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Disease Profile

Mitochondrial trifunctional protein deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

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ICD-10

G71.3

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

TFP deficiency

Categories

Congenital and Genetic Diseases; Heart Diseases; Metabolic disorders;

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
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Orpha Number: 746

Definition
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..

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.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Areflexia
Absent tendon reflexes
0001284
Exercise intolerance
Decreased ability to exercise
Inability to exercise

[ more ]

0003546
Rhabdomyolysis
Breakdown of skeletal muscle
0003201
30%-79% of people have these symptoms
Cardiomyopathy
Disease of the heart muscle
0001638
Chronic hepatic failure
Chronic liver failure
0100626
Congestive heart failure
Cardiac failure
Cardiac failures
Heart failure

[ more ]

0001635
Decreased patellar reflex
Decreased knee jerk reflex
0011808
Difficulty climbing stairs
Difficulty walking up stairs
0003551
Diffuse hepatic steatosis
0006555
Failure to thrive in infancy
Faltering weight in infancy
Weight faltering in infancy

[ more ]

0001531
Hypocalcemia
Low blood calcium levels
0002901
Hypoketotic hypoglycemia
0001985
Left ventricular hypertrophy
0001712
Lethargy
0001254
Lower limb muscle weakness
Lower extremity weakness
Lower limb weakness
Muscle weakness in lower limbs

[ more ]

0007340
Muscle spasm
0003394
Muscular hypotonia
Low or weak muscle tone
0001252
Poor suck
Poor sucking
0002033
Progressive distal muscle weakness
0009063
Skeletal myopathy
0003756
5%-29% of people have these symptoms
Arrhythmia
Abnormal heart rate
Heart rhythm disorders
Irregular heart beat
Irregular heartbeat

[ more ]

0011675
Babinski sign
0003487
Cholestasis
Slowed or blocked flow of bile from liver
0001396
Coma
0001259
Equinovarus deformity
0008110
Equinus calcaneus
0008138
Frequent falls
0002359
Generalized muscle weakness
0003324
Hypoparathyroidism
Decreased parathyroid hormone secretion
0000829
Mitral regurgitation
0001653
Motor delay
0001270
Myalgia
Muscle ache
Muscle pain

[ more ]

0003326
Pes cavus
High-arched foot
0001761
Pigmentary retinopathy
0000580
Respiratory failure
0002878
Seizure
0001250
Toe walking
Toe-walking
0040083
Tricuspid regurgitation
0005180
1%-4% of people have these symptoms
Distal peripheral sensory neuropathy
0007067
Primitive reflex
0002476
Rigors
0025145
Sensorimotor neuropathy
Nerve damage causing decreased feeling and movement
0007141
Percent of people who have these symptoms is not available through HPO
Abnormality of the amniotic fluid
0001560
Autosomal recessive inheritance
0000007
Dilated cardiomyopathy
Stretched and thinned heart muscle
0001644
Elevated hepatic transaminase
High liver enzymes
0002910
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Global developmental delay
0001263
Hydrops fetalis
0001789
Hyperammonemia
High blood ammonia levels
0001987
Lactic acidosis
Increased lactate in body
0003128
Myoglobinuria
0002913
Myopathy
Muscle tissue disease
0003198
Peripheral neuropathy
0009830
Prenatal maternal abnormality
0002686
Respiratory insufficiency
Respiratory impairment
0002093
Small for gestational age
Birth weight less than 10th percentile
Low birth weight

[ more ]

0001518

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.

    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

      Organizations Providing General Support

        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

        • MedlinePlus Genetics 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.