An Overview of Methylmalonic Acidemia

Methylmalonic acidemia (MMA) is a rare and serious genetic disorder that affects multiple body systems. It can potentially cause coma and death, particularly if not correctly diagnosed and treated. Due to a genetic defect, the body is unable to properly process certain parts of proteins, leading to the symptoms of the condition. It is a rare disease, estimated to occur in approximately one in 100,000 infants.

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. In others, symptoms might not appear until later infancy, childhood, or even adulthood.

Many of the symptoms of MMA 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. This is called “decompensation” of the illness, and it may lead to life-threatening symptoms. For example, an infant undergoing a decompensation might have symptoms such as:

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

Even with the best medical interventions, some people with MMA will experience decompensations from the disease. Infants are, particularly at risk.

The disease can also cause long-term problems as well. These can include:

• 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 (like decreased numbers of certain immune cells and anemia)

Additional symptoms are possible as well. But it’s important to note that not everyone with MMA will have all these symptoms. For example, someone with a mild form of MMA might first experience symptoms from kidney disease in adulthood.

Methylmalonic acidemia belongs in a group of disorders known as inborn errors of metabolism. Metabolism refers to the multi-step process by which the nutrients in food are turned into energy. Inborn errors of metabolism are caused by different genetic defects that lead to problems with metabolism.

MMA 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 protein). 

Due to this, the levels of certain products normally present in the body may begin to rise to unhealthy levels. 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.

MMA 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.

This enzyme normally plays an important role in metabolizing a specific type of amino acid (as well as some other important compounds, like certain parts of fats and cholesterol). Therefore, methylmalonic acid begins to accumulate, as well as some other related substances. These compounds can be toxic when they build up in the body, leading to some of the symptoms of the disease.

Other symptoms may result because of dysfunctions in energy production resulting from problems with this step of metabolism.

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 MMA. 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 tests 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.

Some other laboratory tests that may be helpful in diagnosing MA include the following:

• basic blood work such as CMP (to assess for response to infection, anemia, glucose levels, basic organ function, and more)
• blood work to assess various metabolites such as ammonia
• blood work to assess the amino acids present
• blood sample to assess for bacterial infection
• blood test 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.

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

Periods of decompensations from MMA are medical emergencies. Without support, individuals may die during these periods. These might happen before an initial diagnosis or at other periods of stress or illness. These individuals need intensive support in a hospital setting.

For example, these individuals might need interventions like intravenous fluids and glucose, treatment of precipitating factors (like bacterial infection), a tightly managed protein intake, intravenous carnitine, ventilatory support (if necessary), and/or hemodialysis or extracorporeal membrane oxygenation (ECMO, which removes toxic byproducts).

Dietary management is an important part of treatment for MMA. Individuals with MMA should work closely with a dietary specialist who is experienced in rare metabolic diseases.

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.

Certain medications are available that can potentially enhance the removal of some of the toxic metabolic byproducts. These include L-carnitine and Neomycin.

Injections of vitamin B12 (hydroxocobalamin) is 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 MMA.

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 is also an important part of treatment. People with MMA 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.

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.

Researchers are also investigating potential new treatments for MMA, such as gene therapy and antioxidant treatments. These treatments have not received the same rigorous study as treatments already approved by the FDA. Ask your doctor if you are interested in possibly participating in a clinical trial. Or check out the U.S. database for clinical trials.

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 MMA, there is a 25 percent 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.

A diagnosis of MMA is understandably overwhelming for many families. It can take some time to fully grasp what is happening. It helps to have a trustworthy healthcare team that will do their utmost to meet you or your child’s short-term and long-term needs. Fortunately, both diagnosis and treatment have improved in recent years. MMA is a significant condition that will require long-term management, but you should know that you aren’t alone. Don’t hesitate to reach out for support from your friends, family members, healthcare team, and/or support group.