Introduction

Methylmalonic Acidemia (MMA) is an autosomal recessive disorder of amino acid metabolism involving a defect in converting methylmalonyl-coenzyme A (CoA) to succinyl-CoA. In individuals with MMA, the body has trouble breaking down protein, which it needs to help grow and repair itself. Protein is made up of chains of smaller units called amino acids. Four of these amino acids are valine, methionine, isoleucine and threonine. These four amino acids are also called proteinogenic amino acids. Our bodies change amino acids into other substances or energy with the help of enzymes, which is called metabolism. 

In individuals without MMA, valine, methionine, isoleucine, and threonine break down into other substances in the body. For this process to work fully, the body needs the enzymes propionyl coenzyme A carboxylase (PCC) and methylmalonyl coenzyme A mutase (MCM). In MMA, propionic acid, methylmalonic acid and other toxins build up.¹

The enzymes involved are methylmalonyl-CoA epimerase and methylmalonyl-CoA mutase. The cofactors for these enzymes are associated with vitamin B12, meaning they play a role in the processing of vitamin B12 metabolism. Amino acids, bacterial metabolic products, and fats feed into this metabolic process.¹

Genetic and biochemical basis

Methylmalonyl-CoA must be converted into succinyl CoA, which enters the Krebs cycle for subsequent energy production. This conversion is provided by the enzyme methylmalonyl mutase, a unique enzyme that uses vitamin B12 as a cofactor. There are two reasons why this enzyme can be defective. Firstly, due to a mutation, and secondly, in cases of vitamin B12 deficiency. Methylmalonyl-CoA mutase activity is extremely low without the cofactor, making this reaction impossible without vitamin B12. If this enzyme is non-functional, methylmalonyl-CoA and propionyl-CoA accumulate inside the cell's mitochondria. Because propionyl-CoA replaces acetyl CoA in neural membranes, propionyl-CoA accumulation causes demyelination. Similarly, the accumulation of methylmalonyl-CoA also causes demyelination.²

The myelin sheath is characterised by a high proportion of lipids and a relatively low proportion of proteins. In contrast, most biological membranes have an approximately equivalent ratio of proteins to lipids. Like any membrane, the myelin sheath degrades over time and requires continuous repair. To substitute damaged fatty acids, synthesis must provide new fatty acids. This process must be sustained, as fatty acids are produced from acetyl-CoA, with malonyl-CoA as an intermediate metabolite in fatty acid synthesis. However, methylmalonyl-CoA can substitute for malonyl-CoA in this process, producing branched-chain fatty acids that are not normal structural components of the myelin sheath. This disrupts the entire myelin structure and causes demyelination of neural cells. Consequently, in cases of methylmalonic acidaemia, propionyl-CoA and methylmalonyl-CoA contribute to the demyelination of the spinal cord, brain, and peripheral neurons.³

Damage to the nervous system results in symptoms such as lethargy, poor feeding, hypotonia and seizures. Without methylmalonyl-CoA mutase, succinyl CoA cannot be formed, meaning it cannot enter the Krebs cycle. This will lead to reduced activity in the Krebs cycle, decreased energy production, and energy deficiency.

In methylmalonic acidaemia, methylmalonyl-CoA and propionyl-CoA are enzymatically cleaved, resulting in large amounts of methylmalonic and propionic acids entering the circulation. The accumulation of these two acids in methylmalonyl acidemia causes metabolic changes similar to propionic acidaemia. Propionic acid and methylmalonyl acid are organic acids, so their accumulation in the blood causes high anion gap metabolic acidosis. Organic acids inhibit the urea cycle, which results in hyperammonemia. Additionally, these acids are strong inhibitors of gluconeogenesis. The combination of energy deficiency and inhibited gluconeogenesis leads to hypoglycaemia. Low blood glucose levels induce massive production of ketone bodies by the liver tissue. This causes hyper ketosis which further contributes to high anion gap metabolic acidosis.⁴

Symptoms

A patient with either type of acidemia may present with the following symptoms:

• Hyperammonaemia
• Metabolic acidosis with a high anion gap (greater than 10) 
• Failures to thrive and lethargy
• Seizures 
• Hypotonia 
• Vomiting 
• Accumulation of acid waste in their urine

These are all common symptoms observed in patients.⁵

Diagnostic approaches

Standard labs:

• Basic metabolic panel (BMP): Anion gap metabolic acidosis, elevated ammonia, hypoglycemia
• Urinalysis: Presence of ketones (due to increased glucose usage)
• Elevated lactate
• Complete blood count (CBC): To rule out bone marrow suppression
• Urine ketones
• Liver function tests (LFTs)

Metabolic labs:

• Plasma acylcarnitines: Increase in propionyl carnitine (C3), decrease in free carnitine (noted on newborn screening)
• Urine organic acids: Elevated levels of methylmalonic acid
• Increase in serum methylmalonic acid

Genetic testing:

• Biallelic mutation in relevant genes⁶

Treatment strategies

There is no cure for this disorder, but there are ways to manage it. The first and most important approach is to have a diet low in protein. This is because amino acids feed into the affected metabolic pathway, particularly the amino acids that produce methylmalonic acid. Therefore, it is essential to have a diet low in these specific amino acids. Commercial formulas, such as Anamix, are available to support this dietary requirement.  It is also key to avoid fasting, as fasting forces the body to metabolise amino acids or fats for energy rather than carbohydrates, which are less problematic in this condition.

As far as treatment, antibiotics such as neomycin and metronidazole can be used to reduce the gut bacteria which produce propionyl-CoA. Vitamin B12 supplementation can also be administered as a cofactor necessary for the affected enzyme reaction. Vitamin B12 could be administered intramuscularly or orally. Additionally, L-carnitine can be used, as its mechanism involves removing propionyl groups to release CoA.⁷

FAQs

What is the difference between methylmalonic acidemia and propionic acidemia?

A propionyl-CoA carboxylase deficiency brings about PA. MMA is triggered by a deficiency of the enzyme methylmalonyl-CoA mutase (MCM).

What are the chances of having methylmalonic acidemia?

With each pregnancy between two carrier parents, the baby has a one in four likelihood of being unharmed and not a carrier, a 50% (1 in 2) probability of being unaffected and a carrier, and a 25% (1 in 4) chance of developing methylmalonic acidemia.

Summary

Methylmalonic Acidaemia (MMA) is an inherited disorder affecting amino acid metabolism due to a defect in converting methylmalonyl-CoA to succinyl-CoA, essential for energy production in the Krebs cycle. This defect, often resulting from mutations or vitamin B12 deficiency, accumulates toxic metabolites like methylmalonyl-CoA and propionyl-CoA, causing neurological damage through demyelination. Symptoms typically emerge in infancy, including vomiting, lethargy, hypotonia, developmental delays, and metabolic crises such as high anion gap metabolic acidosis and hyperammonaemia. Diagnosis relies on metabolic and genetic testing, revealing elevated levels of methylmalonic acid and other metabolic markers. Management includes a low-protein diet to limit problematic amino acids, vitamin B12 supplementation, antibiotics to reduce propionyl-CoA-producing gut bacteria, and L-carnitine to help clear toxic metabolites. While no cure exists, these interventions aim to alleviate symptoms and improve patient outcomes.