What Is Methylmalonic Acidemia?

Methylmalonic acidemia (MMA) is a rare and potentially fatal genetic disorder that affects metabolism and multiple body systems that affects about one in 100,000 infants. It's caused by a genetic defect that prevents the body from properly processing certain proteins.

This metabolic dysfunction leads to a buildup of methylmalonic acid in the body. Methylmalonic acidemia can cause coma and other serious symptoms if not correctly diagnosed and treated.

This article explains the symptoms of methylmalonic acidemia and how it is passed down within families. It also discusses how MMA is diagnosed and treated, along with some of the long-term impacts.

Symptoms of Methylmalonic Acidemia

Methylmalonic acidemia is a complex disease that can cause a variety of different symptoms. The intensity of these symptoms varies based on the exact genetic mutation causing the disease.

In the most severe cases, symptoms begin almost immediately at birth. In others, they might not appear until later infancy, childhood, or even adulthood.

Many of the symptoms of methylmalonic acidemia get worse in particular situations. These periods of more dangerous illness may be triggered by fasting, fever, vomiting, infection, surgery, stress, or by failing to follow the recommended treatments.

Called “decompensation” of the illness, this may lead to life-threatening symptoms. For example, an infant undergoing a decompensation might experience:

• Difficulty breathing
• Muscle weakness
• Vomiting
• Low energy (lethargy)
• Low body temperature
• Decreased consciousness

This can happen with even with the best medical interventions. Infants are particularly at risk.

Methylmalonic acidemia can lead to serious long-term health conditions as well, including:

• Intellectual disability
• Pancreatitis
• Poor appetite and growth
• Seizures
• Osteoporosis
• Kidney disease, which may cause kidney failure
• Optic nerve atrophy (causing vision problems)
• Stroke of a brain region called the basal ganglia (causing movement problems)
• Blood problems, such as lower numbers of certain immune cells and anemia

Additional symptoms and conditions are possible as well. But it’s important to note that not everyone with MMA will have them all, or experience them at all times. For example, someone with a mild form of methylmalonic acidemia might first experience kidney disease symptoms in adulthood.

What Causes Methylmalonic Acidemia?

Methylmalonic acidemia belongs in a group of disorders known as inborn errors of metabolism.

Metabolism refers to how the body converts nutrients in food into energy. Inborn errors of metabolism are caused by different genetic defects that lead to problems with metabolism.

Methylmalonic acidemia also belongs to a smaller subset of these diseases, termed organic acidurias. These genetic diseases result from difficulties metabolizing certain types of amino acids, the building blocks of proteins. It results in unhealthy levels of products otherwise normally present in the body.

Defects in different enzymes lead to different types of organic aciduria. For example, propionic acidemia is another rare disease in this class. Other rare diseases in this group may have some similar symptoms.

Gene Defects in MMA

More specifically, methylmalonic acidemia can be caused by a defect in one of several different genes. Due to the defect in the gene, the resulting proteins don’t work as well as they should. These defects cause problems with the functioning of a specific protein enzyme, called methylmalonyl-CoA mutase.

In more than 60% of cases, the cause is:

• Mutations in the MMUT gene (methylmalonyl-CoA mutase) responsible for this missing or defective enzyme
• Mutations in the MMAA gene (metabolism of cobalamin associated A) responsible for problems with adenosyl-cobalamin, a cofactor related to methylmalonyl-CoA mutase 

How MMA Is Passed Down

Methylmalonic acidemia is an autosomal recessive genetic condition. This means that a person has to inherit an affected gene from both of their parents to get the disease.

If a couple has had one child born with methylmalonic acidemia, there is a 25% chance that their next child would also have the condition. It’s also important to test existing siblings for the disease since not all people with MMA display symptoms right away.

Early diagnosis and management may then help prevent long-term complications from the disease. Talking with a genetic counselor can be very helpful for many families. This can give you a sense of the risks in your situation. Prenatal testing may also be an option.

Diagnosis

The standard newborn screening tests sometimes provide the diagnosis of methylmalonic acidemia. However, not all places test for this specific disease. Also, infants might first experience symptoms before the results of these screening tests are available.

