What are the other Names for this Condition? (Also known as/Synonyms)

• Isolated Methylmalonic Acidemia
• Methylmalonyl CoA Mutase Deficiency
• MMA (Methylmalonic Aciduria)

What is Methylmalonic Acidemia? (Definition/Background Information)

• Methylmalonic Acidemia (MMA) describes a group of genetic, organic acid disorders in which the body is unable to breakdown certain proteins and fats, resulting in the buildup of methylmalonic acid in blood
• MMA is inherited in an autosomal recessive pattern, meaning that the defective genes must be passed on to the child, from both parents in order to show symptoms of the disorder
• Mutations in many genes, including MUT, MMAA, MMAB, MMADHC, and MCEE, have been found to cause the disorder
• Individuals, who are affected by MMA, have a defect that does not allow for the conversion of methylmalonyl CoA to succinyl CoA. This results, either from mutations in the methylmalonyl CoA mutase enzyme, or from impaired metabolism of vitamin B12
• There are two types of Methylmalonic Acidemia:
  • Vitamin B12 responsive Methylmalonic Acidemia: MMA that is responsive to B12 can be treated using B12 injections
  • Vitamin B12 non-responsive Methylmalonic Acidemia: MMA that is not responsive to B12, cannot be treated using vitamin B12
• The signs and symptoms of MMA are usually observed before the baby is 12 months old and these may include - developmental delays, lethargy, repeated infections, vomiting and dehydration, and even seizures and strokes
• Methylmalonic Acidemia can neither be prevented nor can it be cured. The treatment measures are symptomatic and looks to avoid the excess buildup of methylmalonic acid in the body
• With proper treatment, the prognosis is better and individuals may lead relatively normal lives. However, without a proper diagnosis and treatment of Methylmalonic Acidemia, it could cause complications leading to fatalities, such as metabolic crisis, strokes, and comatose states

Who gets Methylmalonic Acidemia? (Age and Sex Distribution)

• Methylmalonic Acidemia occurs in about 1 in 25,000-48,000 births
• The symptoms are apparent within the first year of life, continuing to affect the individual, as they become older
• MMA affects boys and girls equally

What are the Risk Factors for Methylmalonic Acidemia? (Predisposing Factors)

• Methylmalonic Acidemia is a genetic disorder that is passed on in an autosomal recessive pattern. This means that both parents must pass on the mutated genes (namely MUT, MMAA, MMAB, MMADHC, or MCEE genes), in order for the child to be affected
• If only one parent passes on the mutated gene to the child, then he/she will become a carrier and is not at risk for developing the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Methylmalonic Acidemia? (Etiology)

• Methylmalonic Acidemia (MMA) is an autosomal recessive disorder that is caused by mutations to the MUT, MMAA, MMAB, MMADHC, or MCEE genes
• 60% of MMA cases are caused by a mutation to the MUT gene, which provides instructions for making the methylmalonyl CoA enzyme
• When functioning normally, this enzyme works with vitamin B12 to breakdown amino acids, lipids, and cholesterol. But, when there is a mutation to the MUT gene, the enzyme structure is altered and protein and fat breakdown cannot occur
• MMA caused by mutations to the MMAA, MMAB, and MMADHC genes, lead to the production of mutated proteins that cause methylmalonyl CoA mutase to function improperly. In all of these cases, the buildup of methylmalonic acid eventually occurs
• While most symptoms are the same regardless of which gene has the mutation, the long-term effects of Methylmalonic Acidemia can be predicted by determining, which gene is mutated and how severe the mutation is

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Methylmalonic Acidemia?

Methylmalonic Acidemia begins within the first year of life. The signs and symptoms of MMA may include:

• Dehydration
• Developmental delays
• Lethargy
• Repeated yeast infections
• Vomiting
• Seizures
• Strokes
• Progressive encephalopathy (brain disease)
• Metabolic crisis
• Low muscle tone
• Ketones in urine
• High ammonia levels
• High glycine levels
• Anemia

The symptoms of Methylmalonic Acidemia often become worse in the following situations:

• When the individual has taken (consumed) large amounts of proteins
• When the individual falls sick, or contracts an infection
• Goes too long without food
• Or is stressed

How is Methylmalonic Acidemia Diagnosed?

Methylmalonic Acidemia can be diagnosed using a variety of tests and exams. These include:

• Physical examination with medical and family history evaluation
• Ammonia tests
• Electrolyte level testing
• Methylmalonic acid blood tests
• Plasma amino acid tests
• Other tests may include CT scan or MRI scans
• Complete blood count
• Before birth of the child, genetic testing can be performed to determine the probability that the child may be born with MMA

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Methylmalonic Acidemia?

When treated correctly, Methylmalonic Acidemia can be contained and symptoms minimized. But, complications may occur, which include:

• Seizures and strokes may occur; in such cases, the individual may move into a coma state
• Kidney failure may also occur in individuals with MMA

Eventually, if these health conditions become too severe, it may result in fatalities.

How is Methylmalonic Acidemia Treated?

Currently, there is no cure for Methylmalonic Acidemia. However, treatment options exist to treat and control the symptoms of the disorder. These include:

• Often, healthcare providers suggest a low-protein diet to prevent excess buildup of methylmalonic acid. They may also prescribe vitamin B12 and carnitine supplements
• If these supplements do not help lessen the symptoms, a diet avoiding isoleucine, threonine, methionine, and valine, may be suggested
• Some patients have shown improvements after receiving a liver or kidney transplant, as these transplants provide the body with new cells to break down methylmalonic acid normally

How can Methylmalonic Acidemia be Prevented?

• Currently, there are no specific methods or guidelines to prevent Methylmalonic Acidemia genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Methylmalonic Acidemia? (Outcomes/Resolutions)

• With prompt diagnosis and immediate treatment, individuals with Methylmalonic Acidemia can lessen the severity of their symptoms and lead relatively normal lives
• Although treatment is often complicated, individuals who follow treatment plans have a normal life and greatly reduce their risk of complications like stroke, seizure, and coma
• If, however, the symptoms are not treated properly, individuals affected by Methylmalonic Acidemia may die from their first attack, or experience strokes or seizures that could lead to a coma

Additional and Relevant Useful Information for Methylmalonic Acidemia:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/congenital-genetic-disorders/