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Mitochondrial trifunctional protein deficiency(MTPD1)

MedGen UID:
370665
Concept ID:
C1969443
Disease or Syndrome
Synonym: Trifunctional protein deficiency
SNOMED CT: Mitochondrial trifunctional protein deficiency (237999008); Human trifunctional protein deficiency (237999008); Trifunctional protein deficiency (237999008); Trifunctional enzyme deficiency (237999008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Monarch Initiative: MONDO:0012172
OMIM®: 600890; 609015
OMIM® Phenotypic series: PS609015
Orphanet: ORPHA746

Disease characteristics

Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are caused by impairment of mitochondrial TFP. TFP has three enzymatic activities – long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase. In individuals with LCHAD deficiency, there is isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, while deficiency of all three enzymes occurs in individuals with TFP deficiency. Individuals with TFP deficiency can present with a severe-to-mild phenotype, while individuals with LCHAD deficiency typically present with a severe-to-intermediate phenotype. Neonates with the severe phenotype present within a few days of birth with hypoglycemia, hepatomegaly, encephalopathy, and often cardiomyopathy. The intermediate phenotype is characterized by hypoketotic hypoglycemia precipitated by infection or fasting in infancy. The mild (late-onset) phenotype is characterized by myopathy and/or neuropathy. Long-term complications include peripheral neuropathy and retinopathy. [from GeneReviews]
Authors:
Pankaj Prasun  |  Mary Kate LoPiccolo  |  Ilona Ginevic   view full author information

Additional descriptions

From OMIM
The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death (SIDS; 272120), infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy (Spiekerkoetter et al., 2003). Some patients with MTP deficiency show a protracted progressive course associated with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy. These patients tend to survive into adolescence and adulthood (den Boer et al., 2003). Genetic Heterogeneity of Mitochondrial Trifunctional Protein Deficiency See also MTPD2 (620300), caused by mutation in the HADHB gene, the beta subunit of the mitochondrial trifunctional protein.  http://www.omim.org/entry/609015
From MedlinePlus Genetics
Mitochondrial trifunctional protein deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting).

Signs and symptoms of mitochondrial trifunctional protein deficiency may begin during infancy or later in life. Features that occur during infancy include feeding difficulties, lack of energy (lethargy), low blood glucose (hypoglycemia), weak muscle tone (hypotonia), and liver problems. Infants with this disorder are also at high risk for serious heart problems, breathing difficulties, coma, and sudden death. Signs and symptoms of mitochondrial trifunctional protein deficiency that may begin after infancy include hypotonia, muscle pain, a breakdown of muscle tissue, and a loss of sensation in the extremities (peripheral neuropathy).

Problems related to mitochondrial trifunctional protein deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.  https://medlineplus.gov/genetics/condition/mitochondrial-trifunctional-protein-deficiency

Clinical features

From HPO
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Hereditary myoglobinuria
MedGen UID:
44557
Concept ID:
C0027080
Finding
Presence of myoglobin in the urine.
Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
Primary dilated cardiomyopathy
MedGen UID:
2880
Concept ID:
C0007193
Disease or Syndrome
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure.\n\nIt usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Cholestasis
MedGen UID:
925
Concept ID:
C0008370
Disease or Syndrome
Impairment of bile flow due to obstruction in bile ducts.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Rhabdomyolysis
MedGen UID:
19775
Concept ID:
C0035410
Pathologic Function
Breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream.
Muscle spasm
MedGen UID:
52431
Concept ID:
C0037763
Sign or Symptom
Sudden and involuntary contractions of one or more muscles.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
Generalized weakness or decreased strength of the muscles, affecting both distal and proximal musculature.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Hypoketotic hypoglycemia
MedGen UID:
344733
Concept ID:
C1856438
Finding
A decreased concentration of glucose in the blood associated with a reduced concentration of ketone bodies.
Elevated circulating acylcarnitine concentration
MedGen UID:
892855
Concept ID:
C4073171
Finding
Concentration of acylcarnitine in the blood circulation above the upper limit of normal.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Hydrops fetalis
MedGen UID:
6947
Concept ID:
C0020305
Disease or Syndrome
The abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema.
Abnormality of the amniotic fluid
MedGen UID:
488828
Concept ID:
C0266781
Finding
Abnormality of the amniotic fluid, which is the fluid contained in the amniotic sac surrounding the developing fetus.
Pigmentary retinopathy
MedGen UID:
1643295
Concept ID:
C4551715
Disease or Syndrome
An abnormality of the retina characterized by pigment deposition. It is typically associated with migration and proliferation of macrophages or retinal pigment epithelial cells into the retina; melanin from these cells causes the pigmentary changes. Pigmentary retinopathy is a common final pathway of many retinal conditions and is often associated with visual loss.

