Methylmalonic acidemia (methylmalonyl-CoA mutase) is caused by changes in the MMUT gene. The MMUT gene gives your body instructions for making the enzyme methylmalonyl CoA mutase.

Without a working MMUT gene, your baby's body cannot make enough working methylmalonyl CoA mutase. As a result, their body has trouble breaking down proteins, lipids, and cholesterol. Their body cannot make enough energy, and harmful toxins build up and damage their body.

Normal Function

The MMUT gene provides instructions for making an enzyme called methylmalonyl CoA mutase. This enzyme is active in mitochondria, which are specialized structures inside cells that serve as energy-producing centers.

Methylmalonyl CoA mutase is responsible for a particular step in the breakdown of several protein building blocks (amino acids), specifically isoleucine, methionine, threonine, and valine. The enzyme also helps break down certain types of fats (lipids) and cholesterol. First, several chemical reactions convert the amino acids, lipids, or cholesterol to a molecule called methylmalonyl CoA. Then, working with a compound called adenosylcobalamin (AdoCbl), which is a form of vitamin B12, methylmalonyl CoA mutase converts methylmalonyl CoA to a compound called succinyl-CoA. Other enzymes break down succinyl-CoA into molecules that are later used for energy.

Health Conditions Related to Genetic Changes

Methylmalonic acidemia

More than 200 mutations in the MMUT gene have been identified in people with methylmalonic acidemia, a condition characterized by feeding difficulties, developmental delay, and long-term health problems. These genetic changes prevent the production of functional methylmalonyl CoA mutase or reduce the activity of the enzyme. As a result, certain proteins and lipids are not broken down properly. This defect allows methylmalonyl CoA and other toxic compounds to build up in the body's organs and tissues, causing the signs and symptoms of methylmalonic acidemia.

Mutations that prevent the production of any functional methylmalonyl CoA mutase lead to a form of methylmalonic acidemia designated mut0. Mut0 is the most severe form of this disorder and has the poorest outcome. Mutations that alter the structure of the enzyme but do not completely eliminate its activity lead to a form of the condition designated mut-. The mut- form is typically less severe, with more variable symptoms than the mut0 form.

Other Names for This Gene

• MCM
• methylalonyl-CoA mutase
• methylamlony-CoA isomerase
• methylmalonyl CoA mutase
• methylmalonyl Coenzyme A mutase
• methylmalonyl Coenzyme A mutase precursor
• MUT
• MUTA_HUMAN

Genomic Location

Methylmalonic acidemia is a genetic condition. Babies inherit it from their biological (birth) parents.

• Methylmalonic acidemia is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking MMUT gene to their baby. Only babies with two nonworking MMUT genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the MMUT gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the MMUT gene, they have a 1 in 4 chance of having a child with methylmalonic acidemia.
  • Carriers for methylmalonic acidemia often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with methylmalonic acidemia.
  • Parents who already have a child with methylmalonic acidemia still have a 1 in 4 chance of having another child with methylmalonic acidemia. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of methylmalonic acidemia can vary widely and usually start within the first few days to months of life. Symptoms can be caused by eating foods that the body cannot break down or by long periods without eating. Symptoms can also be brought on by illness or infection. Milder forms of methylmalonic acidemia may not appear until later in infancy or childhood.

Signs of the condition may include the following:

• Vomiting
• Dehydration
• Weak muscle tone (hypotonia)
• Breathing problems
• Tiredness or lack of energy (lethargy)
• Enlarged liver (hepatomegaly)
• Development delay

Newborn screening for methylmalonic acidemia is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of certain substances (called acylcarnitines) are in your baby’s blood. Your body produces these substances when it breaks down fats. Specific organic acids (called methylmalonic acid and methylcitric acid) may also be measured. Babies with high levels of these substances might have methylmalonic acidemia.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for methylmalonic acidemia is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need any of the following tests after an out-of-range screening result:

• Blood and urine tests
• Genetic testing using a blood sample
• Small skin sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have very serious health problems early in life if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen. Some situations can affect screening results, including:

• Babies who were born early (premature)
• Babies who were given carnitine
• Babies with high levels of bilirubin in their blood (hyperbilirubinemia)
• Babies whose mothers have low levels of vitamin B-12 (B-12 deficiency)

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Diet low in certain proteins and fats
• Special formulas and foods
• Regular and frequent meals and snacks
• Vitamin B-12 supplements (only for certain types of methylmalonic acidemia), usually given by a shot (injection) rather than by mouth
• Carnitine supplements in some cases

Children who receive early and ongoing treatment for methylmalonic acidemia can have healthy growth and development. Even with treatment, some children may still have developmental delays or learning difficulties.