FATTY ACID DISORDER

Disorder name: Trifunctional proteinA molecule that makes up many parts of every cell in the body. Examples of proteins include hormones, enzymes, hair, and antibodies. Proteins are made up of 20 different types of individual units called amino acids. It is the order of these amino acids in a protein that determines what form and function a protein has. Each gene holds the instructions for making a single protein. deficiency
Acronym: TFP deficiency
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• What is TFP deficiency?
• What causes TFP deficiency?
• If TFP deficiency is not treated, what problems occur?
• What is the treatment for TFP deficiency?
• What happens when TFP deficiency is treated?
• What causes the TFP enzyme to be absent or not working correctly?
• How is TFP deficiency inherited?
• Is genetic testing available?
• What other testing is available?
• Can you test during a future pregnancy?
• Can other members of the family have TFP deficiency or be carriers?
• Can other family members be tested?
• How many people have TFP deficiency?
• Does TFP deficiency happen more often in a certain ethnic group?
• Does TFP deficiency go by any other names?
• Where can I find more information?

This fact sheet contains general information about TFP deficiency. Every child is different and some of this information may not apply to your child specifically.   Not all is known about TFP deficiency and, at present, there is no standard treatment plan. Certain treatments may be recommended for some children but not others. Children with TFP deficiency should be followed by a metabolic doctor in addition to their primary doctor.

WHAT IS TFP DEFICIENCY?

TFP deficiency stands for “trifunctional protein deficiency.” It is one type of fatty acid oxidationThis is the process used by the body to change fatty acids, the building blocks of fat, into energy. It happens in the mitochondria – the small energy-producing parts found in each cell of the body. disorder. Some people with TFP deficiency have problems breaking down fatFat is one of the three main nutrients in food (carbohydrates, fat, protein). Some foods that contain fat are butter, margarine, oils, nuts, meats, poultry, fish and some dairy products. Extra calories from food are stored as body fat. Stored body fat provides the body with a reserve supply of energy. into energy for the body.

Fatty Acid Oxidation Disorders: Fatty acid oxidation disorders (FAODs)This is a group of rare inherited conditions. FAODs are caused by missing or non-working enzymes. Normally, many enzymes are used by the body to break down fat into energy. In people with FAODs, one of these enzymes is not working and fat cannot be used for energy. If these conditions are not treated, they can lead to serious health problems. are a group of rare inheritedAcquiring a trait from one’s parents. Most traits, such as eye color or hair color, are inherited from a parent through genes. conditions. They are caused by enzymes that do not work properly. A number of enzymesA molecule that helps chemical reactions take place. For example, enzymes in the stomach speed up the process of breaking down food. Each enzyme can participate in many chemical reactions without changing or being used up. are needed to break down fats in the body (a process called fatty acid oxidation). Problems with any of these enzymes can cause a fatty acid oxidation disorder. People with FAODs cannot properly break down fat from either the food they eat or from fat stored in their bodies. The symptoms and treatment vary between different FAODs. They can also vary from person to person with the same FAOD. See the fact sheets for each specific FAOD. FAODs are inherited in an autosomal recessive manner and affect both males and females.

WHAT CAUSES TFP DEFICIENCY?

TFP deficiency occurs when a group of enzymes, called “trifunctional protein” (TFP), is either missing or not working properly. The job of TFP is to break down certain fats from the food we eat into energy. It also breaks down fat already stored in the body

Energy from fat keeps us going whenever our bodies run low of their main source of energy, a type of sugar called glucoseThis is a type of sugar made from the carbohydrates in food. Glucose is found in the blood. It is the main source of energy for the body and brain.. Our bodies rely on fat when we don’t eat for a stretch of time – like when we miss a meal or when we sleep.

