Methylmalonic acidemia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Methylmalonic acidemia is a group of inherited disorders that prevent the body from breaking down proteins and fats (lipids) properly. The effects of methylmalonic acidemia, which usually appear in early infancy, vary from mild to life-threatening. Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delays, excessive tiredness (lethargy), an enlarged liver (hepatomegaly), and difficulty gaining weight and growing at the expected rate (faltering weight). Long-term complications can include feeding problems, intellectual disabilities, movement problems, chronic kidney disease, and inflammation of the pancreas (pancreatitis). People with methylmalonic acidemia can have frequent episodes of excess acid in the blood (metabolic acidosis) that cause serious health complications. Without treatment, this disorder can lead to coma and death in some cases.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the MMUT, MMAA, MMAB, MMADHC, and MCEE genes cause methylmalonic acidemia. The long-term effects of methylmalonic acidemia depend on which gene is altered and the severity of the variant.

About 60 percent of individuals with methylmalonic acidemia have variants in the MMUT gene. This gene provides instructions for making an enzyme called methylmalonyl-CoA mutase. This enzyme works with vitamin B12 (also called cobalamin) to break down several protein building blocks (amino acids), certain lipids, and cholesterol. Variants in the MMUT gene alter the enzyme's structure or reduce the amount of the enzyme, which prevents these molecules from being broken down properly. As a result, a substance called methylmalonic acid and other potentially toxic compounds can accumulate in the body's organs and tissues, causing the signs and symptoms of methylmalonic acidemia.

Variants in the MMUT gene that prevent the production of any functional methylmalonyl-CoA mutase result in a form of the condition designated mut0. Mut0 is the most severe form of methylmalonic acidemia and has the poorest outcomes. Variants that change the structure of methylmalonyl-CoA mutase but do not eliminate its activity cause a form of the condition designated mut-. The mut- form is typically less severe, with more variable symptoms than the mut0 form.

Some cases of methylmalonic acidemia are caused by variants in the MMAA, MMAB, or MMADHC gene. Proteins produced from the MMAA, MMAB, and MMADHC genes are required for the proper function of methylmalonyl-CoA mutase. Specifically, these proteins help produce and regulate vitamin B12, which methylmalonyl-CoA mutase needs to function. Variants that affect proteins produced from these three genes can impair the activity of methylmalonyl-CoA mutase, leading to methylmalonic acidemia.

A few other cases of methylmalonic acidemia are caused by variants in the MCEE gene. This gene provides instructions for producing an enzyme called methylmalonyl CoA epimerase. Like methylmalonyl CoA mutase, this enzyme also plays a role in the breakdown of amino acids, certain lipids, and cholesterol. Disruption in the function of methylmalonyl CoA epimerase leads to a form of methylmalonic acidemia with varied signs and symptoms.

Because variants in these genes only cause elevations in the levels of methylmalonic acid, this condition is sometimes referred to as isolated methylmalonic acidemia. This helps distinguish it from related conditions, such as methylmalonic acidemia with homocystinuria.

It is possible that variants in other, unidentified genes also cause methylmalonic acidemia.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the MMUT, MMAA, MMAB, MMADHC, or MCEE gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Methylmalonic acidemia occurs in an estimated 1 in 50,000 to 100,000 people.

Which doctor should you see?

The suggested department for discussing Methylmalonic acidemia is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.