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Very long chain acyl-CoA dehydrogenase deficiency(ACADVLD)

MedGen UID:
854382
Concept ID:
C3887523
Disease or Syndrome
Synonyms: ACADVLD; VLCAD deficiency
SNOMED CT: Very long chain acyl-coenzyme A dehydrogenase deficiency (237997005); Very long chain acyl-CoA dehydrogenase deficiency (237997005); VLCAD - Very long chain acyl-CoA dehydrogenase deficiency (237997005)
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): ACADVL (17p13.1)
 
Monarch Initiative: MONDO:0008723
OMIM®: 201475
Orphanet: ORPHA26793

Disease characteristics

Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms. [from GeneReviews]
Authors:
Nancy D Leslie  |  Sofia Saenz-Ayala   view full author information

Additional descriptions

From OMIM
Inborn errors of mitochondrial fatty acid beta-oxidation include medium-chain acyl-CoA dehydrogenase deficiency (ACADMD; 201450), short-chain acyl-CoA dehydrogenase deficiency (ACADSD; 201470), and very long-chain acyl-CoA dehydrogenase deficiency. VLCAD deficiency can be classified clinically into 3 forms: a severe early-onset form with high incidence of cardiomyopathy and high mortality; an intermediate form with childhood onset, usually with hypoketotic hypoglycemia and more favorable outcome; and an adult-onset, myopathic form with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria after exercise or fasting (Andresen et al., 1999). Patients reported with long-chain acyl-CoA dehydrogenase (LCAD) deficiency before VLCAD deficiency was defined were later found to have VLCAD deficiency (Strauss et al., 1995; Roe and Ding, 2001).  http://www.omim.org/entry/201475
From MedlinePlus Genetics
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a condition that prevents the body from converting certain fats into energy, particularly during periods without food (fasting).

There are three forms of VLCAD deficiency, and they are defined by when the signs and symptoms of the condition begin. The early-onset form is the most severe and begins in infancy. Signs and symptoms can include lack of energy (lethargy) and muscle weakness. People with VCLAD deficiency can have low blood sugar (glucose), known as hypoglycemia. Affected individuals are also at risk for serious complications such, as liver abnormalities and life-threatening heart problems. 

Individuals with childhood-onset VLCAD deficiency typically experience an enlarged liver (hepatomegaly) and low blood glucose. This form is sometimes referred to as the hepatic or hypoketotic hypoglycemic form because of these signs. Additional signs and symptoms include other liver problems or muscle weakness.

The adult-onset form, which begins in adolescence or adulthood, usually involves muscle pain and the breakdown of muscle tissue (rhabdomyolysis). The destruction of muscle tissue releases a large amount of a protein called myoglobin, which is processed by the kidneys and released in the urine (myoglobinuria). Myoglobinuria causes the urine to be red or brown.

In both children and adults, problems related to VLCAD deficiency can be triggered by periods of fasting, illness, exercise, and exposure to hot or cold temperatures. In children, 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 occur in children who take aspirin during these viral infections.  https://medlineplus.gov/genetics/condition/very-long-chain-acyl-coa-dehydrogenase-deficiency

Clinical features

From HPO
Sudden cardiac death
MedGen UID:
38841
Concept ID:
C0085298
Pathologic Function
The heart suddenly and unexpectedly stops beating resulting in death within a short time period (generally within 1 h of symptom onset).
Exercise-induced myalgia
MedGen UID:
340638
Concept ID:
C1850830
Sign or Symptom
The occurrence of an unusually high amount of muscle pain following exercise.
Exercise-induced myoglobinuria
MedGen UID:
337172
Concept ID:
C1845155
Finding
Presence of myoglobin in the urine following exercise.
Dicarboxylic aciduria
MedGen UID:
343550
Concept ID:
C1856432
Finding
An increased concentration of dicarboxylic acid in the urine.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Reduced left ventricular ejection fraction
MedGen UID:
868398
Concept ID:
C4022792
Finding
A diminution of the volumetric fraction of blood pumped out of the ventricle with each cardiac cycle.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Necrotizing enterocolitis
MedGen UID:
105440
Concept ID:
C0520459
Disease or Syndrome
Inflammation of the intestine leading to bacterial invasion causing cellular damage and death which causes necrosis of the colon and intestine.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Periportal fibrosis
MedGen UID:
337906
Concept ID:
C1849766
Disease or Syndrome
The presence of fibrosis affecting the interlobular stroma of liver.
Hepatocellular necrosis
MedGen UID:
343247
Concept ID:
C1855038
Disease or Syndrome
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
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.
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.
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.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Muscle stiffness
MedGen UID:
113151
Concept ID:
C0221170
Sign or Symptom
A condition in which muscles cannot be moved quickly without accompanying pain or spasm.
Exercise-induced rhabdomyolysis
MedGen UID:
867168
Concept ID:
C4021526
Finding
Rhabdomyolysis induced by exercise.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Respiratory arrest
MedGen UID:
57878
Concept ID:
C0162297
Pathologic Function
Cessation of breathing function.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
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.
Decreased circulating carnitine concentration
MedGen UID:
222973
Concept ID:
C1142132
Disease or Syndrome
Concentration of carnitine in the blood circulation below the lower limit of normal.
Nonketotic hypoglycemia
MedGen UID:
400730
Concept ID:
C1865292
Finding
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Professional guidelines