When TFP is missing or not working well, the body cannot use fats for energy. Instead, it must rely solely on glucose. Although glucose is a good source of energy, there is a limited amount available. Once the glucose has been used up, the body tries to use fat without success. This leads to low blood sugar, called hypoglycemiaThis happens when there is too little sugar (glucose) in the blood. It may cause a person to feel nervous, shaky, weak, or sweaty. It may also cause headache, blurred vision, and hunger. If left untreated, it can cause unconsciousness (coma) and sometimes even death., and to the build up of harmful substances in the blood.

IF TFP DEFICIENCY IS NOT TREATED, WHAT PROBLEMS OCCUR?

TFP deficiency can cause mild symptoms in some people or more serious health problems in others. There are three types of TFP deficiency: early, childhood, and mild.

Babies and children with early and childhood TFP deficiency can have episodes of illness called metabolic crisisThis is a serious health condition caused by low blood sugar and the build-up of toxic substances in the blood. Symptoms of a metabolic crisis are poor appetite, nausea, vomiting, diarrhea, extreme sleepiness, irritable mood and behavior changes. If not treated, breathing problems, seizures, coma, and sometimes even death can occur.Metabolic crises happen more often in people with certain metabolic disorders (some fatty acid oxidation disorders, amino acid disorders, and organic acid disorders). They are often triggered by things like illness or infection, going without food for a long time, and, in some cases, heavy exercise.. Some of the first symptoms of a metabolic crisis are:

• extreme sleepiness
• behavior changes
• irritable mood
• muscle weakness
• poor appetite

Some of these other symptoms may also follow:

• fever
• nausea
• diarrhea
• vomiting
• hypoglycemia
• increased levels of acidic substances in the blood, called metabolic acidosisThis happens when acidic substances build up in the blood. It can cause rapid breathing, confusion, and extreme sleepiness. If not treated, it may lead to shock, coma or death.

If a metabolic crisis is not treated, a child with TFP deficiency can develop:

• breathing problems
• seizuresThese are also called "convulsions" or "fits." During a seizure, a person loses consciousness and control of his or her muscles. It may also cause involuntary movements. Seizures can happen for many reasons. Some causes are metabolic disorders, a metabolic crisis, brain injury, and infection.
• comaThis is a sleep-like condition from which a person cannot be awakened. People in a coma are unconscious. A coma can be caused by many things. Two causes are untreated low blood sugar (hypoglycemia) and a metabolic crisis., sometimes leading to death

Periods of hypoglycemia can happen without other symptoms of metabolic crisis. Hypoglycemia causes:

• weakness
• shakiness
• dizziness
• clammy, cold skin
• if untreated, coma, and sometimes death

In children with TFP deficiency, either hypoglycemia or a metabolic crisis can happen:

• after going too long without food
• after long periods of exercise
• during illness or infection
• during times of stress, such as surgery

Early TFP deficiency
Babies with early TFP deficiency usually show symptoms anywhere from birth through age two. The first symptoms are often:

• poor appetite
• sluggishness
• extreme sleepiness
• muscle weakness
• absent reflexesAn automatic and involuntary action of an organ or muscle in response to a stimulus. Examples of reflexes include the kick of the lower leg when the anterior knee is tapped and pupil constriction in response to bright light. Sometimes, certain expected reflexes do not happen automatically. This is called an absence of reflexes.
• no response to pain
• delays in walking and learning

Babies with early TFP deficiency often have many episodes of metabolic crisis.

Other effects of early TFP deficiency can include:

• serious heart problems and enlarged heart
• build-up of fat in the liver and other liver problems
• breathing problems

Infants with early TFP deficiency who remain untreated usually die of heart or breathing problems by three years of age.

Childhood TFP deficiency
Childhood TFP deficiency can cause episodes of hypoglycemia and metabolic crisis. Between these episodes, children with TFP deficiency are usually healthy. However, repeated episodes may cause brain damage. This could result in learning problems or intellectual disabilities.

Bouts of muscle weakness and pain happen in some children, especially after heavy exercise, stress, or illness.

Mild/muscle TFP deficiency
The mild type of TFP deficiency has been reported in a small number of people. Symptoms can begin anywhere from age two to adulthood.

