Methylmalonic Acidaemia

Methylmalonic acidaemia is a rare inherited disorder where the body cannot properly break down certain proteins and fats, leading to a dangerous buildup of toxic substances that can affect the brain, kidneys, and other organs throughout life.

Table of contents

• What is methylmalonic acidaemia?
• What causes this condition?
• Signs and symptoms
• How is it diagnosed?
• Treatment and management
• Possible complications
• Living with the condition

What is methylmalonic acidaemia?

Methylmalonic acidaemia (MMA) refers to a group of inherited disorders in which the body is unable to process certain proteins and fats properly.^[1] People with this disease can’t change, or metabolize, a substance called methylmalonyl-coenzyme A. The result is a buildup of methylmalonic acid in the body.^[1]

This is a rare genetic disorder of the liver. People with this condition are unable to produce an enzyme that is needed to break down and use certain proteins and fats found in food.^[2] This causes a buildup of acids and other harmful substances in the blood, urine and other cells, including brain cells.^[2]

The condition may occur in approximately 1 in 25,000 to 48,000 people, but the precise incidence is not known.^[1][3] The true prevalence may be higher because many neonatal deaths may be caused by unrecognized metabolic disorders.^[3] It is estimated that fewer than 80 babies are born with methylmalonic acidemias each year in the United States.^[18]

The effects of methylmalonic acidaemia vary from mild to life-threatening. This condition, which can appear in early infancy or the first year of life, is characterized by excessive tiredness, vomiting, dehydration, weak muscle tone, acid-base imbalance and in some patients, high levels of ammonia.^[1] Without treatment, the disorder can lead to coma and death in some cases.^[1]

What causes this condition?

MMA is a genetic disorder, meaning it is passed down through families. The faulty gene (a mutation) must be passed down to a child from both parents.^[2] This is called an autosomal recessive disorder, which means the defective gene must be passed onto the child from both parents.^[8]

Methylmalonic acidaemia is an autosomal recessive disorder of amino acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA.^[3] Conversion of methylmalonyl-CoA to succinyl-CoA requires the enzyme methylmalonyl-CoA mutase and the cofactor 5′-deoxyadenosylcobalamin.^[3]

Individuals with methylmalonic acidaemia can be divided into two groups: patients with isolated MMA, where only methylmalonic acid is elevated, and patients with combined defects who also have increased levels of homocysteine.^[1]

Isolated methylmalonic acidaemia is caused by mutations in the MMAA, MMAB, and MUT genes. About half of the patients with isolated methylmalonic acidaemia have mutations in the MUT gene.^[1] 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.^[1] Mutations in the MUT gene are estimated to cause 60% of MMA cases. The gene has been mapped to chromosome 6p12-21.2.^[3]

The metabolic precursor of methylmalonyl-CoA is propionyl-CoA, which is the product of the degradation of four essential amino acids: isoleucine, valine, methionine, and threonine, as well as the degradation of odd-chain fatty acids and cholesterol.^[6][10]

MMA can manifest itself differently depending on several factors: absence of enzyme (MMA type mut0), reduction in enzyme activity (MMA type mut-), defect in the synthesis of 5′-deoxyadenosylcobalamin (MMA types cblA, cblB, cblH), or defect in cobalamin (vitamin B12) metabolism (MMA types cblC, cblD, cblE, cblF, cblG, cblJ).^[3]

Signs and symptoms

The disease is most often diagnosed within the first few months of life.^[2] Babies may appear normal at birth, but develop symptoms once they start eating more protein, which can cause the condition to get worse.^[8] The disease can cause seizures and stroke.^[8]

Methylmalonic acidaemia causes episodes of severe illness called decompensation events, which are the result of the build-up of toxic substances in the blood. The first decompensation event usually occurs a few days after birth.^[2]

Symptoms may include:^[2]

• Poor feeding and loss of appetite
• Vomiting
• Weak muscle tone (hypotonia)
• Lack of energy (lethargy)
• Seizures
• Coma

Other symptoms can include brain disease that gets worse (progressive encephalopathy), dehydration, developmental delays, and failure to thrive.^[8]

Patients typically present at the age of 1 month to 1 year with such neurologic manifestations as seizure, encephalopathy (a condition affecting brain function), and stroke.^[3] Several cases have involved stroke in the bilateral globus pallidi (specific areas of the brain).^[3]

The accumulation of methylmalonic acid and other metabolites in the body of patients causes brain tissue damage, which can manifest as various degrees of intellectual disability and severe neurological dysfunction.^[4]

How is it diagnosed?