Diagnosis of methylmalonic acidemia requires a thorough medical history and exam. Laboratory testing is critical as well. It’s important that diagnosis happens as quickly as possible since affected individuals are often very ill. Also, untreated decompensations can worsen the long-term complications of MMA (for example, causing permanent brain damage).

Many different types of medical problems can lead to neurological and other symptoms such as those seen in decompensated methylmalonic acidemia. It can be a challenge to rule out these other possible diagnoses and narrow down on the specific cause. Since MMA is a rare condition, a medical specialist may be needed to help diagnose the disease.

In people with MMA, these levels should be higher than usual. However, there are also some other different inborn errors of metabolism that can cause methylmalonic acid to build up as a result of different genetic problems.

Blood tests that may be helpful in diagnosing methylmalonic acidemia include:

• Comprehensive metabolic panel CMP, to check for response to infection, anemia, glucose levels, basic organ function, and more
• Tests for various metabolites such as ammonia
• Testing to assess the presence of amino acids
• Samples to assess for bacterial infection
• Tests for vitamin B12 and homocysteine

Additional genetic tests can help finalize the diagnosis and can also identify the specific genetic mutation involved. In some cases, this may affect treatment options.

How MMA Is Treated

The treatment for methylmalonic acidemia depends on a person's history with the disorder and their specific symptoms. These options vary according to whether the needed treatment is immediate because of an emergency context, or if they're meant for long-term care.

Emergency Treatment

Periods of decompensations from methylmalonic acidemia are medical emergencies. Without support in this time, individuals may die. These periods might happen before an initial diagnosis or at other times of stress or illness. Intensive support in a hospital setting is necessary.

Some interventions that might be needed during an emergency include:

• Intravenous (IV) fluids
• Glucose (sugar) administration
• Treatment for bacterial infection
• Strict diet for protein intake
• IV carnitine therapy
• Breathing support
• Hemodialysis or extracorporeal membrane oxygenation (ECMO) to remove toxic byproducts

Diet

Dietary management is an important part of treatment for methylmalonic acidemia. A dietary specialist who is experienced in rare metabolic diseases can help guide nutritional support.

However, limiting protein too severely has its own negative health impacts. That’s why it’s helpful to work with a professional. A feeding tube is also sometimes helpful to help ensure proper nutrition, especially during decompensations.

Long-Term Treatments

L-carnitine (a supplement) and Neomycin (an antibiotic) can potentially enhance the removal of some of the toxic metabolic byproducts from the body.

Injections of vitamin B12 (hydroxocobalamin) are a very helpful treatment for people with specific genetic subtypes of MMA, but not for all subtypes.

Other long-term medications might also be needed to treat complications. For example, someone might need to take a bisphosphonate drug to help treat osteoporosis related to methylmalonic acidemia.

Liver transplant is also an option for some people with MMA. It doesn’t cure the disease, but it can help a person experience less frequent and less severe decompensations. Kidney transplant might also be needed for people with severe kidney disease.

Preventing Decompensations

Preventing decompensations is also an important part of treatment. People with methylmalonic acidemia should not fast or increase their intake of protein because this might trigger a decompensation.

If an individual with MMA is ill, such as from a virus, it’s important that they decrease protein intake and receive additional fluids with sugar. This can help prevent a decompensation.

Affected individuals need to be closely monitored whenever they are exposed to stressors that might trigger a decompensation. That way, treatment can begin promptly if necessary.

Monitoring

People with methylmalonic acidemia also need regular monitoring for long-term complications of the condition. For example, this should include regular eye exams and tests of kidney function.

Ideally, people with MMA should see a specialist with experience in rare genetic diseases. Treatment and monitoring will require a range of medical professionals working together as a team.

New Potential Treatments

Researchers are also investigating potential new treatments for methylmalonic acidemia, such as gene therapy and antioxidant treatments. These treatments have not received the same rigorous study as treatments already approved by the Food and Drug Administration.

Ask your healthcare provider if you are interested in participating in a clinical trial. Or, check out the United States database for clinical trials.

A Word From Verywell

A diagnosis of methylmalonic acidemia can be challenging for many families. Fortunately, both diagnosis and treatment have improved in recent years.

MMA is a significant condition that will require long-term management, so be sure to reach out for support from family members, your healthcare team, and available support groups.