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Medium-chain acyl-coenzyme A dehydrogenase deficiency(ACADMD)

MedGen UID:
65086
Concept ID:
C0220710
Disease or Syndrome
Synonyms: ACADMD; CARNITINE DEFICIENCY SECONDARY TO MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY; MCADD; Medium chain acyl-CoA dehydrogenase deficiency
SNOMED CT: MCAD deficiency (128596003); Medium-chain acyl-coenzyme A dehydrogenase deficiency (128596003); MCAD - Medium chain acyl-CoA dehydrogenase deficiency (128596003); Medium chain acyl-CoA dehydrogenase deficiency (128596003)
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): ACADM (1p31.1)
 
Monarch Initiative: MONDO:0008721
OMIM®: 201450
Orphanet: ORPHA42

Disease characteristics

Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. Symptomatic individuals experience hypoketotic hypoglycemia in response to either prolonged fasting (e.g., weaning the infant from nighttime feedings) or during intercurrent and common infections (e.g., viral gastrointestinal or upper respiratory tract infections), which typically cause loss of appetite and increased energy requirements when fever is present. Untreated severe hypoglycemic episodes can be accompanied by seizures, vomiting, lethargy, coma, and death. Metabolic decompensation during these episodes can result in elevated liver transaminases and hyperammonemia. Individuals with MCAD deficiency who have experienced the effects of uncontrolled metabolic decompensation are also at risk for chronic myopathy. Early identification and avoidance of prolonged fasting can ameliorate these findings. However, children with MCAD deficiency are at risk for obesity after initiation of treatment due to the frequency of feeding. [from GeneReviews]
Authors:
Irene J Chang  |  Christina Lam  |  Jerry Vockley   view full author information

Additional descriptions

From OMIM
Inherited deficiency of medium-chain acyl-CoA dehydrogenase (ACADMD) is characterized by intolerance to prolonged fasting, recurrent episodes of hypoglycemic coma with medium-chain dicarboxylic aciduria, impaired ketogenesis, and low plasma and tissue carnitine levels. The disorder may be severe, and even fatal, in young patients (Matsubara et al., 1986).  http://www.omim.org/entry/201450
From MedlinePlus Genetics
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting).

Signs and symptoms of MCAD deficiency typically appear during infancy or early childhood and can include vomiting, lack of energy (lethargy), and low blood glucose (hypoglycemia). In rare cases, symptoms of this disorder are not recognized early in life, and the condition is not diagnosed until adulthood. People with MCAD deficiency are at risk of serious complications such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death.

Problems related to MCAD 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/medium-chain-acyl-coa-dehydrogenase-deficiency

Clinical features

From HPO
Hyperglycinuria
MedGen UID:
107456
Concept ID:
C0543541
Disease or Syndrome
The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria (IG; 242600), a benign inborn error of amino acid transport, is also a normal finding in neonates and infants under 6 months of age (Chesney, 2001). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG) (summary by Broer et al., 2008). A phenotype of combined glucosuria and glycinuria has been described (see 138070).
Medium chain dicarboxylic aciduria
MedGen UID:
349718
Concept ID:
C1860081
Finding
An increase in the level of medium chain dicarboxylic acid in the urine.
Elevated urinary 7-hydroxyoctanoic acid level
MedGen UID:
1054187
Concept ID:
CN377437
Finding
The amount of 7-hydroxyoctanoic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
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.
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
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 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.
Decreased circulating carnitine concentration
MedGen UID:
1850526
Concept ID:
C5848230
Finding
Concentration of carnitine in the blood circulation below the lower limit of normal.
Reduced tissue medium-chain acyl-CoA dehydrogenase activity
MedGen UID:
1052495
Concept ID:
CN376952
Finding
Concentration or activity of medium-chain acyl-CoA dehydrogenase (EC 1.3.8.7;MCAD) in tissues is below the lower limit of normal.

Term Hierarchy

Professional guidelines

PubMed

Mütze U, Nennstiel U, Odenwald B, Haase C, Ceglarek U, Janzen N, Garbade SF, Hoffmann GF, Kölker S, Haas D
Eur J Pediatr 2022 Jun;181(6):2415-2422. Epub 2022 Mar 16 doi: 10.1007/s00431-022-04421-y. PMID: 35294644Free PMC Article
McGregor TL, Berry SA, Dipple KM, Hamid R; COUNCIL ON GENETICS
Pediatrics 2021 Jan;147(1) doi: 10.1542/peds.2020-040303. PMID: 33372121
Kaye CI; Committee on Genetics, Accurso F, La Franchi S, Lane PA, Northrup H, Pang S, Schaefer GB
Pediatrics 2006 Sep;118(3):1304-12. doi: 10.1542/peds.2006-1782. PMID: 16960984

