Long-chain L-3 Hydroxyacyl-CoA Dehydrogenase Deficiency, Metabolic Disorder, Fatty acid oxidation disorder Screening -Infant

Summary of Recommendation and Evidence

Population	Recommendation	Grade (What's This?)
Screening of both genders	The genetic screening for Long-chain L-3 Hydroxyacyl-CoA Dehydrogenase Deficiency is recommended.	B

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, often shortened to LCHAD deficiency, is a rare autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats into energy.

OVERVIEW

The trifunctional protein catalyzes 3 steps in the beta-oxidation of fatty acids, including the hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase. It is formed by 2 subunits encoded by 2 different genes (HADA and HADB) located on the same chromosome (2p23). In LCHAD deficiency, specific missense mutations within the alpha subunit (HADA) cause the disease. Mutations that completely abolish the function of the protein cause trifunctional protein (TFP) deficiency. TFP deficiency can be caused either by mutations in the alpha (HADA) or beta subunit (HADB); LCHAD is caused by specific missense mutations in the alpha subunit that allow the reaction to start, but not be completed. LCHAD and TFP deficiency cause cellular damage from accumulation of 3-OH-fatty acids, impaired energy production from longer chain fatty acids, and consequent hypoglycemic crises during prolonged fasting or increased energy demands, such as fever or other stress.

SCREENING

Finding

Elevated C16-OH +/- and C18:1-OH

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=100%

PREVALENCE

The incidence of LCHAD deficiency in the United States is approximately 1:363,738.

INHERITANCE

LCHAD is inherited in an autosomal recessive manner. It affects both boys and girls equally.

MATERNAL & FAMILY HISTORY

HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelet count), acute fatty liver of pregnancy (AFLP) syndrome, and increased incidence of pre-eclampsia and eclampsia can be seen in mothers carrying a child with LCHAD or TFP deficiency. These complications can be life-threatening in the mother and lead to premature birth.

PRENATAL TESTING

Prenatal testing involves DNA testing in cells obtained by amniocentesis or chorionic villous sampling (CVS).

CLINICAL CHARACTERISTICS

With treatment prior to hypoglycemic crises, the child’s intelligence is likely to be normal, but progression of peripheral neuropathy and retinitis pigmentosa can occur. Without treatment, hypoglycemic episodes may lead to developmental delay and neurologic impairment.

Cardiomyopathy and/or hepatic failure may result in death. Pigmentary retinopathy develops with time. Neuropathy is more frequent and usually occurs earlier in patients with trifunctional protein deficiency. Symptoms, whether mild or severe, may begin anytime between birth and 3 years of age. All patients have exercise intolerance and develop myoglobinuria and muscle pain with strenuous exercise.

Initial symptoms/signs may include:

Poor feeding
Vomiting
Lethargy
Hypotonia
Heptomegaly
Cardiac insufficiency
Cardiomyopathy
Lab findings:

Elevated liver function tests
Elevated CK
Metabolic acidosis
Lactic acidosis
Hypoglycemia

Without effective treatment, subsequent symptoms may include:

Hepatic disease
Cardiomyopathy
Cardiac conduction defects (arrhythmia)
Peripheral neuropathy
Pigmentary retinopathy
Rhabdomyolysis

EARLY SIGNS

Not all children with long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) show signs of the condition. For those children who will show signs, the first signs often appear between birth and two years of age.

Signs of LCHAD include:

Sleeping longer or more often
Tiredness
Weak muscle tone (also called hypotonia)
Nausea and vomiting
Irritability
Restlessness
Behavior changes

Many of these signs may occur when your baby eats foods that his or her body cannot break down. They can be triggered by long periods of time without eating, illnesses, and infections.

CAUSES

When we eat food, enzymes help break it down. Certain enzymes break down fats into their building blocks, fatty acids. Other enzymes break down these fatty acids.

Fatty acids are built like chains, and they come in a variety of lengths. They are categorized as either short, medium, long, or very long. Different enzymes work on different length fatty acids.

The enzyme long-chain acyl-CoA dehydrogenase breaks down “long” fatty acids. If you have a question about what makes a “long” fatty acid.

Babies with long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) either do not make enough or make non-working long-chain acyl-CoA dehydrogenase enzymes. Babies with LCHAD cannot break down long chain fatty acids for energy. This is harmful because your baby’s heart and muscles need fatty acids for energy. Fatty acids are also important energy sources when there are not enough sugars in the body, such as in between meals.

LCHAD is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for LCHAD, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with LCHAD is rare, when both parents are carriers, they can have more than one child with the condition.

TREATMENT

Dietary Treatment

Your baby will need to be on a restricted diet in order to avoid high-fat foods that his or her body cannot break down. A nutritionist or dietician can help you plan an appropriate diet for your child.

Your baby will also need to eat often because long periods of time without food can trigger many of the signs mentioned in the Early Signs section.

Supplements

The most common treatment for children with long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) is Medium Chain Triglyceride (MCT) oil. MCT oil helps give your body energy because it contains fats that people with LCHAD can break down. Talk to your baby’s doctor before starting this type of treatment.

Your baby’s doctor might also prescribe L-carnitine supplements. L-carnitine is a substance naturally produced by the body, but your baby’s body might not make enough of it. Prescription L-carnitine supplements can help break down fats for energy and remove harmful substances from the body.

Your baby may also benefit from DHA supplements. DHA is a natural supplement that your baby’s doctor can prescribe to help protect your baby’s eyesight. Talk to your baby’s doctor before starting these supplements.

EXPECTED OUTCOMES

Children who receive treatment for long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) have healthy growth and development.

Some children with LCHAD still have episodes of low blood sugar, even with treatment. You may need to monitor your child’s blood sugar levels.

Early screening and treatment is important because low blood sugar episodes can cause developmental delays, heart and liver problems, or result in a coma.