Medium-chain acyl-CoA dehydrogenase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting).

Signs and symptoms of MCAD deficiency typically appear during infancy or early childhood and can include vomiting, lack of energy (lethargy), and low blood glucose (hypoglycemia). In rare cases, symptoms of this disorder are not recognized early in life, and the condition is not diagnosed until adulthood. People with MCAD deficiency are at risk of serious complications such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death.

Problems related to MCAD deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the ACADM gene cause MCAD deficiency. This gene provides instructions for making an enzyme called medium-chain acyl-CoA dehydrogenase, which is required to break down (metabolize) a group of fats called medium-chain fatty acids. These fatty acids are found in foods and the body's fat tissues. Fatty acids are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.

Mutations in the ACADM gene lead to a shortage (deficiency) of the MCAD enzyme within cells. Without sufficient amounts of this enzyme, medium-chain fatty acids are not metabolized properly. As a result, these fats are not converted to energy, which can lead to the characteristic signs and symptoms of this disorder such as lethargy and hypoglycemia. Medium-chain fatty acids or partially metabolized fatty acids may also build up in tissues and damage the liver and brain. This abnormal buildup causes the other signs and symptoms of MCAD 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 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

In the United States, the estimated incidence of MCAD deficiency is 1 in 17,000 people. The condition is more common in people of northern European ancestry than in other ethnic groups.

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.

Decreased liver function · Frequent (79-30%)

Reduced ability of the liver to perform its functions.

Decreased plasma total carnitine · Frequent (79-30%)

A decreased concentration of total carnitine in the blood.

Dicarboxylic aciduria · Frequent (79-30%)

An increased concentration of dicarboxylic acid in the urine.

Exercise-induced myalgia · Frequent (79-30%)

The occurrence of an unusually high amount of muscle pain following exercise.

Fatigable weakness · Frequent (79-30%)

A type of weakness that occurs after a muscle group is used and lessens if the muscle group has some rest. That is, there is diminution of strength with repetitive muscle actions.

Fatigable weakness of neck muscles · Frequent (79-30%)

A type of weakness of a skeletal muscle in the neck that occurs after a muscle group is used and lessens if the muscle group has some rest. That is, there is diminution of strength with repetitive muscle actions.

Hepatomegaly · Frequent (79-30%)

Abnormally increased size of the liver.

Hyperammonemia · Frequent (79-30%)

An increased concentration of ammonia in the blood.

Hypotonia · Frequent (79-30%)

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.

Proximal muscle weakness · Frequent (79-30%)

A lack of strength of the proximal muscles.

Reduced tendon reflexes · Frequent (79-30%)

A reduction (hyporeflexia) or complete absence (areflexia) of the involuntary muscle contraction normally elicited by a reflex stimulus, such as tapping a deep tendon.

Vomiting · Frequent (79-30%)

Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.

Abnormal lactate dehydrogenase activity · Occasional (29-5%)

A deviation from the normal serum concentration/activity of lactate dehydrogenase (LDH), which catalyzes the reduction of pyruvate to form lactate.

Arrhythmia · Occasional (29-5%)

Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.

Other findings in the same source

From: Orphanet

Additional reported features include Ataxia (Occasional (29-5%)); Bilateral tonic-clonic seizure (Occasional (29-5%)); Cachexia (Occasional (29-5%)); Cardiomegaly (Occasional (29-5%)); Coma (Occasional (29-5%)); Delayed speech and language development (Occasional (29-5%)); Diarrhea (Occasional (29-5%)); Distal arthrogryposis (Occasional (29-5%)); Elevated circulating creatine kinase concentration (Occasional (29-5%)); Elevated circulating hepatic transaminase concentration (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 Medium-chain acyl-CoA dehydrogenase 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

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Medium-chain acyl-CoA dehydrogenase deficiency. 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.

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.