Trifunctional Protein Deficiency, Metabolic Disorder, Fatty acid oxidation disorder Screening -Infant

Trifunctional Protein Deficiency, Metabolic Disorder, Fatty acid oxidation disorder Screening -Infant

Trifunctional Protein Deficiency, Metabolic Disorder, Fatty acid oxidation disorder Screening

Summary of Recommendation and Evidence

Population

Recommendation

Grade
(What's This?)

Screening of both genders

The genetic screening for Trifunctional protein deficiency (TFP) is recommended.

B

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 TFP deficiency in the United States is approximately 1:363,738.

INHERITANCE

TFP 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:
  1. Elevated liver function tests
  2. Elevated CK
  3. Metabolic acidosis
  4. Lactic acidosis
  5. Hypoglycemia

Without effective treatment, subsequent symptoms may include:

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

EARLY SIGNS

There are three distinct forms of trifunctional protein deficiency (TFP) based on the age of onset: early, childhood, and mild. If your baby has early TFP, you will start seeing signs between birth and age 2, whereas individuals with childhood TFP show signs after infancy. Mild TFP is very uncommon. If your child has mild TFP, he or she could start showing signs any time between 2 years of age and adulthood.

Signs of early TFP include:

  • Poor appetite
  • Sleeping longer or more often
  • Tiredness
  • Weak muscle tone (called hypotonia)
  • Fever
  • Vomiting
  • Diarrhea
  • Low blood sugar (called hypoglycemia)
  • Irritability
  • Behavior changes
  • No reflexes or pain responses
  • Developmental delays

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. Some enzymes help break down fats into their building blocks, called fatty acids. Other enzymes break down these fatty acids.

Fatty acids are built like chains, and these chains come in various lengths. They are classified as either short, medium, long, or very long. Different enzymes are made to break down different length fatty acids. An enzyme complex (multiple enzymes attached to each other) called trifunctional protein helps break down “long” fatty acid chains.

If your baby has trifunctional protein deficiency (TFP), then his or her body either does not make enough or makes non-working trifunctional protein enzymes. This is harmful to the body because your baby’s heart and muscles need fatty acids for energy. Your baby’s body also needs to break down fatty acids when there is not enough sugar, such as between meals.

TFP is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for TFP, 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 TFP is rare, when both parents are carriers, they can have more than one child with the condition.

TREATMENT

Your baby will need to be on a restricted diet in order to avoid certain high-fat foods that your baby’s body cannot break down. A dietician or a nutritionist can help you plan a diet that keeps your baby healthy while giving him or her the nutrients necessary for healthy growth.

Your baby will also need to eat often to avoid many of the signs mentioned in the Early Signs section.

Supplements and Medications

Your baby’s doctor might recommend supplements for your baby. Medium Chain Triglyceride (MCT) oil is a supplement that provides energy for your baby because it contains fatty acids that people with trifunctional protein deficiency (TFP) can digest. Talk to your baby’s doctor before starting this treatment.

Some children with TFP also take prescription L-carnitine supplements. L-carnitine is a substance that the body makes naturally, but your baby’s body might not make enough of it. Taking L-carnitine can help your baby with TFP break down fats and remove harmful substances from the body. Your baby’s doctor will need to write you a prescription for these supplements.

Lifestyle Changes

You will need to keep your baby out of extremely hot and cold temperatures. Extreme temperatures can promote muscle breakdown.

EXPECTED OUTCOMES

If your child has childhood or mild trifunctional protein deficiency (TFP), he or she can live a healthy life with the help of treatment. Some children could still have hypoglycemic (low blood sugar) episodes, even with treatment.

Babies with early TFP may benefit from treatments. However, most babies are at risk of dying young from heart and breathing problems, even with treatment.

If TFP is not treated, hypoglycemic episodes can lead to coma or even death.