VLCAD Deficiency

Introduction

VLCAD deficiency is one example of a fatty acid oxidation disorder (FAOD). At the International Network for Fatty Acid Oxidation Research and Management (INFORM), we want to educate the general public on these disorders. We also want to give the families of those affected access to the latest research surrounding fatty oxidation disorders and help create a FAODs support group.

What is VLCAD Deficiency?

Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD deficiency) is a rare inherited disorder of fat metabolism that prevents the body from making enough energy during stress, illness, and fasting. After the body has used up its stores of available sugars it uses fats to make energy. In each cell in the body, this breakdown of fats happens in the mitochondria, or the “powerhouses of the cell.” For someone with a VLCAD deficiency, the first step in the breakdown of fats is missing or reduced.

Genetics

VLCAD deficiency occurs when an individual inherits one disease-causing change in the ACADVL gene from each parent. With each subsequent pregnancy, there is a 25% chance that the child will have the VLCAD deficiency. In addition, pregnant women have an increased risk for pregnancy complications if they are carrying an affected baby (HELLP syndrome). Genetic counseling can benefit affected individuals, as well as their families. Blood-related siblings of those diagnosed with this disorder should be tested for VLCAD in case a diagnosis was missed.

Signs and Symptoms of VLCAD Deficiency

Today in the United States, the majority of fatty acid oxidation disorder patients are identified right after birth because of a newborn screening program that involves taking a blood spot from the infant’s heel. Although VLCAD is usually detected from newborn screening as well, the signs of VLCAD deficiency can occur at any age, from birth to early adulthood. The disorder varies from mild to life-threatening, with different symptoms in the same patient as he or she ages.

Patients with VLCAD deficiency all have a specific form of low blood sugar called hypoketotic hypoglycemia. When healthy people fast or expend extra calories in exercise they burn fat. At the end of the fat-burning, some of its products are turned into protective molecules called ketones, that provide energy for the brain. In disorders like VLCAD deficiency, few ketones are found in the blood or urine after stress because a product from the burning of fat (beta-oxidation) is required to make ketones. Since VLCAD patients cannot even begin to oxidize fat, their hypoglycemia comes without ketones (hypoketotic hypoglycemia). This specific type of low blood sugar is only seen in FAODs.

Infants who are symptomatic early may experience symptoms like:

  • Life-threatening low blood sugar (hypoglycemia)
  • High blood ammonia
  • Coma within days or weeks after birth from low blood sugar

From about two months to two years of age, affected infants will experience various symptoms and are at risk for many serious problems. They may suffer from:

  • Lethargy (looking tired and listless)
  • Irritability
  • Noticeably enlarged liver (hepatomegaly) when they are sick
  • A weakened heart muscle (cardiomyopathy)
  • Abnormal heart rhythms
  • Total failure of the combined lung and heart function

During later childhood and early adulthood, low blood sugar episodes associated with life-threatening comas and heart problems become less common. Instead, patients may experience:

  • Periodic severe muscle pain caused by skeletal muscle breakdown (rhabdomyolysis)
  • Urine that is a brownish red color (myoglobinuria).

This muscle breakdown is increased by illness, stress, cold/heat or exercise. Unchecked severe rhabdomyolysis is serious and must be treated promptly. Patients with a milder form may only have episodes of muscle pain after a severe illness or intense exercise.

Between acute episodes, some individuals with VLCAD deficiency are well, but others may have:

  • Poor muscle tone (hypotonia)
  • Chronic heart problems like cardiomyopathy or heart failure

These problems depend on the nature and severity of the condition, the patient’s age, and other factors. Abnormalities of heart rhythm can occur at any age and may be life threatening.

How to Diagnose VLCAD Deficiency

Most VLCAD deficiency cases are identified in the first three to four days of life through newborn screening of blood by tandem mass spectrometry. These infants are referred to a physician for immediate diagnosis and intervention. Clinical studies of blood and urine are done to differentiate a VLCAD deficiency from other fatty acid defects with similar signs and symptoms. Each of these conditions has specific blood and urine findings that help confirm the exact diagnosis. VLCAD deficiency can also be confirmed by genetic testing for disease-causing changes in the ACADVL gene or by measurement of VLCAD enzyme activity in blood or skin cells.

Prenatal diagnosis can be done during pregnancy using cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). If an ill child has not been screened for VLCAD as a newborn, diagnostic testing may involve analysis of specific fats called acylcarnitines, levels of free carnitine in the blood, and very long chain fat derivatives in the urine.

In some cases, VLCAD deficiency-affected individuals may also be identified later in life, either because they were not screened properly at birth or not screened at all. It is also possible that they have a milder form of the deficiency that did not show up in infancy.

Treatment

Management of VLCAD deficiency is focused primarily on preventing acute episodes of low blood sugar (hypoglycemia). This process includes avoiding fasting and using a very low-fat, high-carbohydrate diet, with frequent feeding. Fasting in the first year of life can increase from 4 to 8 hours and should be limited to less than 10 hours after the age of 2 years. In some severe cases, continuous feeding with a tube may be necessary to avoid hypoglycemia, especially overnight.

A doctor may recommend special nutritional treatments such as medium-chain triglycerides like MCT oil), carnitine (Carnitor), and/or riboflavin (Vitamin B2) supplements. Limiting exercise, avoiding cold/heat exposure, and not fasting may be sufficient enough to control the symptoms in mild cases.

Medical treatment should be sought immediately if there is a loss of consciousness or severe confusion as these are signs of dangerously low blood sugar. At the medical facility, intravenous glucose-containing fluids are given to address the hypoglycemia. All patients should carry an emergency letter that details their prescribed treatment to manage severe episodes.

Investigational Therapies and Fatty Acid Oxidation Research

A clinical trial is currently being conducted on treatment of VLCAD deficiency with triheptanoin (UX007, Ultragenyx Pharmaceuticals), an artificial fat that is used instead of MCT oil in the diet. Published clinical trial data indicate fewer episodes of low blood sugar and muscle breakdown (rhabdomyolysis) as well as hospitalizations in patients treated with triheptanoin. Heart function may also be improved.

Other fatty acid oxidation research has looked at the use of Bezafibrate. Bezafibrate is an experimental medication originally developed to lower blood cholesterol. It has also been shown to increase the amount of VLCAD protein in cells. Limited clinical studies using benzafibrate to treat VLCAD deficiency have been published, but no active clinical trials are in progress. A similar but more powerful potential drug will soon be evaluated in clinical trials for VLCAD deficiency in the U.S.

Information on current clinical trials for both government funded and some private industry projects are posted at ClinicalTrials.Gov.

Jerry Vockley, the founder of Inform Network, created this organization to act as a source of the most up-to-date and accurate information on fatty oxidation disorders.

 

Related Readings:

Help! My Child Has a Fatty Acid Oxidation Disorder

GMDI/SERN VLCAD Nutrition Guidelines

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