Carnitine palmitoyltransferase II deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Carnitine palmitoyltransferase II (CPT II) deficiency is a condition that prevents the body from using certain fats for energy, particularly during periods of fasting. There are three main types of CPT II deficiency that vary in severity and the age at which symptoms first appear: a lethal neonatal form, a severe infantile hepatocardiomuscular form, and a myopathic form.

The lethal neonatal form of CPT II deficiency becomes apparent soon after birth. Infants with this form of the disorder develop respiratory failure, liver failure, a weakened heart muscle (cardiomyopathy), and an irregular heartbeat (arrhythmia). In many cases, the brain and kidneys are also structurally abnormal. Affected individuals have low levels of glucose in the blood and low levels of ketones, which are produced during the breakdown of fats and used for energy. Together, these signs are called hypoketotic hypoglycemia. If affected individuals fast for long periods of time, they can experience seizures or coma. Because of these serious health complications, infants with the lethal neonatal form of CPT II deficiency usually live for only a few days to a few months.

The severe infantile hepatocardiomuscular form of CPT II deficiency affects the liver, heart, and muscles. Signs and symptoms usually appear within the first year of life. This form involves recurring episodes of hypoketotic hypoglycemia, seizures, liver dysfunction, cardiomyopathy, arrhythmia, and muscle weakness (myopathy) in the arms and legs. Signs and symptoms of this form of CPT II deficiency can be triggered by fasting or by illnesses such as viral infections. Individuals with the severe infantile hepatocardiomuscular form of CPT II deficiency are at risk for liver failure, nervous system damage, coma, and sudden death.

The myopathic form is the least severe type of CPT II deficiency. This form is characterized by recurrent episodes of muscle pain (myalgia) and occasional weakness that is associated with the breakdown of muscle tissue (rhabdomyolysis). The destruction of muscle tissue releases a protein called myoglobin. This excess myoglobin may cause urine to be red or brown (myoglobinuria). Episodes of myalgia and rhabdomyolysis may be triggered by exercise, stress, exposure to extreme temperatures, infections, or fasting. The first episode of myalgia usually occurs during childhood or adolescence. The severity and frequency of episodes varies among affected individuals. Most people with the myopathic form of CPT II deficiency have no signs or symptoms of the disorder between episodes.

People with CPT II deficiency are often encouraged to avoid triggers such as long periods of fasting and intensive exercise to limit the occurrence of serious health problems.

CPT II deficiency is often detected shortly after birth by newborn screening, which identifies abnormal levels of certain compounds in the blood. In individuals with CPT II deficiency, the blood levels of certain fats are elevated.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the CPT2 gene cause CPT II deficiency. This gene provides instructions for making an enzyme called carnitine palmitoyltransferase 2.

This enzyme is essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them into energy. During periods of fasting, fats are an important energy source for the liver and other tissues. Fatty acid oxidation takes place within mitochondria, which are the energy-producing centers. Before they can enter mitochondria, groups of fats called long-chain fatty acids must first be attached to a compound called carnitine. Once these fatty acids are inside mitochondria, carnitine palmitoyltransferase 2 removes the carnitine and prepares them for fatty acid oxidation.

Variants in the CPT2 gene reduce the activity of carnitine palmitoyltransferase 2. As a result, there are not enough enzymes available to remove carnitine from long-chain fatty acids. With carnitine still attached, these fatty acids (known as long-chain acylcarnitines) cannot be broken down and used for energy. Reduced energy production can lead to some of the features of CPT II deficiency, such as hypoketotic hypoglycemia, myalgia, and muscle weakness. Long-chain acylcarnitines, which are detected in newborn screening tests, may also build up in cells and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of CPT II 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 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. Rarely, people with only one variant in the CPT2 gene (known as carriers) have shown symptoms of the myopathic form of CPT II deficiency after strenuous activity, such as running long distances. More research is needed to determine how frequently carriers of CPT2 gene variants have health problems and under what circumstances.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

CPT II deficiency is a rare disorder. The lethal neonatal form has been described in at least 20 families, while the severe infantile hepatocardiomuscular form has been identified in approximately 30 families. The myopathic form is the most common form, with more than 300 reported cases.

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.

Muscle weakness · Very frequent (99-80%)

Reduced strength of muscles.

Myalgia · Very frequent (99-80%)

Pain in muscle.

Reduced carnitine O-palmitoyltransferase activity · Very frequent (99-80%)

Reduced carnitine O-palmitoyltransferase (CPT II; EC 2.3.1.21) activity or level, leading to a reduced activity of the reaction: palmitoyl-CoA + L-carnitine = CoA + L-palmitoylcarnitine. (CPT II activity can be measured in tissues including fibroblasts, lymphoblasts, and skeletal muscle.

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

A decreased concentration of free (unbound) carnitine in the blood.

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

A decreased concentration of total carnitine in the blood.

Elevated circulating creatine kinase concentration · Frequent (79-30%)

The activity of creatine kinase in the blood circulation is above the upper limit of normal.

Elevated plasma acylcarnitine levels · Frequent (79-30%)

The concentration of fatty acylcarnitine in the blood circulation is above the upper limit of normal.

Exercise intolerance · Frequent (79-30%)

A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.

Other findings in the same source

From: Orphanet

Additional reported features include Exercise-induced myalgia (Frequent (79-30%)); Hyperlipidemia (Frequent (79-30%)); Myoglobinuria (Frequent (79-30%)); Myopathy (Frequent (79-30%)); Red-brown urine (Frequent (79-30%)); Cold-induced muscle cramps (Occasional (29-5%)); Episodic abdominal pain (Occasional (29-5%)); Exercise-induced muscle cramps (Occasional (29-5%)); Headache (Occasional (29-5%)); Hepatomegaly (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 Carnitine palmitoyltransferase II 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 Carnitine palmitoyltransferase II 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.

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.