Introduction

Methylmalonic acidemia (MMA) is a rare genetic disorder that prevents the body from breaking down certain proteins and fats,¹ leading to an accumulation of methylmalonic acid in the body. It is an inborn error of metabolism disorder.¹⁴ Understanding the clinical features and symptoms of this disorder is crucial for its diagnosis and management.

Methylmalonic acidemia is an autosomal recessive disorder,¹ meaning the affected individual will have inherited one copy of the faulty gene from both their parents. For an individual to be affected, both of their parents must be either carriers of the genes or affected themselves.

Genetic basis and types

There are two types of MMA: isolated MMA (only methylmalonic acid levels are increased) or associated with a condition called homocystinuria.

Isolated MMA is caused by mutations in the MMAA, MMAB and MUT genes.

• MMAA gene - Responsible for cobalamin A (cblA) type of methylmalonic acidemia. Individuals have trouble producing the enzyme cobalamin A²
• MMAB gene - Responsible for cobalamin B (cblB) type of methylmalonic acidemia.  Individuals have trouble producing cobalamin B
• MUT gene - Its mutation causes an alteration in the enzyme methylmalonyl-CoA mutase,¹ causing a buildup of methylmalonyl-CoA, a substance that is toxic in high amounts

Cobalamin A and B are involved in the function of the enzyme methylmalonyl-CoA mutase.

Combined MMA and homocystinuria is commonly caused by a mutation in the MMACHC gene, which disrupts the cobalamin, or B12, pathway.³ 

Pathophysiology and metabolic impact

Due to genetic mutations, there is a buildup of methylmalonic acid alongside other toxic metabolites. These toxic substances can disrupt normal cellular functions, damage organs and impact multiple large systems, such as the nervous system, the kidneys or the liver.⁴

Clinical features and symptoms

When symptoms of MMA first appear in an individual differ between cases. In more severe cases, symptoms appear immediately after birth. However, for other people, they may appear later on in infancy. The intensity of the symptoms also differs between people. During a period of illness or stress, symptoms may worsen.⁵

Neonatal period

 During the first four weeks of life, symptoms include poor feeding, vomiting, tiredness (lethargy), weak muscle tone (hypotonia), metabolic acidosis, and hyperammonemia.

Infancy and early childhood

Symptoms during infancy can be characterised by a failure to thrive, developmental delays, neurological and gastrointestinal issues. Neurological symptoms can include seizures, hypotonia or hypertonia, and movement disorders. Gastrointestinal symptoms can include vomiting and trouble feeding.⁵

Late childhood to adolescence

Episodic metabolic crises are a symptom of MMA in adolescence. These occur when there is a build-up of toxic metabolites.⁶ Triggered by illness, fasting or stress, its symptoms include lethargy, vomiting and/or dehydration. 

Chronic kidney disease, growth retardation and cognitive impairment are also symptoms. The latter two depict the physical and mental delays that individuals with MMA experience. Growth retardation can occur due to illness or nutritional deficiencies.

Adulthood

Prolonged symptoms of MMA can lead to long-term effects in adulthood, including neurological degeneration such as peripheral neuropathy, cognitive decline,⁷ psychiatric symptoms including depression and anxiety, and an increased risk of cardiovascular disease.

Complications and associated conditions

• Metabolic decomposition - The deterioration of metabolism caused by an accumulation of metabolites⁸
• Chronic kidney disease - Methylmalonic acid can directly damage kidney cells
• Pancreatitis - It may develop as a result of metabolic decomposition⁹
• Cardiomyopathy
• Increased risk of infection 

Diagnosis

The diagnosis of MMA takes a holistic approach, combining a multitude of techniques including clinical evaluation, laboratory tests and genetic testing. As the symptoms of MMA can appear immediately after birth, newborn screening can be informative in the diagnosis of MMA. Typically, this involves a physical examination and a blood test. 

Laboratory tests can be carried out during different life stages, depending on the onset of symptoms. A urine test is an important indicator of MMA. This looks for elevation of methylmalonic acid, ammonia and lactate in the blood and urine. 

Genetic testing can be carried out later on to confirm the diagnosis and state which gene has mutated. 

Management and treatment

Acute management

Emergency treatment of metabolic crises involves the close monitoring of vital signs such as heart rate and blood pressure. Neurological assessments are carried out to detect any signs of permanent damage or suspected seizures. Blood tests are taken to assess methylmalonic acid levels, among other things.¹⁰ After these assessments, appropriate treatment will be given, such as nutritional guidance, supplements and toxin removal strategies. 

Hemodialysis is sometimes required for severe cases where kidney disease is involved. It filters waste from the blood, particularly methylmalonic acid and other toxic metabolites.¹¹

Long-term management

Individuals with MMA are encouraged to follow a special low-protein, high-calorie diet. A Low-protein diet restricts the intake of isoleucine, threonine, methionine, and valine, all amino acids that can be transformed into methylmalonic acid in an affected individual.¹ The high-calorie aspect of the diet ensures that they still receive all other essential nutrients required for a healthy body.

Pharmacological treatment

Supplements of vitamin B12, or cobalamin, may be given via injection to decrease levels of methylmalonic acid in the blood.¹²

Carnitine can be given to improve metabolism by eliminating toxic substances.¹³

A course of antibiotics may be prescribed by a GP to reduce propionate production.¹

Prognosis

Like most disorders, the prognosis of MMA differs based on the severity of the symptoms and its diagnosis. Early diagnosis and intervention lead to a better prognosis as they reduce associated complications and encourage growth. The severity of the mutation also influences the prognosis, with a more severe mutation having a poorer prognosis. 

With appropriate management of the disorder, a good prognosis can be achieved. Early and aggressive management can help with growth and development, preserve cognitive and motor functions, and improve life expectancy. Alongside treatment, most individuals will require extra help, such as special education services and emotional support. This will help them to develop at a similar rate to their healthy peers.  

Conclusion

Methylmalonic acidemia (MMA) is a complex disorder characterised by its variety of clinical features and symptoms, ranging from mild to severe and covering various life stages. Early and accurate diagnosis is important for successful intervention. Taking a multidisciplinary approach early on improves the prognosis. Moving forward, it is necessary that further investigation is carried out to improve the treatment of MMA, improving the quality of life of individuals with the disorder.