PubMed

Van Calcar SC, Sowa M, Rohr F, Beazer J, Setlock T, Weihe TU, Pendyal S, Wallace LS, Hansen JG, Stembridge A, Splett P, Singh RH
Mol Genet Metab 2020 Sep-Oct;131(1-2):23-37. Epub 2020 Oct 6 doi: 10.1016/j.ymgme.2020.10.001. PMID: 33093005
Janeiro P, Jotta R, Ramos R, Florindo C, Ventura FV, Vilarinho L, Tavares de Almeida I, Gaspar A
Eur J Pediatr 2019 Mar;178(3):387-394. Epub 2019 Jan 7 doi: 10.1007/s00431-018-03315-2. PMID: 30617651
Tucci S
J Inherit Metab Dis 2017 May;40(3):317-323. Epub 2017 Feb 28 doi: 10.1007/s10545-017-0016-8. PMID: 28247148

Curated

GMDI (SERN), VLCAD Nutrition Management Guidelines, v. 1.4, 2022

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C14:1 +/- other long-chain acylcarnitines, Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency, 2022

VLCAD Nutrition Management Guidelines

Recent clinical studies

Etiology

Rouyer A, Tard C, Dessein AF, Spinazzi M, Bédat-Millet AL, Dimitri-Boulos D, Nadaj-Pakleza A, Chanson JB, Nicolas G, Douillard C, Laforêt P
Eur J Neurol 2024 Feb;31(2):e16138. Epub 2023 Nov 28 doi: 10.1111/ene.16138. PMID: 38015438
Al-Busaidi SA, Al Nou'mani JA, Al-Falahi Z, Al-Farsi R, Kumar S, Al-Murshedi F, Awlad-Thani K, Al Nabhani A, Al Alawi AM
Clin Biochem 2023 Jun;116:16-19. Epub 2023 Mar 7 doi: 10.1016/j.clinbiochem.2023.03.005. PMID: 36893960
Van Calcar SC, Sowa M, Rohr F, Beazer J, Setlock T, Weihe TU, Pendyal S, Wallace LS, Hansen JG, Stembridge A, Splett P, Singh RH
Mol Genet Metab 2020 Sep-Oct;131(1-2):23-37. Epub 2020 Oct 6 doi: 10.1016/j.ymgme.2020.10.001. PMID: 33093005
Peng G, Tang Y, Gandotra N, Enns GM, Cowan TM, Zhao H, Scharfe C
J Inherit Metab Dis 2020 Sep;43(5):934-943. Epub 2020 Apr 17 doi: 10.1002/jimd.12236. PMID: 32216101Free 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

Diagnosis

Mak J, Peng G, Le A, Gandotra N, Enns GM, Scharfe C, Cowan TM
J Inherit Metab Dis 2023 Mar;46(2):194-205. Epub 2023 Feb 2 doi: 10.1002/jimd.12591. PMID: 36680545Free PMC Article
Fatehi F, Okhovat AA, Nilipour Y, Mroczek M, Straub V, Töpf A, Palibrk A, Peric S, Rakocevic Stojanovic V, Najmabadi H, Nafissi S
Eur J Neurol 2020 Nov;27(11):2257-2266. Epub 2020 Jul 24 doi: 10.1111/ene.14402. PMID: 32558070Free PMC Article
Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ
Mol Genet Metab 2015 Nov;116(3):139-45. Epub 2015 Sep 2 doi: 10.1016/j.ymgme.2015.08.011. PMID: 26385305Free PMC Article
Schiff M, Mohsen AW, Karunanidhi A, McCracken E, Yeasted R, Vockley J
Mol Genet Metab 2013 May;109(1):21-7. Epub 2013 Feb 13 doi: 10.1016/j.ymgme.2013.02.002. PMID: 23480858Free PMC Article
Zhang D, Christianson J, Liu ZX, Tian L, Choi CS, Neschen S, Dong J, Wood PA, Shulman GI
Cell Metab 2010 May 5;11(5):402-11. doi: 10.1016/j.cmet.2010.03.012. PMID: 20444420Free PMC Article

