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Mitochondrial trifunctional protein deficiency 2(MTPD2)

MedGen UID:
1841010
Concept ID:
C5830374
Disease or Syndrome
Synonym: MTPD2
 
Gene (location): HADHB (2p23.3)
 
Monarch Initiative: MONDO:0958185
OMIM®: 620300

Definition

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 (summary by 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). See mitochondrial trifunctional protein deficiency-1 (609015), caused by mutation in the HADHA gene (600890), the alpha subunit of mitochondrial trifunctional protein. [from OMIM]

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.
Recurrent myoglobinuria
MedGen UID:
333201
Concept ID:
C1838877
Finding
Recurring episodes of myoglobinuria, i.e., of the presence of myoglobin in the urine. This is usually a consequence of rhabdomyolysis, i.e., of the destruction of muscle tissue.
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.
Hypotension
MedGen UID:
5715
Concept ID:
C0020649
Finding
Low Blood Pressure, vascular hypotension.
Mitral regurgitation
MedGen UID:
7670
Concept ID:
C0026266
Disease or Syndrome
An abnormality of the mitral valve characterized by insufficiency or incompetence of the mitral valve resulting in retrograde leaking of blood through the mitral valve upon ventricular contraction.
Tricuspid regurgitation
MedGen UID:
11911
Concept ID:
C0040961
Disease or Syndrome
Failure of the tricuspid valve to close sufficiently upon contraction of the right ventricle, causing blood to regurgitate (flow backward) into the right atrium.
Cerebral hemorrhage
MedGen UID:
423648
Concept ID:
C2937358
Pathologic Function
Hemorrhage into the parenchyma of the brain.
Left ventricular dilatation
MedGen UID:
1002992
Concept ID:
CN323253
Finding
Enlargement of the chamber of the left heart ventricle.
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.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
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 alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
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.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Increased circulating NT-proBNP concentration
MedGen UID:
1385064
Concept ID:
C4477024
Finding
An elevated level of circulating N-terminal part of the prohormone of B-type natriuretic peptide (BNP).
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Professional guidelines

PubMed

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

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
Jankowski M, Daca-Roszak P, Obracht-Prondzyński C, Płoski R, Lipska-Ziętkiewicz BS, Ziętkiewicz E
J Appl Genet 2022 Dec;63(4):691-701. Epub 2022 Aug 15 doi: 10.1007/s13353-022-00713-z. PMID: 35971028Free 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
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
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

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
Jankowski M, Daca-Roszak P, Obracht-Prondzyński C, Płoski R, Lipska-Ziętkiewicz BS, Ziętkiewicz E
J Appl Genet 2022 Dec;63(4):691-701. Epub 2022 Aug 15 doi: 10.1007/s13353-022-00713-z. PMID: 35971028Free 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
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
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

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
Madsen KL, Stemmerik MG, Buch AE, Poulsen NS, Lund AM, Vissing J
J Clin Endocrinol Metab 2019 Sep 1;104(9):3610-3613. doi: 10.1210/jc.2019-00453. PMID: 30990523
Hatab SZ, Singh A, Felner EI, Kamat P
Ann Pharmacother 2014 Dec;48(12):1642-5. Epub 2014 Sep 15 doi: 10.1177/1060028014549991. PMID: 25225198
Martin JM, Gillingham MB, Harding CO
Mol Genet Metab 2014 Jun;112(2):139-42. Epub 2014 Apr 6 doi: 10.1016/j.ymgme.2014.03.012. PMID: 24780638Free PMC Article
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

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
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
Spiekerkoetter U, Mueller M, Cloppenburg E, Motz R, Mayatepek E, Bueltmann B, Korenke C
Mol Genet Metab 2008 Aug;94(4):428-430. Epub 2008 May 15 doi: 10.1016/j.ymgme.2008.04.002. PMID: 18485779
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

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
Shahrokhi M, Shafiei M, Galehdari H, Shariati G
Arch Iran Med 2017 Jan;20(1):22-27. PMID: 28112527
Diekman EF, van der Pol WL, Nievelstein RA, Houten SM, Wijburg FA, Visser G
J Inherit Metab Dis 2014 May;37(3):405-13. Epub 2013 Dec 5 doi: 10.1007/s10545-013-9666-3. PMID: 24305961
Spiekerkoetter U, Mueller M, Cloppenburg E, Motz R, Mayatepek E, Bueltmann B, Korenke C
Mol Genet Metab 2008 Aug;94(4):428-430. Epub 2008 May 15 doi: 10.1016/j.ymgme.2008.04.002. PMID: 18485779

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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