Mitochondrial trifunctional protein deficiency

Title

Other Names:

TFP deficiency

Categories:

Congenital and Genetic Diseases; Heart Diseases; Metabolic disorders; Congenital and Genetic Diseases; Heart Diseases; Metabolic disorders; Nervous System Diseases; Newborn Screening See More

Summary Summary

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

Orpha Number: 746

Disease definition

Mitochondrial trifunctional protein (TFP) deficiency (TFPD) is a 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..

Epidemiology

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

Clinical description

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.

Etiology

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.

Diagnostic methods

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.

Differential diagnosis

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.

Antenatal diagnosis

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.

Genetic counseling

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

Management and treatment

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

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: 2/24/2014

Symptoms Symptoms

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Pigmentary retinopathy	Very rare (present in 1%-4% of cases)
Abnormality of the amniotic fluid	-
Autosomal recessive inheritance	-
Congestive heart failure	-
Dilated cardiomyopathy	-
Elevated hepatic transaminases	-
Failure to thrive	-
Generalized muscle weakness	-
Hydrops fetalis	-
Hyperammonemia	-
Hypoketotic hypoglycemia	-
Lactic acidosis	-
Muscular hypotonia	-
Myoglobinuria	-
Peripheral neuropathy	-
Prenatal maternal abnormality	-
Respiratory failure	-
Rhabdomyolysis	-
Small for gestational age	-

Last updated: 9/1/2017

Diagnosis Diagnosis

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.

Newborn Screening

An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
National Newborn Screening and Global Resource Center (NNSGRC) provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

Do you have updated information on this condition? Let us know.

Research Research

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.

Clinical Research Resources

ClinicalTrials.gov lists trials that are studying or have studied Mitochondrial trifunctional protein deficiency. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Organizations Organizations

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.

Organizations Supporting this Disease

FOD (Fatty Oxidation Disorder) Family Support Group
P.O. Box 54
Okemos, MI 48805-0054
Telephone: 517-381-1940
Fax: 866-290-5206
E-mail: deb@fodsupport.org
Website: http://www.fodsupport.org
MitoAction
PO Box 51474
Boston, MA 02205
Toll-free: 888-648-6228
Telephone: 1-888-MITO-411 (648-6411) for support line
E-mail: info@mitoaction.org
Website: http://www.mitoaction.org

Do you know of an organization? Send us your suggestions.

Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by GeneTests, the American College of Medical Genetics, and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Learn More Learn More

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.

Where to Start

Genetics Home Reference (GHR) contains information on Mitochondrial trifunctional protein deficiency. This website is maintained by the National Library of Medicine.
The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.

In-Depth Information

The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Mitochondrial trifunctional protein deficiency. Click on the link to view a sample search on this topic.

News & Events News & Events

News

Don’t Miss the NCATS Toolkit for Patient-Focused Therapy Development Event
August 31, 2017
Funding Opportunities Now Available for the Undiagnosed Diseases Network (UDN) Phase II
August 30, 2017
IRDiRC Goals 2017-2027: New Rare Disease Research Goals for the Next Decade
August 10, 2017

NCATS Co-Sponsored Conferences

Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base Tuesday, December 2, 2014 - Wednesday, December 3, 2014
Location: NIH Campus, Bethesda, MD
Description: The goal of this meeting is to explore the use of nutritional interventions, including dietary supplements, in primary mitochondrial disorders (PMD); identify gaps in knowledge; develop a research agenda; and identify research opportunities to promote an evidence base for the use of nutritional interventions in primary mitochondrial disorders.

Contact: Kathryn Camp, MS, RD, CSP,(301) 435-3608, campkm@od.nih.gov

Co-funding Institute(s): Office of Dietary Supplements, Office of Rare Diseases Research
2013 Neurobiology of Disease in Children Symposium: Mitochondrial Disease Wednesday, October 30, 2013 - Wednesday, October 30, 2013
Location: Austin, TX
Description: The topic for the 2013 NDC Symposium is Mitochondrial Disease. The NDC Symposium is a forum for preeminent investigators assembled to discuss recent accomplishments and future directions with a large group of child neurologists, program officers from the National Institutes of Health, and members of dedicated foundations and associations.

Contact:

Co-funding Institute(s): National Institute of Neurological Disorders and Stroke, Office of Rare Diseases Research
- Agenda ( - 38KB)

Other Conferences

The International Network for Fatty Acid Oxidation Research and Management (INFORM) has been formed in order to promote research and discussion into the cause, diagnosis, and management of inborn errors of fatty acid oxidation. INFORM will sponsor an inaugural symposium to be held on September 6, 2014 in Innsbruck, Austria following SSIEM, with annual meetings thereafter. The Network will provide a collaborative framework for ongoing communication and research between the members.

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