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Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

MedGen UID:
778253
Concept ID:
C3711645
Disease or Syndrome
Synonyms: Deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase; LCHAD Deficiency
SNOMED CT: Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (726021008); LCHADD - long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (726021008); Long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (726021008)
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).
 
Gene (location): HADHA (2p23.3)
 
Monarch Initiative: MONDO:0012173
OMIM®: 609016
Orphanet: ORPHA5

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
Isolated deficiency of long-chain 3-hydroxyl-CoA dehydrogenase (LCHAD) is an autosomal recessive disorder characterized by early-onset cardiomyopathy, hypoglycemia, neuropathy, and pigmentary retinopathy, and sudden death (IJlst et al., 1996).  http://www.omim.org/entry/609016
From MedlinePlus Genetics
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) 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 LCHAD deficiency typically appear during infancy or early childhood. Many affected infants have feeding difficulties, such as an extreme dislike of certain foods  or of eating at all (food or feeding aversion), nausea, and vomiting. Other signs and symptoms include lack of energy (lethargy), low blood glucose (hypoglycemia), weak muscle tone (hypotonia), delayed development of milestones, liver problems, and abnormalities in the light-sensitive tissue at the back of the eye (retina). Affected individuals can have impaired vision or difficulty seeing things far away (myopia) or in low light (night blindness). These vision problems worsen over time. Later in childhood, people with this condition may experience muscle pain, breakdown of muscle tissue (rhabdomyolysis), and a loss of sensation in their arms and legs (peripheral neuropathy). Infants and children with LCHAD deficiency are also at risk of serious heart problems, such as a weakened heart (cardiomyopathy) and heart failure; breathing difficulties; coma; and sudden death.

Problems related to LCHAD deficiency can be triggered when the body is under stress, for example during periods of fasting, illnesses such as viral infections, or weather extremes. 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/long-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency

Clinical features

From HPO
Sudden death
MedGen UID:
8257
Concept ID:
C0011071
Pathologic Function
Rapid and unexpected death.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
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.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Decreased 3-hydroxyacyl-CoA dehydrogenase level
MedGen UID:
1381484
Concept ID:
C4477062
Finding
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLong chain 3-hydroxyacyl-CoA dehydrogenase deficiency

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
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
David J, Chrastina P, Pešková K, Kožich V, Friedecký D, Adam T, Hlídková E, Vinohradská H, Novotná D, Hedelová M, Al Taji E, Holubová A, Skalická V, Macek M, Gaillyová R, Votava F
Cent Eur J Public Health 2019 Jun;27(2):153-159. doi: 10.21101/cejph.a5441. PMID: 31241292

Curated

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

Recent clinical studies

Etiology

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
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
Haglind CB, Nordenström A, Ask S, von Döbeln U, Gustafsson J, Stenlid MH
J Inherit Metab Dis 2015 Mar;38(2):315-22. Epub 2014 Aug 21 doi: 10.1007/s10545-014-9750-3. PMID: 25141826
den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA
Pediatrics 2002 Jan;109(1):99-104. doi: 10.1542/peds.109.1.99. PMID: 11773547
Tyni T, Pihko H
Acta Paediatr 1999 Mar;88(3):237-45. doi: 10.1080/08035259950169954. PMID: 10229030

Diagnosis

Rigaudière F, Delouvrier E, Le Gargasson JF, Milani P, Ogier de Baulny H, Schiff M
Doc Ophthalmol 2021 Jun;142(3):371-380. Epub 2021 Jan 4 doi: 10.1007/s10633-020-09802-y. PMID: 33392894
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
Haglind CB, Nordenström A, Ask S, von Döbeln U, Gustafsson J, Stenlid MH
J Inherit Metab Dis 2015 Mar;38(2):315-22. Epub 2014 Aug 21 doi: 10.1007/s10545-014-9750-3. PMID: 25141826
den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA
Pediatrics 2002 Jan;109(1):99-104. doi: 10.1542/peds.109.1.99. PMID: 11773547
Tyni T, Pihko H
Acta Paediatr 1999 Mar;88(3):237-45. doi: 10.1080/08035259950169954. PMID: 10229030

Therapy

Kahraman AB, Yildiz Y, Gokmen-Ozel H, Kadayifcilar S, Sivri S
Neuromuscul Disord 2023 Apr;33(4):315-318. Epub 2023 Feb 19 doi: 10.1016/j.nmd.2023.02.008. PMID: 36893607
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
Gillingham MB, Connor WE, Matern D, Rinaldo P, Burlingame T, Meeuws K, Harding CO
Mol Genet Metab 2003 Jun;79(2):114-23. doi: 10.1016/s1096-7192(03)00073-8. PMID: 12809642Free PMC Article
Gillingham M, Van Calcar S, Ney D, Wolff J, Harding C
J Inherit Metab Dis 1999 Apr;22(2):123-31. doi: 10.1023/a:1005437616934. PMID: 10234607Free PMC Article

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
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
Wilcken B
J Inherit Metab Dis 2010 Oct;33(5):501-6. Epub 2010 Jan 5 doi: 10.1007/s10545-009-9001-1. PMID: 20049534
den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA
Pediatrics 2002 Jan;109(1):99-104. doi: 10.1542/peds.109.1.99. PMID: 11773547
Tyni T, Pihko H
Acta Paediatr 1999 Mar;88(3):237-45. doi: 10.1080/08035259950169954. PMID: 10229030

Clinical prediction guides

Schwantje M, Mosegaard S, Knottnerus SJG, van Klinken JB, Wanders RJ, van Lenthe H, Hermans J, IJlst L, Denis SW, Jaspers YRJ, Fuchs SA, Houtkooper RH, Ferdinandusse S, Vaz FM
FASEB J 2024 Feb 29;38(4):e23478. doi: 10.1096/fj.202302163R. PMID: 38372965
Gaston G, Babcock S, Ryals R, Elizondo G, DeVine T, Wafai D, Packwood W, Holden S, Raber J, Lindner JR, Pennesi ME, Harding CO, Gillingham MB
Commun Biol 2023 Aug 29;6(1):890. doi: 10.1038/s42003-023-05268-1. PMID: 37644104Free 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
García García LC, Zamorano Martín F, Rocha de Lossada C, García Lorente M, Luque Aranda G, Escudero Gómez J
Arch Soc Esp Oftalmol (Engl Ed) 2021 Sep;96(9):496-499. Epub 2020 Nov 28 doi: 10.1016/j.oftale.2020.07.013. PMID: 34479707
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

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

Supplemental Content

Table of contents

    Clinical resources

    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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