Trifunctional protein (TFP) deficiency is a genetic, metabolic condition that affects the body’s ability to use certain fats, known as long-chain fatty acids, to produce energy.¹ These fatty acids are usually broken down (oxidised) to produce energy through a process called β-oxidation. This β-oxidation process requires the mitochondrial trifunctional protein (MTP), which is an enzyme (protein) complex involved in three of the steps in the process.^2,3 In TFP deficiency, the function of the entire MTP complex is affected, resulting in the body being unable to produce enough energy, especially during fasting, illness and exercise, and a build-up of harmful metabolic by-products.

Symptoms of TFP deficiency vary widely between individuals in severity and onset (age when symptoms develop).^2-4 The symptoms are often described as the following forms:

• neonatal onset – symptoms develop within days after birth and are very severe. Babies with neonatal onset develop severe metabolic crisis that can affect the brain and heart function, and often results in early death.
• infantile onset (or neonatal – early infancy-onset) – individuals develop symptoms within early childhood (infancy) and are moderately severe. Children may have episodes of metabolic crisis often brought upon by illness or fasting, and the heart and liver can also be affected. There is also risk of sudden death. This form is less common than the neonatal and late onset.
• late onset – individuals with late onset only develop symptoms after early childhood (infancy) and mainly affect the muscles as well as nerves, eyes and heart. Episodes of metabolic crisis can also occur and in rare cases, life-threatening respiratory failure may develop.

In Australia, TFP deficiency is often detected shortly after birth via newborn bloodspot screening (NBS) programs. Additional testing is required to confirm the diagnosis. For individuals who are not screened at birth, TFP deficiency is often diagnosed after symptoms develop.

Please note that there is a separate condition known as Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency that is also caused by a defect in the mitochondrial trifunctional protein (MTP). In LCHAD deficiency, only one of the three steps in the β-oxidation process is affected, whilst in TFP deficiency, all three steps are affected.^3-5

Synonyms:^1-2 TFPD; Mitochondrial trifunctional protein deficiency; Human trifunctional protein deficiency; Trifunctional enzyme deficiency

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:746 Mitochondrial trifunctional protein deficiency

ICD-11: 5C52.01 Disorders of mitochondrial fatty acid oxidation

Symptoms of TFP deficiency vary widely between individuals in severity and onset (age when symptoms develop).^2-4 The symptoms are often described as the following forms:^1-4

Neonatal onset

Symptoms are severe and often present within days after birth as severe metabolic crisis with hypoglycaemia (low blood glucose), lactic acidosis (build up of lactic acid in the blood) and hyperammonaemia (toxic build up of ammonia in blood). Babies may show signs of weakness, difficulty feeding, extreme tiredness and lack of energy (lethargy), nausea and vomiting. They may also have an enlarged liver (hepatomegaly) and encephalopathy (where brain function is affected) as well as cardiomyopathy (condition that affects the heart muscle, preventing it from pumping blood effectively). Individuals are at risk of seizures, heart failure, coma and early death.

Infantile onset

Symptoms are moderately severe and tend to present sometime within early childhood (infancy). Children may have episodes of metabolic crisis that are often brought upon by illness or fasting, and the heart and liver can also be affected. There is also risk of sudden death. This form is less common than the neonatal and late onset of TFP deficiency.

Late onset

Symptoms often don’t develop until after early childhood (infancy) and mainly affect the muscles as well as nerves, eyes and heart. Symptoms may include myalgia (muscle pain), muscle weakness and myoglobinuria (presence of a muscle protein called myoglobin in the urine, which is caused by muscle breakdown known as rhabdomyolysis). Episodes of the symptoms are usually brought upon (triggered) by prolonged exercise, infections, fasting or cold temperatures.

Other complications may include peripheral neuropathy (damage to the nerves that carry signals between the brain, spinal cord and the rest of the body), retinopathy (damage to the retina of the eyes, which can affect vision) as well as cardiomyopathy. Episodes of metabolic crisis can also occur and in rare cases, life-threatening respiratory failure may develop.

There may be other symptoms and complications associated with TFP deficiency that were not included here. Maternal complications may be seen in women who are pregnant with a child with TFP deficiency, even if the women themselves do not have TFP deficiency. These maternal complications are liver-related, such as acute fatty liver of pregnancy (AFLP) and HELLP syndrome where there is haemolysis (breakdown of red blood cells), elevated liver enzymes (a sign of liver damage or stress), and low blood platelet counts.

Please speak to your medical team to learn more about the symptoms of this condition.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

TFP deficiency is a genetic condition. It is caused by disease-causing genetic changes (variants) in the HADHA or HADHB genes on chromosome 2.^2-4  Individuals with genetic changes in the HADHB gene tend to have the milder form of TFP deficiency but not in all cases.³ Those with genetic changes in the HADHA gene may have the severe or mild form.

All individuals have two copies (alleles) of the HADHA and HADHB genes – one copy inherited from each parent. TFP deficiency is an autosomal recessive condition,^2-3 which means both copies of the HADHA or HADHB gene must have the disease-causing genetic variants. More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

Screening

In Australia, TFP deficiency is usually detected via the newborn bloodspot screening (NBS) programs.  Shortly after birth and with parental consent, a nurse or midwife will collect the baby’s blood via a heel prick blood test. The healthcare provider will then send it to a specific laboratory to test for a range of rare conditions, including TFP deficiency. If the test results suggest that there is a risk of the baby having one of the screened conditions, laboratory staff will promptly get in touch with healthcare providers. The healthcare providers will then arrange for the baby to have further testing to confirm if the baby actually has the condition. The healthcare providers will also organise for the baby to receive urgent care if required. Depending on your state or territory, parents may or may not receive a notification if the test results are clear. You can find out more about NBS in your state or territory at Australian Government Department of Health, Disability and Ageing: Delivering newborn bloodspot screening programs.

