Mitochondrial trifunctional protein deficiency

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.

A rare disorder of fatty acid oxidation characterized by a wide clinical spectrum ranging from severe neonatal manifestations including cardiomyopathy, hypoglycemia, metabolic acidosis, skeletal myopathy and neuropathy, liver disease and death to a mild phenotype with peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy..

TFPD has been reported in less than 100 cases in the literature.

The neonatal onset, severe form manifests as hepatic steatosis, cardiomyopathy, skeletal myopathy and neuropathy and is usually fatal. A moderately severe form, with onset usually from the neonatal period to 18 months of age, presents primarily with hypoketotic hypoglycemia and metabolic acidosis which is often precipitated by prolonged fasting and/or intercurrent illness. Both forms can manifest with neuropathy with or without cardiomyopathy and can be fatal. The mild form merges with the moderately severe infantile form and can present from a few months of age until adolescence as a peripheral polyneuropathy with episodic rhabdomyolysis triggered by prolonged fasting, illness, exercise or exposure to heat or cold. There is respiratory failure associated with the episodes of rhabdomyolysis. A pigmentary retinopathy may also develop over time. Very occasionally, adults presenting for the first time with a previously unrecognized disease are described.

The TFP, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids which are the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase (LCEH), and long-chain thiolase (LCTH) steps. The HADHA gene (2p23) encodes the LCEH and LCHAD enzymes and the HADHB gene (2p23) encodes the LCTH enzyme. Two mutations in either one of these two genes causes TFPD.

Urine organic acids may show a C6-C14 (hydroxy) dicarboxylic aciduria, and blood acylcarnitine analysis often shows increased long chain hydroxyacyl carnitine species (C14-OH, C16-OH, C18-OH, C18:1-OH). Both urine and blood markers are less reliable and more variable than those seen in LCHAD deficiency (see this term). This is because defects in LCEH may block the formation of hydroxy-metabolites. Reduced enzyme activity in at least two (usually all 3) enzymes in cultured fibroblasts is seen. Molecular analysis confirming bi-allelic non-1528C>G mutations in the HADHA gene or bi-allelic mutations in the HADHBgene confirms diagnosis. Newborn screening is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal.

Sudden infant death syndrome and isolated LCHAD deficiency (see this term) form part of the differential diagnosis. LCHAD deficiency is clinically indistinguishable from severe TFPD.

Prenatal diagnosis is possible by analyzing enzyme activity in chorionic villi samples, once a deficiency of TFP has been established in the index case/family. Molecular analysis is the preferred option when two mutations have been identified in a family.

TFPD is an autosomal recessive disorder and genetic counseling is possible.

Treatment involves adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids. Fasting and exposure to environmental extremes must be strictly avoided and exercise should be limited.

Prognosis for the severe neonatal form of TFPD is very poor. The later onset mild form has a far more favorable prognosis.

Visit the Orphanet disease page for more resources.

Last updated: 2/1/2014

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.