U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Multiple acyl-CoA dehydrogenase deficiency(MADD)

MedGen UID:
75696
Concept ID:
C0268596
Disease or Syndrome
Synonyms: Ethylmalonic-adipicaciduria; GA 2; GA II; Glutaric acidemia type 2; Glutaric acidemia type II; Glutaric aciduria, type 2; MADD
SNOMED CT: Glutaric aciduria, type 2 (22886006); Ethylmalonic-adipicaciduria (22886006); Glutaric acidemia, type 2 (22886006); MADD - multiple acyl-CoA dehydrogenase deficiency (22886006); Glutaric aciduria type II (22886006); MAD - Multiple acyl-CoA dehydrogenase deficiency (22886006)
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).
 
Genes (locations): ETFA (15q24.2-24.3); ETFB (19q13.41); ETFDH (4q32.1)
 
Monarch Initiative: MONDO:0009282
OMIM®: 231680
Orphanet: ORPHA26791

Disease characteristics

Excerpted from the GeneReview: Multiple Acyl-CoA Dehydrogenase Deficiency
Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which presentations can be divided into type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset). Individuals with type I or II MADD typically become symptomatic in the neonatal period with severe metabolic acidosis, which may be accompanied by profound hypoglycemia and hyperammonemia. Many affected individuals die in the newborn period despite metabolic treatment. In those who survive the neonatal period, recurrent metabolic decompensation resembling Reye syndrome and the development of hypertrophic cardiomyopathy can occur. Congenital anomalies may include dysmorphic facial features, large cystic kidneys, hypospadias and chordee in males, and neuronal migration defects (heterotopias) on brain MRI. Individuals with type III MADD, the most common presentation, can present from infancy to adulthood. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can also be seen. Rarely, individuals with late-onset MADD (type III) may develop severe sensory neuropathy in addition to proximal myopathy. [from GeneReviews]
Authors:
Pankaj Prasun   view full author information

Additional descriptions

From OMIM
Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (GA1; 231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (Goodman, 1993; Olsen et al., 2003). The heterogeneous clinical features of patients with MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress (summary by Frerman and Goodman, 2001). Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (Liang et al., 2009).  http://www.omim.org/entry/231680
From MedlinePlus Genetics
Glutaric acidemia type II is an inherited disorder that interferes with the body's ability to break down proteins and fats to produce energy. Incompletely processed proteins and fats can build up in the body and cause the blood and tissues to become too acidic (metabolic acidosis).

Glutaric acidemia type II usually appears in infancy or early childhood as a sudden episode called a metabolic crisis, in which acidosis and low blood glucose (hypoglycemia) cause weakness, behavior changes such as poor feeding and decreased activity, and vomiting. These metabolic crises, which can be life-threatening, may be triggered by common childhood illnesses or other stresses.

In the most severe cases of glutaric acidemia type II, affected individuals may also be born with physical abnormalities. These may include brain malformations, an enlarged liver (hepatomegaly), a weakened and enlarged heart (dilated cardiomyopathy), fluid-filled cysts and other malformations of the kidneys, unusual facial features, and genital abnormalities. Glutaric acidemia type II may also cause a characteristic odor resembling that of sweaty feet.

Some affected individuals have less severe symptoms that begin later in childhood or in adulthood. In the mildest forms of glutaric acidemia type II, muscle weakness developing in adulthood may be the first sign of the disorder.  https://medlineplus.gov/genetics/condition/glutaric-acidemia-type-ii

