrier.
Once an at-risk sibling is known to be unaffected, the risk of his/her being
a carrier is 2/3 (66 percent). Carriers are asymptomatic. The offspring of an
individual with methylmalonic acidemia are carriers for a disease-causing mutation.
Each sibling of an individual with methylmalonic acidemia is at a 50 percent
risk of being a carrier.
How do doctors care for people with methylmalonic acidemia?
Methylmalonic acidemia is treated primarily with a low-protein, high-calorie diet,
certain medications, antibiotics and in some cases organ transplantation. Medication
treatment consists of dietary supplementation with cobalamin, carnitine, and protein
restriction. If cobalamine supplementation doesn't help, a diet restricting isoleucine,
threonine, methionine, and valine may be useful.
Is there a cure for methylmalonic acidemia?
There is no cure for methylmalonic acidemia and unfortunately, affected patients
may not survive their first attack.
Last Reviewed: May 30, 2008
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