3-methylcrotonyl-CoA carboxylase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

3-methylcrotonyl-CoA carboxylase deficiency (also called MCC deficiency) is an inherited disorder in which the body is unable to process certain proteins. People with this disorder have a shortage of an enzyme that helps break down proteins that contain a particular building block (amino acid) called leucine.

The signs and symptoms of MCC deficiency can vary among individuals, even among individuals in the same family. Some people with the genetic changes that cause MCC deficiency will not develop symptoms until adulthood, while many will never develop signs or symptoms.

Some affected individuals develop signs and symptoms in infancy or early childhood after an event such as an infection, a long period without food, or the introduction of a high-protein diet. Features of MCC deficiency may include feeding difficulties, delayed development, vomiting, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, MCC deficiency can lead to seizures; breathing difficulties; and comas, which can be life-threatening.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the MCCC1 or MCCC2 gene cause 3-methylcrotonyl-CoA carboxylase deficiency. The condition is sometimes referred to as 3-methylcrotonyl-CoA carboxylase 1 deficiency or 3-methylcrotonyl-CoA carboxylase 2 deficiency depending on the specific gene that is affected. These two genes provide instructions for making different parts (subunits) of an enzyme called 3-methylcrotonyl-CoA carboxylase (MCC). This enzyme plays a critical role in breaking down proteins obtained from food. Specifically, MCC is responsible for the fourth step in the breakdown of leucine, an amino acid that is part of many proteins.

Variants in the MCCC1 or MCCC2 gene reduce or eliminate the activity of MCC, preventing the body from processing leucine properly. In some people, these variants do not cause signs or symptoms. In others, toxic byproducts of leucine processing build up to harmful levels, which can damage the brain. This damage underlies the signs and symptoms of MCC deficiency.

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 either the MCCC1 gene or the MCCC2 gene in each cell must have a variant to cause the disorder. These gene variants increase the risk of developing the signs and symptoms of MCC deficiency. 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

As many as 1 in 36,000 newborns may receive a diagnosis of MCC deficiency.

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.

Abnormality of leucine metabolism · Very frequent (99-80%)

Any deviation from the normal concentration of leucine in the blood circulation.

Hypoglycemia · Very frequent (99-80%)

A decreased concentration of glucose in the blood.

Hypotonia · Very frequent (99-80%)

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

Organic aciduria · Very frequent (99-80%)

Excretion of non-amino organic acids in urine.

Abnormality of movement · Frequent (79-30%)

An abnormality of movement with a neurological basis characterized by changes in coordination and speed of voluntary movements.

Hyperammonemia · Frequent (79-30%)

An increased concentration of ammonia in the blood.

Failure to thrive in infancy · Frequent (79-30%)

Abnormality of the cerebral vasculature · Occasional (29-5%)

An anomaly of the cerebral blood vessels.

Spasticity · Occasional (29-5%)

A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.

Respiratory insufficiency · Occasional (29-5%)

Which doctor should you see?

The suggested department for discussing 3-methylcrotonyl-CoA carboxylase deficiency 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

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.

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.