Combined malonic and methylmalonic aciduria

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of certain chemicals, known as malonic acid and methylmalonic acid, in the body. A distinguishing feature of this condition is higher levels of methylmalonic acid than malonic acid in the urine, although both are elevated.

The signs and symptoms of CMAMMA can begin in childhood. In some children, the buildup of acids causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs. Other signs and symptoms may include involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (faltering weight), low blood glucose (hypoglycemia), and coma. Some affected children have an unusually small head size (microcephaly).

Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the ACSF3 gene cause CMAMMA. This gene provides instructions for making an enzyme that plays a role in the formation (synthesis) of fatty acids. Fatty acids are building blocks used to make fats (lipids). The ACSF3 enzyme performs a chemical reaction that converts malonic acid to malonyl-CoA, which is the first step of fatty acid synthesis in cellular structures called mitochondria. Based on this activity, the enzyme is classified as a malonyl-CoA synthetase. The ACSF3 enzyme also converts methylmalonic acid to methylmalonyl-CoA, making it a methylmalonyl-CoA synthetase as well.

The effects of ACSF3 gene mutations are unknown. Researchers suspect that the mutations lead to altered enzymes that have little or no function. Because the enzyme cannot convert malonic and methylmalonic acids, they build up in the body. Damage to organs and tissues caused by accumulation of these acids may be responsible for the signs and symptoms of CMAMMA, although the mechanisms are unclear.

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 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

CMAMMA appears to be a rare disease. Approximately a dozen cases have been reported in the scientific literature.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Dicarboxylic acidemia · Very frequent (99-80%)

The concentration of dicarboxylic acid in the blood circulation is above the upper limit of normal.

Dicarboxylic aciduria · Very frequent (99-80%)

An increased concentration of dicarboxylic acid in the urine.

Methylmalonic acidemia · Very frequent (99-80%)

The concentration of methylmalonic acid in the blood circulation is above the upper limit of normal.

Methylmalonic aciduria · Very frequent (99-80%)

Increased concentration of methylmalonic acid in the urine.

Seizure · Frequent (79-30%)

A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

Acidosis · Occasional (29-5%)

Abnormal acid accumulation or depletion of base.

Atypical behavior · Occasional (29-5%)

Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.

Axial hypotonia · Occasional (29-5%)

Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.

Delayed speech and language development · Occasional (29-5%)

A degree of language development that is significantly below the norm for a child of a specified age.

Dystonia · Occasional (29-5%)

An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.

Elevated circulating hepatic transaminase concentration · Occasional (29-5%)

Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.

Encephalopathy · Occasional (29-5%)

Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.

Failure to thrive · Occasional (29-5%)

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

Focal impaired awareness seizure · Occasional (29-5%)

Focal impaired awareness seizure (or focal seizure with impaired or lost awareness) is a type of focal-onset seizure characterized by some degree (which may be partial) of impairment of the person's awareness of themselves or their surroundings at any point during the seizure.

Other findings in the same source

From: Orphanet

Additional reported features include Generalized clonic seizure (Occasional (29-5%)); Global developmental delay (Occasional (29-5%)); Hypoglycemia (Occasional (29-5%)); Impaired continence (Occasional (29-5%)); Intermittent diarrhea (Occasional (29-5%)); Ketoacidosis (Occasional (29-5%)); Memory impairment (Occasional (29-5%)); Microcephaly (Occasional (29-5%)); Migraine (Occasional (29-5%)); Nasogastric tube feeding (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Combined malonic and methylmalonic aciduria is Metabolic Medicine, with a metabolic specialist / clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with metabolic specialist / 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.

• Is a biochemical or molecular result needed to clarify the diagnosis?
• Does this condition require an individual plan for illness or reduced food intake?
• Should nutrition advice come from a specialist metabolic dietitian?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Combined malonic and methylmalonic aciduria. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

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.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

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.