Episodes of muscle weakness are common. Breakdown of muscle fibers can occur. This usually happens:

• after strenuous exercise or exertion
• during illness or infection
• after going without food for a long period of time

Signs of muscle breakdown are:

• muscle aches
• cramps
• weakness
• reddish-brown color to the urine
• breathing problems

If muscle symptoms are not treated, kidney failure can occur.

The mild type of TFP deficiency does not cause metabolic crises or heart or liver problems.

WHAT IS THE TREATMENT FOR TFP DEFICIENCY?

Your baby’s primary doctor will work with a metabolic doctor and a dietician familiar with TFP deficiency to care for your child. to care for your child.

Certain treatments may be advised for some children but not others. When necessary, treatment is usually needed throughout life. The following are treatments that may be recommended for children with TFP deficiency:

1.  Avoid going a long time without food
Infants and young children with TFP deficiency need to eat frequently to prevent hypoglycemia or a metabolic crisis. Your metabolic doctorThis is a doctor or medical geneticist who has special training in diagnosing and treating metabolic disorders. They often work in university hospitals or large medical centers. will tell you how often your child needs to be fed.  In general, it is often suggested that infants be fed every four to six hours. Some babies need to eat even more frequently than this. It is important that infants be fed during the night. They may need to be woken up to eat if they do not wake up on their own. Your metabolic doctor and dieticianThis is a person with special training in food and nutrition. A registered dietician (RD) has met the necessary educational requirements and has passed a national examination. If your child has a metabolic disorder, it is important for you to work with a registered dietician. They help create healthy food plans for people with metabolic disorders or other special needs. will give you an appropriate feeding plan for your infant. Your doctor will also give you a ‘sick day’ plan tailored to your child’s needs for you to follow during illnesses or other times when your child will not eat.

Your metabolic doctor will continue to advise you on how often your child should eat as he or she gets older.  When they are well, many teens and adults with TFP deficiency can go without food for up to 12 hours without problems. The other treatments usually need to be continued throughout life.

2.  Diet 
A diet low in fat and high in carbohydrates is often recommended. CarbohydratesThis is one of the three types of nutrients in food (carbohydrates, fats, proteins). Sugars and starches are the most important types of carbohydrates. They are broken down by the body into glucose, the main source of energy for the body. Carbohydrates are found in foods such as: bread, cereal, pasta, grains, fruits and vegetables. Milk and dairy products, fruit drinks, sugar, candy, and sweet desserts also contain carbohydrates. give the body many types of sugar that can be used as energy. In fact, for children needing this treatment, most foods in the diet should be carbohydrates (bread, pasta, fruit, vegetables, etc.) and protein (lean meat and low-fat dairy foods). Any diet changes should be made under the guidance of an experienced dietician.

People with TFP deficiency cannot use certain building blocks of fat called long-chain fatty acidsThis is one of many types of fatty acids, the building blocks of fat. Long-chain fatty acids are made up of chains of 12 or more carbon atoms..  Your dietician can help create a food plan low in these fats. Much of the rest of the fat in the diet will likely be in the form of medium-chain fatty acidsThese are the building blocks of fat. Fat from food is broken down by enzymes into fatty acids. These are changed by other enzymes and are used as energy or stored as body fat. Some types of fatty acids are: short-chain, medium-chain, long-chain, and very-long chain..

Ask your doctor if your child needs to have any changes in his or her diet.

3. Medium Chain Triglycerides
Medium Chain Triglyceride (MCT) are often used as part of the food plan for people with TFP deficiency. MCTs are available in MCT oil and in triheptanoin (DOJOLVI ®) – a medication made of MCTs. These supplements have medium chain fatty acidsThis is one of many types of fatty acids, the building blocks of fat. Medium-chain fatty acids are made up of chains of 4 to 12 carbon atoms. that can be used in small amounts for energy. Your metabolic doctor or dietician can tell you how to use these supplements. You will need to get a prescription from your doctor to get these MCTs supplements.