Methylmalonic acidaemia can be diagnosed through newborn screening.^[2] Testing for methylmalonic acidaemia is often done as part of a newborn screening exam. The United States Department of Health and Human Services recommends screening for this condition at birth because early detection and treatment is helpful.^[8]

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.^[18] Babies with high levels of these substances might have methylmalonic acidaemia.^[18]

Additional genetic testing can verify the diagnosis.^[2] Tests that may be done to diagnose this condition include:^[8]

• Blood ammonia test
• Blood gases
• Complete blood count
• CT scan or MRI of the brain
• Electrolyte levels
• Genetic testing
• Methylmalonic acid blood test
• Plasma amino acid test

The diagnosis of MMA mainly depends on clinical symptoms, newborn screening, biochemical detection, gene sequencing and neuroimaging diagnosis.^[4]

The constellation of laboratory findings in MMA includes: metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia (high levels of ammonia in the blood), and hyperglycinemia.^[6][10]

Neuroimaging examination has important clinical significance in the diagnosis and prognosis of MMA.^[4]

Treatment and management

Treatment focuses on managing the symptoms.^[2] People with MMA must follow a special low-protein diet.^[2]

Treatment consists of cobalamin and carnitine supplements and a low-protein diet. The child’s diet must be carefully controlled.^[8] If supplements do not help, the health care provider may also recommend a diet that avoids substances called isoleucine, threonine, methionine, and valine.^[8]

A low natural protein diet (1.5 g–1.0 g/kg/day) can be the foundation of treatment, but temporary supplementation with precursor-free amino acids, vitamin-mineral mixture, and energy supplements may be necessary at different timepoints (in childhood, adolescence, adulthood and pregnancy).^[19]

A low-protein diet can help reduce the number of attacks. People with this condition should avoid those who are sick with contagious illnesses, such as colds and the flu.^[8]

In catabolic stress in MMA due to acute illness (for example, perinatal stress, infection, injury, surgery with endogenous protein breakdown) or when excessive protein is ingested, there is an increase in the offending amino acids as well as in propionic acid, leading to an accumulation of methylmalonic acid.^[6][10]

Liver or kidney transplantation (or both) have been shown to help some patients. These transplants provide the body with new cells that help breakdown methylmalonic acid normally.^[8] However, based on liver transplantation reports meant to address the issue of metabolic derangement in MMA, the neurologic consequences of MMA may not be a result of metabolic abnormalities in the liver; rather, they may be a local metabolic disturbance in the brain. Liver transplantation has been found not to prevent further neurologic worsening or occurrence of stroke-like episodes.^[3]

Carglumic acid has been used as an adjunctive therapy to standard care for the treatment of acute hyperammonemia due to MMA, with evidence showing it can improve the quality of life of patients with this rare disease.^[11]

Possible complications

Over time, MMA can result in serious complications, such as enlarged liver, kidney failure, intellectual and motor disability, and vision problems.^[2]

Complications may include:^[8]

• Coma
• Death
• Kidney failure
• Pancreatitis
• Cardiomyopathy
• Recurrent infections
• Hypoglycemia

How this toxic buildup affects the body can vary drastically from one person to another. For some, it causes seizures, strokes, growth problems, developmental delays and frequent episodes of severe illness.^[2]

Mental outcome tends to be worse in propionic acidemia (a related condition), and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in propionic acidemia.^[12]

Living with the condition

Babies may not survive their first episode of symptoms from this disease. Those who survive often have problems with the development of the nervous system, although normal cognitive development can occur.^[8]

Childhood psychomotor development can be slightly delayed but within the normal range in adulthood with proper management.^[19] Careful clinical, biochemical, and dietetic monitoring is crucial to ensure a favourable outcome in MMA.^[19]

People with MMA should seek medical help right away if they are having a seizure for the first time. They should also see a provider if there are signs of failure-to-thrive or developmental delays.^[8]

Genetic counseling may be helpful for couples with a family history of this disorder who wish to have a baby.^[8]

The outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine, except for vitamin B12 responsive forms of MMA. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.^[12]

Successful long-term follow-up of patients with MMA from childhood, throughout pregnancy, delivery, and postpartum has been documented, confirming that with intensive biochemical and medical follow-up, good outcomes are possible.^[19]