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C8 with Lesser Elevations of C6 and C10 Acylcarnitine, Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency, 2021

American College of Medical Genetics and Genomics, Algorithm, C8 Elevated + Lesser Elevations of C6 and C10, 2021

Recent clinical studies

Therapy

McGregor TL, Berry SA, Dipple KM, Hamid R; COUNCIL ON GENETICS
Pediatrics 2021 Jan;147(1) doi: 10.1542/peds.2020-040303. PMID: 33372121
Madsen KL, Preisler N, Orngreen MC, Andersen SP, Olesen JH, Lund AM, Vissing J
J Clin Endocrinol Metab 2013 Apr;98(4):1667-75. Epub 2013 Feb 20 doi: 10.1210/jc.2012-3791. PMID: 23426616
Van Hove JL, Kahler SG, Millington DS, Roe DS, Chace DH, Heales SJ, Roe CR
Pediatr Res 1994 Jan;35(1):96-101. doi: 10.1203/00006450-199401000-00020. PMID: 8134205
Rinaldo P, Schmidt-Sommerfeld E, Posca AP, Heales SJ, Woolf DA, Leonard JV
J Pediatr 1993 Apr;122(4):580-4. doi: 10.1016/s0022-3476(05)83539-5. PMID: 8463904
Hegyi T, Ostfeld B, Gardner K
N J Med 1992 May;89(5):385-92. PMID: 1635678

Prognosis

Tian Y, Zhu X, Lv S, Jia C, Zhang L, Ni M, Xu Y, Peng R, Liu S, Zhao D
Clin Chim Acta 2022 Nov 1;536:155-161. Epub 2022 Sep 9 doi: 10.1016/j.cca.2022.09.008. PMID: 36096209
Mütze U, Nennstiel U, Odenwald B, Haase C, Ceglarek U, Janzen N, Garbade SF, Hoffmann GF, Kölker S, Haas D
Eur J Pediatr 2022 Jun;181(6):2415-2422. Epub 2022 Mar 16 doi: 10.1007/s00431-022-04421-y. PMID: 35294644Free PMC Article
Bentler K, Zhai S, Elsbecker SA, Arnold GL, Burton BK, Vockley J, Cameron CA, Hiner SJ, Edick MJ, Berry SA; Inborn Errors of Metabolism Collaborative
Mol Genet Metab 2016 Sep;119(1-2):75-82. Epub 2016 Jul 15 doi: 10.1016/j.ymgme.2016.07.002. PMID: 27477829Free PMC Article
Iafolla AK, Thompson RJ Jr, Roe CR
J Pediatr 1994 Mar;124(3):409-15. doi: 10.1016/s0022-3476(94)70363-9. PMID: 8120710
Wilcken B, Hammond J, Silink M
Arch Dis Child 1994 May;70(5):410-2. doi: 10.1136/adc.70.5.410. PMID: 8017963Free PMC Article

Clinical prediction guides

Tian Y, Zhu X, Lv S, Jia C, Zhang L, Ni M, Xu Y, Peng R, Liu S, Zhao D
Clin Chim Acta 2022 Nov 1;536:155-161. Epub 2022 Sep 9 doi: 10.1016/j.cca.2022.09.008. PMID: 36096209
Bentler K, Zhai S, Elsbecker SA, Arnold GL, Burton BK, Vockley J, Cameron CA, Hiner SJ, Edick MJ, Berry SA; Inborn Errors of Metabolism Collaborative
Mol Genet Metab 2016 Sep;119(1-2):75-82. Epub 2016 Jul 15 doi: 10.1016/j.ymgme.2016.07.002. PMID: 27477829Free PMC Article
Madsen KL, Preisler N, Orngreen MC, Andersen SP, Olesen JH, Lund AM, Vissing J
J Clin Endocrinol Metab 2013 Apr;98(4):1667-75. Epub 2013 Feb 20 doi: 10.1210/jc.2012-3791. PMID: 23426616
Prosser LA, Kong CY, Rusinak D, Waisbren SL
Pediatrics 2010 Feb;125(2):e286-94. doi: 10.1542/peds.2009-0605. PMID: 20123779
Bodman M, Smith D, Nyhan WL, Naviaux RK
Arch Neurol 2001 May;58(5):811-4. doi: 10.1001/archneur.58.5.811. PMID: 11346377

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 ACT, 2021
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C8 with Lesser Elevations of C6 and C10 Acylcarnitine, Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency, 2021
    • ACMG Algorithm, 2021
      American College of Medical Genetics and Genomics, Algorithm, C8 Elevated + Lesser Elevations of C6 and C10, 2021

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