4. L-CarnitineThis is a natural substance found in muscle cells. It helps the body make energy from the fat in food and the fat stored in the body. It also helps the cells get rid of harmful wastes made during the breakdown of fat. Carnitine supplements may be used as a treatment for some metabolic disorders.
Some children may be helped by L-carnitine. This is a safe and natural substance that helps body cells create energy. It also helps the body get rid of harmful wastes. Your doctor will decide whether your child needs L-carnitine.  Unless you are advised otherwise, use only L-carnitine prescribed by your doctor.

Do not use any medication or supplement without checking with your doctor.

5. Call your doctor at the start of any illness
Always call your doctor when your child has any of the following:

• poor appetite
• low energy or excessive sleepiness
• vomiting
• diarrhea
• an infection
• a fever
• persistent muscle pain or weakness
• reddish-brown color to the urine

Children with TFP deficiency need to eat extra starchy food and drink more fluids during any illness – even if they may not feel hungry – or they could develop a metabolic crisis. Children who are sick often don’t want to eat. If they won’t or can’t eat, children with TFP deficiency may need to be treated in the hospital to prevent hypoglycemia or a metabolic crisis. Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.

6.  Avoid heavy exercise and extreme cold
Long periods of heavy exercise can trigger symptoms in people with TFP deficiency. Effects of exercise can include muscle aches, cramps, and weakness. Muscle fibers may break down. This can turn the urine to a reddish-brown color.

If muscle symptoms occur, prompt treatment is needed to prevent kidney damage. Children or adults with muscle symptoms should:

• drink fluids right away
• eat something starchy or sugary
• get to a hospital for treatment

To prevent muscle symptoms:

• avoid prolonged or heavy exercise
• avoid extreme cold
• eat starchy or sugary foods before and during periods of moderate exercise or exertion

WHAT HAPPENS WHEN TFP DEFICIENCY IS TREATED?

Early TFP deficiency
Most babies with early TFP deficiency die of heart or breathing problems, even when treated. However, treatment may help prolong life in some babies.

Childhood TFP deficiency
With prompt and careful treatment, children with TFP deficiency can often live healthy lives with typical growth and development. However, some children continue to have episodes of hypoglycemia or metabolic crisis, even with treatment. This can cause permanent brain damage and may result in learning problems or intellectual disabilities.

Mild/muscle TFP deficiency
When treated, people with mild/muscle TFP deficiency usually remain healthy. This form does not affect intelligence.

WHAT CAUSES THE TFP ENZYME TO BE ABSENT OR NOT WORKING CORRECTLY?

Genes tell the body how to make enzymes. The HADHA and HADHB genesA segment of DNA that contains the instructions to make a specific protein (or part of a protein). Genes are contained on chromosomes. Chromosomes, and the genes on those chromosomes, are passed on from parent to child. Errors in the DNA that make up a gene are called variants and can lead to diseases. instructs the body to make the enzymes in the trifunctional protein. Everyone has two copies of the HADHA and HADHB genes. People with TFP deficiency have changes, also called variantsA variant is a change or alteration in a person’s DNA sequence. Variants can happen in genes and affect how the gene functions. There are different types of variants – they can be non-problem causing (benign), disease-causing (pathogenic) or of unknown significance. The term variants is now used in place of the term mutation. in both copies of either their HADHA genes or their HADHB genes.

Because of the changes in either the HADHA or the HADHB genes, the TFP enzymes do not work properly or are not made at all.

HOW IS TFP DEFICIENCY INHERITED?

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

Everyone has two copies of the HADHA and HADHB genes that make the enzymes in the TFP enzyme group. In children with TFP deficiency, one set of these genes – either HADHA or HADHB – does not work correctly. These children inherit one non-working gene for the TFP deficiency from each parent.