Newborn bloodspot screening is a reliable way to check for certain rare conditions early in life. Although it’s extremely rare, cases can sometimes be missed. If you are concerned your baby may have a condition that they have already been screened for, you should contact a medical professional.

Diagnosis

A diagnosis of TFP deficiency may be suspected based on an abnormal result from NBS but additional tests or a clinical examination will be required to confirm a diagnosis. For individuals who are not screened at birth, TFP deficiency is often diagnosed after symptoms develop.

Diagnosis of TFP deficiency may be made based on clinical evaluation of symptoms, laboratory tests on blood samples (to detect for increased levels of specific long-chain acylcarnitines) and urine samples (to look for specific organic acids), measurement of enzyme activity, and confirmed by genetic testing.^2-3

As part of the diagnostic process, doctors may do a differential diagnosis, which is to rule out other conditions that have similar symptoms, such as sudden infant death syndrome, isolated LCHAD deficiency, VLCAD deficiency, Carnitine uptake deficiency, Carnitine acylcarnitine translocase (CACT) deficiency, Carnitine palmitoyltransferase I (CPT I) deficiency, Carnitine palmitoyltransferase II (CPT II) deficiency, Glutaric acidaemia type II (Multiple acyl-CoA dehydrogenase deficiency)and Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.^2-3

Please speak to your medical team to learn more about the available pathways for diagnosis of this condition.

There is currently no curative treatment for TFP deficiency. Early diagnosis and appropriate management can help reduce the risk of serious life-threatening complications, in particulara for the milder form of TFP deficiency.^2-5 For the severe form, early death may still occur even with treatment. 

Metabolic crisis, such as hypoglycaemia, metabolic acidosis and hyperammonaemia, and rhabdomyolysis, are medical emergencies and should be treated promptly and accordingly.

Management of TFP deficiency includes a low-fat diet with medium-chain triglyceride supplementation and avoidance of fasting.^2-4 This involves frequent feeds, with the recommended time between food depending on age. If required, this may also include continuous overnight feeding and use of uncooked cornstarch at bedtime to ensure there is sufficient glucose supply during the night.³ During time of illness, more frequent feeding and supplementation with carbohydrates is often required. For individualas with carnitine deficiency, carnitine supplementation may be used.³

Symptomatic management (management of symptoms) may include feeding therapy, physiotherapy, occupational therapy, speech therapy, management of heart complications, peripheral neuropathy and retinopathy.³

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities. For many rare diseases, treatment options may be limited. Participation in a clinical trial may provide access to new or emerging therapies.

Healthcare professionals involved in the clinical care of individuals with TFP deficiency may include general practitioners (GP), paediatricians, metabolic physicians, metabolic dietitians, cardiologists, neurologists, ophthalmologists, speech therapists, occupational therapists, physiotherapists and others.³ The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.  It is recommended that care be managed by a metabolic specialist team. 

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

This may not be applicable to all rare diseases but for many, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness and is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. If this is relevant to you and you wish to find out more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

If you know of any relevant clinical care guidelines, please let us know via the  Contribute page.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

In addition, individuals, their parents, families and carers often develop extensive expertise on their specific rare disease. It is important to recognise that they can contribute valuable knowledge about their rare condition. Rare diseases often impact individuals differently, so it’s important to consider a person’s lived experience.

Below are some considerations for the emergency management of individuals living with TFP deficiency, including when presenting to emergency departments:³

• individuals are at risk of hypoglycaemia, metabolic acidosis and hyperammonaemia, particularly during fasting, illness, or other metabolic stress. These are medical emergencies that require immediate treatment. Administration of intravenous intralipids during an acute metabolic crisis is contraindicated; it is recommended that supplemental calories be provided in the form of carbohydrates.
• individuals may also be at risk of cardiomyopathy and cardiac failure
•  fasting, inadequate caloric provision and high-fat diet are to be avoided
• individuals should be monitored to ensure they are not dehydrated (as this leads to risk of rhabdomyolysis and acute renal failure)
• metabolic specialist team should be consulted

The following organisation provides support for all mitochondrial conditions.

Australian Organisation:

Mito Foundation
Website: https://www.mito.org.au/contact/

The Mito Foundation is the only organisation dedicated to supporting and empowering people impacted by mitochondrial disease (mito) in Australia. It provides resources and support services for people impacted by mito, and their families, while increasing awareness and understanding of this devastating disease. The foundation aims to transform outcomes for the mito community by driving meaningful change and funding essential research into the prevention, diagnosis, treatment and cures of mitochondrial disorders.

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

Trifunctional protein deficiency varies between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information relevant to trifunctional protein deficiency can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Mitochondrial trifunctional protein deficiency
• National Organization for Rare Disorders (NORD): mitochondrial trifunctional protein deficiency
• MedlinePlus Genetics: Mitochondrial trifunctional protein deficiency

Orphanet: Mitochondrial trifunctional protein deficiency

GeneReviews^®: Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency

Online Mendelian Inheritance in Man, OMIM^®: #609015 Mitochondrial trifunctional protein deficiency 1; MTPD1

Online Mendelian Inheritance in Man, OMIM^®: #620300 – Mitochondrial trifunctional protein deficiency 2; MTPD2

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.