Therapy

Al-Busaidi SA, Al Nou'mani JA, Al-Falahi Z, Al-Farsi R, Kumar S, Al-Murshedi F, Awlad-Thani K, Al Nabhani A, Al Alawi AM
Clin Biochem 2023 Jun;116:16-19. Epub 2023 Mar 7 doi: 10.1016/j.clinbiochem.2023.03.005. PMID: 36893960
Mak J, Peng G, Le A, Gandotra N, Enns GM, Scharfe C, Cowan TM
J Inherit Metab Dis 2023 Mar;46(2):194-205. Epub 2023 Feb 2 doi: 10.1002/jimd.12591. PMID: 36680545Free PMC Article
Alhashem A, Mohamed S, Abdelraheem M, AlGufaydi B, Al-Aqeel A
Saudi Med J 2020 Jun;41(6):590-596. doi: 10.15537/smj.2020.6.25131. PMID: 32518924Free PMC Article
Yamada K, Taketani T
J Hum Genet 2019 Feb;64(2):73-85. Epub 2018 Nov 6 doi: 10.1038/s10038-018-0527-7. PMID: 30401918
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

Prognosis

Division of Biochemistry and Metabolism, Medical Genetics Branch, Chinese Medical Association, Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health
Zhejiang Da Xue Xue Bao Yi Xue Ban 2022 Feb 25;51(1):122-128. doi: 10.3724/zdxbyxb-2022-0107. PMID: 36161784Free PMC Article
Sugihara K, Yuasa M, Isozaki Y, Hata I, Ohshima Y, Hamazaki T, Kakiuchi T, Arao M, Igarashi N, Kotani Y, Fukuda T, Kagawa R, Tajima G, Shigematsu Y
Pediatr Res 2022 Nov;92(5):1391-1399. Epub 2022 Feb 8 doi: 10.1038/s41390-022-01979-z. PMID: 35136200
Yamada K, Taketani T
J Hum Genet 2019 Feb;64(2):73-85. Epub 2018 Nov 6 doi: 10.1038/s10038-018-0527-7. PMID: 30401918
Tucci S
J Inherit Metab Dis 2017 May;40(3):317-323. Epub 2017 Feb 28 doi: 10.1007/s10545-017-0016-8. PMID: 28247148
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

Clinical prediction guides

Sugihara K, Yuasa M, Isozaki Y, Hata I, Ohshima Y, Hamazaki T, Kakiuchi T, Arao M, Igarashi N, Kotani Y, Fukuda T, Kagawa R, Tajima G, Shigematsu Y
Pediatr Res 2022 Nov;92(5):1391-1399. Epub 2022 Feb 8 doi: 10.1038/s41390-022-01979-z. PMID: 35136200
Stenlid R, Olsson D, Cen J, Manell H, Haglind C, Chowdhury AI, Bergsten P, Nordenström A, Halldin M
Clin Transl Sci 2022 Jan;15(1):182-194. Epub 2021 Aug 26 doi: 10.1111/cts.13133. PMID: 34437764Free PMC Article
Alhashem A, Mohamed S, Abdelraheem M, AlGufaydi B, Al-Aqeel A
Saudi Med J 2020 Jun;41(6):590-596. doi: 10.15537/smj.2020.6.25131. PMID: 32518924Free PMC Article
Rovelli V, Manzoni F, Viau K, Pasquali M, Longo N
Mol Genet Metab 2019 May;127(1):64-73. Epub 2019 Apr 16 doi: 10.1016/j.ymgme.2019.04.001. PMID: 31031081
Hesse J, Braun C, Behringer S, Matysiak U, Spiekerkoetter U, Tucci S
J Inherit Metab Dis 2018 Nov;41(6):1169-1178. Epub 2018 Sep 7 doi: 10.1007/s10545-018-0245-5. PMID: 30194637

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

    • GMDI, 2022
      GMDI (SERN), VLCAD Nutrition Management Guidelines, v. 1.4, 2022
    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C14:1 +/- other long-chain acylcarnitines, Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency, 2022
    • GMDI/SERN, 2021
      VLCAD Nutrition Management Guidelines

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