Parents of children with TFP deficiency rarely have the disorder. Instead, each parent has a single non-working gene for TFP deficiency. They are called carriersA person who has one copy of a gene mutation for a particular autosomal recessive disorder (remember genes come in pairs). Carriers are not affected by the disorder. However, they can pass on the gene variant to their children. Children who inherit two such gene variants will be affected by the disorder. The term variants is now used in place of the term mutation.. Carriers do not have TFP deficiency because their other HADHA or HADHB gene is working correctly.

When both parents are carriers, there is a 25% chance in each pregnancy for the child to have TFP deficiency. There is a 50% chance for the child to be a carrier, just like the parents. And, there is a 25% chance for the child to have two working genes.

GeneticRelating to (or due to) genes and heredity or the field of studying genes and heredity. counseling is available to families who have children with TFP deficiency. Genetic counselors can answer your questions about how TFP deficiency is inherited, choices during future pregnancies, and how to test other family members. Ask your doctor about a referral to a genetic counselorThese are health care providers who have special training in genetic conditions. They help families understand genetic disorders and how they are passed down. Genetic counselors offer information and support to people who have genetic conditions in their families or are concerned that they may have a child with an inherited disorder..

IS GENETIC TESTING AVAILABLE?

Genetic testing for TFP deficiency can be done on a blood sample. Genetic testing, also called DNA testing, looks for changes, also called variants, in the HADHA and HADHB genes that cause TFP deficiency. In some affected children, both variants can be found. However, in other children, neither or only one of the two gene changes can be found, even though we know they are present.

DNADeoxyribonucleic acid (DNA) is a molecule found in the chromosomes that carries genetic information. DNA is composed of four units (called bases) that are designated A, T, G, and C. The sequence of the bases spell out instructions for making all of the proteins needed by an organism. A gene is a section of DNA that holds the instructions for a specific protein. A change in one or more of the DNA bases making up a gene is called a mutation. Some mutations change the protein instructions and can lead to particular health problems or disorders. Each parent passes half of their chromosomes, and thus half of their DNA instructions, onto their children. It is these instructions that cause certain traits, such as eye or hair color, to be inherited. testing is not necessary to diagnose your child. It can be helpful for carrier testing or prenatal diagnosis, discussed below. Ask your metabolic doctor or genetic counselor if you have questions about DNA testing for TFP deficiency.

WHAT OTHER TESTING IS AVAILABLE?

TFP deficiency can be confirmed by special enzyme tests using a skin or muscle sample. Talk to your doctor or your genetic counselor if you have questions about testing for TFP deficiency.

CAN YOU TEST DURING A FUTURE PREGNANCY?

If both gene changes have been found in your child with TFP deficiency, DNA testing can be done during future pregnancies. The sample needed for this test is obtained by either CVS or amniocentesisThis is a test done during pregnancy. A needle is used to remove a small sample of fluid from the sac around the fetus. The sample can be used to test for certain genetic disorders in the fetus. Amniocentesis to test for genetic conditions is usually done between 13 and 20 weeks of pregnancy..

If DNA testing would not be helpful, special enzyme tests can be done during pregnancy using cellsThe smallest living unit. Cells make up all organs and tissues in multi-cellular organisms, like humans. They can also live independently, as in bacteria and other microorganisms. At a minimum, a cell is surrounded by a membrane, contains DNA at some stage in its life, and is able to replicate itself into two equal parts. from the fetus. Again, the sample needed for this test is obtained by either CVS or amniocentesis.

Parents may either choose to have testing during pregnancy or wait until birth to have the baby tested. Parents may also choose to use assisted reproductive techniques to decrease the chance that their future children would have TFP deficiency. A genetic counselor can talk to you about your choices and answer questions about prenatal testing or testing your baby after birth.

CAN OTHER MEMBERS OF THE FAMILY HAVE TFP DEFICIENCY OR BE CARRIERS?

Having TFP deficiency
The brothers and sisters of a baby with TFP deficiency have a chance of being affected, even if they haven’t had symptoms. Finding out whether other children in the family have TFP deficiency is important because early treatment may prevent serious health problems. Talk to your doctor or genetic counselor about testing your other children for TFP deficiency.

