VLCADD Deficiency

Introduction

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. When 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, the “powerhouses of the cell.” In VLCAD deficiency, the first step in the breakdown of fats is missing or reduced.

Signs and symptoms

Today in the United States, the majority of VLCAD deficiency patients are identified right after birth because of a newborn screening program that involves taking a blood spot from the infant’s heel.  However, 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 a he or she ages. Infants who are symptomatic early may have life-threatening low blood sugar (hypoglycemia), which may result in a coma within days or weeks after birth. Blood ammonia may also be high.

From about two months to two years of age, affected infants are at risk for many serious problems, including a weakened heart muscle (cardiomyopathy), abnormal heart rhythms, and even total failure of the combined lung and heart function. Infants may look tired and listless (lethargy), be irritable, and the liver may be noticeably enlarged (hepatomegaly) when they are sick.

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. These 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 VLCADD 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 this group of disorders.

During later childhood and early adulthood, low blood sugar episodes associated with life-threatening comas and heart problems become less common. Instead patients may have periodic severe muscle pain caused by skeletal muscle breakdown (rhabdomyolysis) with their urine showing 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 VLCADD deficiency are well, but some may have poor muscle tone (hypotonia) or chronic heart problems such as cardiomyopathy or heart failure, depending on the nature and severity of the condition, age, and other factors. Abnormalities of heart rhythm can occur at any age and may be life threatening.

Diagnosis

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 confirm VLCAD deficiency versus 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. The specific diagnosis 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.

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

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 VLCADD 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.

Genetics

VLCAD deficiency occurs when an individual inherits one disease-causing change in the ACADVL gene from each parent.  With each pregnancy, there is a 25% chance to have another child with 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. Siblings should be tested for VLCAD, in case a diagnosis was missed.

Treatment

Management of VLCAD deficiency is focused primarily on preventing acute episodes of low blood sugar (hypoglycemia). This 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 such as MCT oil), carnitine (Carnitor) and/or riboflavin (Vitamin B2) supplements. Limiting exercise and cold/heat exposure and avoiding fasting may be sufficient to control the symptoms in mild cases.

Medical treatment should be sought immediately if there is 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 carry an emergency letter that details their prescribed treatment to manage severe episodes.

Investigational Therapies

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 of muscle breakdown (rhabdomyolysis) and hospitalizations in patients treated with triheptanoin. Heart function may also be improved.

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 is posted at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

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