Professional guidelines

PubMed

Schwantje M, Fuchs SA, de Boer L, Bosch AM, Cuppen I, Dekkers E, Derks TGJ, Ferdinandusse S, Ijlst L, Houtkooper RH, Maase R, van der Pol WL, de Vries MC, Verschoof-Puite RK, Wanders RJA, Williams M, Wijburg F, Visser G
J Inherit Metab Dis 2022 Jul;45(4):804-818. Epub 2022 Apr 19 doi: 10.1002/jimd.12502. PMID: 35383965Free PMC Article

Curated

American College of Medical Genetics and Genomics, Algorithm, LCHAD/TFP: C16-OH Elevated +/-C18-OH, 2022

Recent clinical studies

Etiology

Wongchaisuwat N, Gillingham MB, Yang P, Everett L, Gregor A, Harding CO, Sahel JA, Nischal KK, Scanga HL, Black D, Vockley J, Arnold G, Pennesi ME
Ophthalmic Genet 2024 Apr;45(2):140-146. Epub 2024 Jan 30 doi: 10.1080/13816810.2024.2303682. PMID: 38288966Free PMC Article
Schwantje M, Ebberink MS, Doolaard M, Ruiter JPN, Fuchs SA, Darin N, Hedberg-Oldfors C, Régal L, Donker Kaat L, Huidekoper HH, Olpin S, Cole D, Moat SJ, Visser G, Ferdinandusse S
J Inherit Metab Dis 2022 Jul;45(4):819-831. Epub 2022 May 5 doi: 10.1002/jimd.12503. PMID: 35403730Free PMC Article
Schwantje M, Fuchs SA, de Boer L, Bosch AM, Cuppen I, Dekkers E, Derks TGJ, Ferdinandusse S, Ijlst L, Houtkooper RH, Maase R, van der Pol WL, de Vries MC, Verschoof-Puite RK, Wanders RJA, Williams M, Wijburg F, Visser G
J Inherit Metab Dis 2022 Jul;45(4):804-818. Epub 2022 Apr 19 doi: 10.1002/jimd.12502. PMID: 35383965Free PMC Article
Winter S, Buist NR, Longo N, Armenian SH, Lopaschuk G, Wasilewska A
Ann Nutr Metab 2016;68 Suppl 3:21-23. Epub 2016 Dec 9 doi: 10.1159/000448323. PMID: 27931031
Boese EA, Jain N, Jia Y, Schlechter CL, Harding CO, Gao SS, Patel RC, Huang D, Weleber RG, Gillingham MB, Pennesi ME
Ophthalmology 2016 Oct;123(10):2183-95. Epub 2016 Aug 2 doi: 10.1016/j.ophtha.2016.06.048. PMID: 27491397Free PMC Article

Diagnosis

Schwantje M, Ebberink MS, Doolaard M, Ruiter JPN, Fuchs SA, Darin N, Hedberg-Oldfors C, Régal L, Donker Kaat L, Huidekoper HH, Olpin S, Cole D, Moat SJ, Visser G, Ferdinandusse S
J Inherit Metab Dis 2022 Jul;45(4):819-831. Epub 2022 May 5 doi: 10.1002/jimd.12503. PMID: 35403730Free PMC Article
Yang J, Yuan D, Tan X, Zeng Y, Tang N, Chen D, Tan J, Cai R, Huang J, Yan T
Mol Med Rep 2022 Feb;25(2) Epub 2021 Dec 8 doi: 10.3892/mmr.2021.12563. PMID: 34878152Free PMC Article
Grünert SC, Eckenweiler M, Haas D, Lindner M, Tsiakas K, Santer R, Tucci S, Spiekerkoetter U
J Inherit Metab Dis 2021 Jul;44(4):893-902. Epub 2021 Mar 10 doi: 10.1002/jimd.12372. PMID: 33638202
Winter S, Buist NR, Longo N, Armenian SH, Lopaschuk G, Wasilewska A
Ann Nutr Metab 2016;68 Suppl 3:21-23. Epub 2016 Dec 9 doi: 10.1159/000448323. PMID: 27931031
den Boer ME, Dionisi-Vici C, Chakrapani A, van Thuijl AO, Wanders RJ, Wijburg FA
J Pediatr 2003 Jun;142(6):684-9. doi: 10.1067/mpd.2003.231. PMID: 12838198