TFP deficiency carriers
Brothers and sisters who do not have TFP deficiency still have a chance to be carriers like their parents. Except in special cases, carrier testing should only be done in people over 18 years of age.

If you are a parent of a child with TFP deficiency, your brothers and sisters have a 50% chance to be a TFP deficiency carrier. It is important for other family members to be told that they could be carriers. There is a small chance they are also at risk to have children with TFP deficiency.

All states offer newborn screeningA screening test that looks for different disorders using a small sample of blood taken from a newborn’s heel. A positive or abnormal newborn screening result means that there are slight differences that were found in the baby’s blood, and further testing is needed to figure out if the baby has a metabolic disorder. for TFP deficiency. However, when both parents are carriers, newborn screeningThe process of testing for disease in a person who does not show signs of having the disease (nonsymptomatic or asymptomatic person). The goal of screening is to catch the disease in its early stages. results are not sufficient to rule out the condition in a newborn baby. In this case, special diagnostic testing should be done in addition to newborn screening.

During pregnancy, women carrying fetuses with TFP deficiency are at risk to develop serious medical problems. There is a small risk of:

• excessive vomiting
• abdominal pain
• high blood pressure
• jaundiceThis is a yellow color to the skin and whites of the eyes. It is often a sign of liver damage.
• severe bleeding
• abnormal fat storage in the liver

All women with a family history of TFP deficiency should share this information with their obstetricians and other health care providers before and during any future pregnancies. Knowing about these risks allows early treatment.

CAN OTHER FAMILY MEMBERS BE TESTED?

Diagnostic testing
Brothers and sisters can be tested for TFP deficiency by DNA testing or special enzyme tests to determine if they also have TFP deficiency.

Carrier testing
If both gene changes have been found in your child with TFP deficiency, other family members can have DNA testing to see if they are carriers.

HOW MANY PEOPLE HAVE TFP DEFICIENCY?

TFP deficiency is a very rare disorder. It is estimated that 1 in 750,000 babies is born with TFP deficiency.

DOES TFP DEFICIENCY HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?

TFP deficiency does not happen more often in any specific race, ethnic group, geographical area, or county.

DOES TFP DEFICIENCY GO BY ANY OTHER NAMES?

TFP deficiency is sometimes also called:

• mitochondrial trifunctional protein deficiency

WHERE CAN I FIND MORE INFORMATION?

Fatty Oxidation Disorders (FOD) Family Support Group
http://www.fodsupport.org

Organic Acidemia Association
http://www.oaanews.org

United Mitochondrial Disease Foundation
http://www.umdf.org

Metabolic Support UK
https://www.metabolicsupportuk.org/

Baby’s First Test
http://www.babysfirsttest.org

MedlinePlus
https://medlineplus.gov/genetics/condition/mitochondrial-trifunctional-protein-deficiency/

DOCUMENT INFO:

Created by:	www.newbornscreening.info
Reviewed by:	HI, CA, OR, and WA metabolic specialists
Review date:	April 2, 2011 July 13, 2013 May 4, 2020 March 1, 2023
Update on:	March 1, 2023

 

DISCLAIMER:

THIS INFORMATION DOES NOT PROVIDE MEDICAL ADVICE. All content (“Content”), including text, graphics, images and information are for general informational purposes only. You are encouraged to confer with your doctor or other health care professional with regard to information contained on this information sheet. After reading this information sheet, you are encouraged to review the information carefully with your doctor or other healthcare provider. The Content is not intended to be a substitute for professional medical advice, diagnosis or treatment. NEVER DISREGARD PROFESSIONAL MEDICAL ADVICE, OR DELAY IN SEEKING IT, BECAUSE OF SOMETHING YOU HAVE READ ON THIS INFORMATION SHEET. This project is supported by a grant from the MaternalHaving to do with the mother. and Child Health Bureau, Health Resources and Service Administration, Genetic Services Branch, MCH Project #:UH7MC30774-01-00 http://mchb.hrsa.gov