Mitochondrial trifunctional protein deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency are two related types of genetic conditions where the enzymes that are needed to break down long-chain fats are unable to function properly. This prevents the body from creating needed energy during times of stress, illness, fasting, and exercise, which can lead to medical symptoms. The body usually gets its energy by breaking down, or burning, fats and sugars. People with FAODs cannot properly break down certain types of fats.
TFP is a protein complex with three separate enzymes that work together to break down long-chain fats. The LCHAD enzyme is the second enzyme in the TFP protein complex and is altered in LCHAD deficiency. TFP typically creates a deficiency in all three enzymes. When someone has a deficiency in the TFP protein complex, very little energy is created from long-chain fats.
Long-Chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency
- Autosomal recessive
Cause and Genetics
TFP/LCHAD deficiency is caused by genetic changes in one of two genes: HADHa or HADHb. These genes both provide instructions for the body to make TFP. Most genetic changes in the gene HADHa cause problems with LCHAD function. Changes in the gene HADHb usually affect all three enzymatic functions of the TFP. People usually have two copies of both of these genes, one inherited from each parent. TFP deficiency occurs when there are changes in both copies of either HADHa or HADHb (autosomal recessive inheritance). Someone who has a change in only one copy of either of these genes is called a carrier, and they usually do not have any medical symptoms. If both parents are carriers, there is a 1 in 4 chance with each pregnancy that their child will have TFP/LCHAD deficiency.
Frequency - More Information
TFP deficiency is considered a rare condition and the exact number of affected individuals is not known. The number of people affected with LCHAD deficiency is also unknown, but may be more common in people from Finland. Newborn screening has confirmed an estimated incidence of 1.2/100,000.
Affected Biological Gender
Both Male and Female
Signs and Symptoms
People with TFP/LCHAD deficiency can have a wide range of signs and symptoms. Whether your child was diagnosed via newborn screening may also affect when, if, and how these symptoms present. Always check with your doctor if your child is doing something out of “their” normal, as every child may present with symptoms a little differently.
Signs and symptoms may include:
- Extreme tiredness (lethargy) or acting “sluggish”
- Poor feeding
- Enlarged, weakened heart (cardiomyopathy)
- Abnormal heart rhythm (arrhythmia)
- Liver malfunctions that can become life-threatening
- Specific type of vision loss (pigmentary retinopathy)
- Low blood sugar (hypoglycemia)
- Nerve damage in the legs and hands (peripheral neuropathy)
- Low muscle tone (hypotonia)
- Muscle weakness (myopathy)
- Muscle breakdown (rhabdomyolysis)
- Reddish-brown urine (myoglobinuria)
The potential for muscle breakdown (rhabdomyolysis), is increased by illness, stress, cold/heat and exercise, and should be treated promptly. Medical treatment should be sought immediately if there is loss of consciousness or severe confusion (decompensation), as these are signs of dangerously low blood sugar.
These signs and symptoms may vary depending on age, treatment, and if in crisis. With proper treatment, some of these symptoms may be attenuated/controlled in patients between episodes of crisis.
Most cases of TFP/LCHAD deficiency are identified by routine newborn screening. If newborn screening is suggestive of TFP/LCHAD deficiency, additional tests may be performed including:
- Measuring biochemical markers in the blood or urine
- Measuring enzyme activity in skin cells or white blood cells
- Performing a genetic test to look for changes in genes that can cause FAODs
Some people with milder cases of TFP deficiency are not diagnosed until adolescence. These individuals often present with:
- Repeated episodes of severe muscle pain
- Muscle breakdown, especially after heavy exercise (rhabdomyolysis)
- Reddish-brown urine (myoglobinuria)
In some cases, a diagnosis of TFP/LCHAD deficiency can be made before birth. If there is a family history of TFP/LCHAD deficiency, or if parents are known carriers, prenatal testing can be performed.
Some pregnant mothers will experience a life-threatening syndrome called HELLP syndrome during pregnancy. This may include high blood pressure, abnormal liver functions, and decreased blood clotting.
Newborn Screening: Recommended Uniform Screening Panel (RUSP)
Treatment and Management
Treatment and management of TFP/LCHAD deficiency may include:
- Specialized medical formulas
- Regular eating schedules to prevent low blood sugar (hypoglycemia)
- Continuous feeding directly into the stomach in severe cases, especially at night
- Low-fat, high-carbohydrate diet (some dieticians may also increase protein)
- Medicine called triheptanoin (Dojolvi)
- MCT supplementation
- Intravenous (IV) sugar-containing fluids called D10 during a metabolic crisis
- Supplementation with docosahexaenoic acid (DHA) to help prevent vision damage to part of the eye called the retina (retinopathy)
Parents should call their healthcare provider immediately if babies show symptoms like excessive sleepiness, vomiting, diarrhea, a fever, poor appetite, or an infection. Medical treatment should be sought immediately if there is loss of consciousness or severe confusion (decompensation), as these are signs of dangerously low blood sugar.
Patients should discuss the appropriate preparation for anesthesia with their metabolic team.
- Mitochondrial trifunctional protein deficiency – About the Disease – The National Institutes of Health
- MTP/LCHAD Deficiency | Fatty Acid Oxidation Disorders Diagnosis – The INFORM Network
- Newborn screening information for trifunctional protein deficiency | Baby’s First Test
- What is LCHADD? – ThinkGenetic, Inc.
- Rücklová, Kristina et al. “Impact of Newborn Screening and Early Dietary Management on Clinical Outcome of Patients with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency and Medium Chain Acyl-CoA Dehydrogenase Deficiency-A Retrospective Nationwide Study.” Nutrients vol. 13,9 2925. 24 Aug. 2021.
Connecting with others impacted by a rare disease allows for vital information to be shared about day-to-day life, prevents isolation, and gives hope. Please contact MitoAction for peer support opportunities at 888-MITO-411 or email firstname.lastname@example.org.
Other resources we recommend are:
- New Patient Kit for Mitochondrial Conditions
- Planning for Emergencies
- Monthly Expert Series
- Energy in Action Podcast
MitoAction does not provide medical advice, diagnosis, treatment, or legal advice. It is essential that all those living with or caring for someone with a Mitochondrial or FAOD disease have an emergency protocol letter. These letters, which are written and signed by a doctor, share details about prescribed treatment during crises and in emergency room settings. Always check with your doctor if you or your child has concerns as everyone may present with symptoms differently. Before beginning any treatment or therapy, please consult with your physician.
Last Updated: 11/15/2022