Therapy

Preusse M, Paraschaki G, Lutz S
Neuropediatrics 2022 Jun;53(3):213-216. Epub 2022 Jan 28 doi: 10.1055/s-0042-1742305. PMID: 35098523
Gillingham MB, Heitner SB, Martin J, Rose S, Goldstein A, El-Gharbawy AH, Deward S, Lasarev MR, Pollaro J, DeLany JP, Burchill LJ, Goodpaster B, Shoemaker J, Matern D, Harding CO, Vockley J
J Inherit Metab Dis 2017 Nov;40(6):831-843. Epub 2017 Sep 4 doi: 10.1007/s10545-017-0085-8. PMID: 28871440Free PMC Article
Winter S, Buist NR, Longo N, Armenian SH, Lopaschuk G, Wasilewska A
Ann Nutr Metab 2016;68 Suppl 3:21-23. Epub 2016 Dec 9 doi: 10.1159/000448323. PMID: 27931031
Immonen T, Turanlahti M, Paganus A, Keskinen P, Tyni T, Lapatto R
Acta Paediatr 2016 May;105(5):549-54. Epub 2016 Feb 5 doi: 10.1111/apa.13313. PMID: 26676313
Keller MD, Ganesh J, Heltzer M, Paessler M, Bergqvist AG, Baluarte HJ, Watkins D, Rosenblatt DS, Orange JS
Pediatrics 2013 Feb;131(2):e629-34. Epub 2013 Jan 6 doi: 10.1542/peds.2012-0899. PMID: 23296427

Prognosis

Li Y, He C, Li S, Wang J, Jiang L, Guo Y
Eur J Med Genet 2021 Dec;64(12):104344. Epub 2021 Sep 17 doi: 10.1016/j.ejmg.2021.104344. PMID: 34543737
Shahrokhi M, Shafiei M, Galehdari H, Shariati G
Arch Iran Med 2017 Jan;20(1):22-27. PMID: 28112527
Boese EA, Jain N, Jia Y, Schlechter CL, Harding CO, Gao SS, Patel RC, Huang D, Weleber RG, Gillingham MB, Pennesi ME
Ophthalmology 2016 Oct;123(10):2183-95. Epub 2016 Aug 2 doi: 10.1016/j.ophtha.2016.06.048. PMID: 27491397Free PMC Article
Olpin SE, Clark S, Andresen BS, Bischoff C, Olsen RK, Gregersen N, Chakrapani A, Downing M, Manning NJ, Sharrard M, Bonham JR, Muntoni F, Turnbull DN, Pourfarzam M
J Inherit Metab Dis 2005;28(4):533-44. doi: 10.1007/s10545-005-0533-8. PMID: 15902556
den Boer ME, Dionisi-Vici C, Chakrapani A, van Thuijl AO, Wanders RJ, Wijburg FA
J Pediatr 2003 Jun;142(6):684-9. doi: 10.1067/mpd.2003.231. PMID: 12838198

Clinical prediction guides

Yang J, Yuan D, Tan X, Zeng Y, Tang N, Chen D, Tan J, Cai R, Huang J, Yan T
Mol Med Rep 2022 Feb;25(2) Epub 2021 Dec 8 doi: 10.3892/mmr.2021.12563. PMID: 34878152Free PMC Article
Rücklová K, Hrubá E, Pavlíková M, Hanák P, Farolfi M, Chrastina P, Vlášková H, Kousal B, Smolka V, Foltenová H, Adam T, Friedecký D, Ješina P, Zeman J, Kožich V, Honzík T
Nutrients 2021 Aug 24;13(9) doi: 10.3390/nu13092925. PMID: 34578803Free PMC Article
Grünert SC, Eckenweiler M, Haas D, Lindner M, Tsiakas K, Santer R, Tucci S, Spiekerkoetter U
J Inherit Metab Dis 2021 Jul;44(4):893-902. Epub 2021 Mar 10 doi: 10.1002/jimd.12372. PMID: 33638202
Lotz-Havla AS, Röschinger W, Schiergens K, Singer K, Karall D, Konstantopoulou V, Wortmann SB, Maier EM
Orphanet J Rare Dis 2018 Jul 20;13(1):122. doi: 10.1186/s13023-018-0875-6. PMID: 30029694Free PMC Article
Shahrokhi M, Shafiei M, Galehdari H, Shariati G
Arch Iran Med 2017 Jan;20(1):22-27. PMID: 28112527

Recent systematic reviews

Fraser H, Geppert J, Johnson R, Johnson S, Connock M, Clarke A, Taylor-Phillips S, Stinton C
Orphanet J Rare Dis 2019 Nov 15;14(1):258. doi: 10.1186/s13023-019-1226-y. PMID: 31730477Free PMC Article
Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H
J Inherit Metab Dis 2014 Nov;37(6):889-98. Epub 2014 Jul 15 doi: 10.1007/s10545-014-9729-0. PMID: 25022222

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    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, LCHAD/TFP: C16-OH Elevated +/-C18-OH, 2022

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