Clinical features

From HPO
Glycosuria
MedGen UID:
42267
Concept ID:
C0017979
Finding
An increased concentration of glucose in the urine.
Polycystic kidney disease
MedGen UID:
9639
Concept ID:
C0022680
Disease or Syndrome
The presence of multiple cysts in both kidneys.
Glutaric aciduria
MedGen UID:
75695
Concept ID:
C0268594
Disease or Syndrome
The concentration of glutaric acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Abnormality of the genital system
MedGen UID:
155422
Concept ID:
C0744356
Finding
An abnormality of the genital system.
Proximal tubulopathy
MedGen UID:
326534
Concept ID:
C1839603
Disease or Syndrome
Dysfunction of the proximal tubule, which is the portion of the duct system of the nephron of the kidney which leads from Bowman's capsule to the loop of Henle.
Generalized aminoaciduria
MedGen UID:
339863
Concept ID:
C1847868
Finding
An increased concentration of all types of amino acid in the urine.
Ethylmalonic aciduria
MedGen UID:
355967
Concept ID:
C1865353
Finding
The concentration of ethylmalonic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Renal cortical cysts
MedGen UID:
370605
Concept ID:
C1969144
Finding
Cysts of the cortex of the kidney.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Nausea
MedGen UID:
10196
Concept ID:
C0027497
Sign or Symptom
A sensation of unease in the stomach together with an urge to vomit.
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 periportal necrosis
MedGen UID:
852664
Concept ID:
C0546389
Disease or Syndrome
A type of hepatic necrosis that is concentrated around the necrosis of hepatocytes localized around the intrahepatic branch of portal vein.
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
Abnormal pinna morphology
MedGen UID:
167800
Concept ID:
C0857379
Congenital Abnormality
An abnormality of the pinna, which is also referred to as the auricle or external ear.
Gliosis
MedGen UID:
4899
Concept ID:
C0017639
Pathologic Function
Gliosis is the focal proliferation of glial cells in the central nervous system.
Hypoglycemic coma
MedGen UID:
5710
Concept ID:
C0020617
Disease or Syndrome
Coma induced by low blood sugar.
Pachygyria
MedGen UID:
504794
Concept ID:
CN001193
Finding
Pachygyria is a malformation of cortical development with abnormally wide gyri with sulci 1,5-3 cm apart and abnormally thick cortex measuring more than 5 mm (radiological definition). See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
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.
Wide anterior fontanel
MedGen UID:
400926
Concept ID:
C1866134
Finding
Enlargement of the anterior fontanelle with respect to age-dependent norms.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Pulmonary hypoplasia
MedGen UID:
78574
Concept ID:
C0265783
Congenital Abnormality
A congenital abnormality in which the lung parenchyma is not fully developed. It may be associated with other congenital abnormalities.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Acidosis
MedGen UID:
1296
Concept ID:
C0001122
Pathologic Function
Abnormal acid accumulation or depletion of base.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Elevated circulating glutaric acid concentration
MedGen UID:
871132
Concept ID:
C4025603
Finding
An increased concentration of glutaric acid in the blood.
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Abnormal facial shape
MedGen UID:
98409
Concept ID:
C0424503
Finding
An abnormal morphology (form) of the face or its components.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Developmental cataract
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
A cataract that occurs congenitally as the result of a developmental defect, in contrast to the majority of cataracts that occur in adulthood as the result of degenerative changes of the lens.
Electron transfer flavoprotein-ubiquinone oxidoreductase defect
MedGen UID:
871117
Concept ID:
C4025586
Finding
A deficiency of the electron transfer flavoprotein-ubiquinone oxidoreductase.

Professional guidelines

PubMed

Maier EM, Mütze U, Janzen N, Steuerwald U, Nennstiel U, Odenwald B, Schuhmann E, Lotz-Havla AS, Weiss KJ, Hammersen J, Weigel C, Thimm E, Grünert SC, Hennermann JB, Freisinger P, Krämer J, Das AM, Illsinger S, Gramer G, Fang-Hoffmann J, Garbade SF, Okun JG, Hoffmann GF, Kölker S, Röschinger W
J Inherit Metab Dis 2023 Nov;46(6):1043-1062. Epub 2023 Sep 12 doi: 10.1002/jimd.12671. PMID: 37603033
Lin Y, Zheng W, Chen Y, Huang C, Fu Q, Chen D, Peng W
Clin Chim Acta 2022 Dec 1;537:181-187. Epub 2022 Nov 5 doi: 10.1016/j.cca.2022.10.024. PMID: 36334790
Horvath R
J Inherit Metab Dis 2012 Jul;35(4):679-87. Epub 2012 Jan 10 doi: 10.1007/s10545-011-9434-1. PMID: 22231380

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C4 and C5 +/- Other Acylcarnitines, Glutaric Acidemia II (GA-II) (MADD), 2022

American College of Medical Genetics and Genomics, Algorithm, Glutaric Acidemia II (GA-II)/ MADD, Riboflavin Metabolism Disorder, Ethylmalonic Encephalopathy: C4 and C5 elevated +/- other elevated acylcarnitines (AC), 2022

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

Etiology

Lin Y, Zheng W, Chen Y, Huang C, Fu Q, Chen D, Peng W
Clin Chim Acta 2022 Dec 1;537:181-187. Epub 2022 Nov 5 doi: 10.1016/j.cca.2022.10.024. PMID: 36334790
Zhou D, Ye M, Hu Z, Zhang Y, Zhu L, Yang R, Huang X
Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 Aug 25;50(4):454-462. doi: 10.3724/zdxbyxb-2021-0261. PMID: 34704421Free PMC Article
Plantone D, Pardini M, Rinaldi G
Clin Drug Investig 2021 Jun;41(6):513-527. Epub 2021 Apr 22 doi: 10.1007/s40261-021-01038-1. PMID: 33886098
Huang K, Duan HQ, Li QX, Luo YB, Yang H
Neuropathology 2020 Dec;40(6):531-539. Epub 2020 Jun 30 doi: 10.1111/neup.12667. PMID: 32608139
Angelini C
Biochim Biophys Acta 2015 Apr;1852(4):615-21. Epub 2014 Jul 2 doi: 10.1016/j.bbadis.2014.06.031. PMID: 24997454

Diagnosis

Lin Y, Zheng W, Chen Y, Huang C, Fu Q, Chen D, Peng W
Clin Chim Acta 2022 Dec 1;537:181-187. Epub 2022 Nov 5 doi: 10.1016/j.cca.2022.10.024. PMID: 36334790
Zhang J, Han J, Wang Y, Wu Y, Ma L, Song X, Ji G
Balkan Med J 2022 Jul 22;39(4):290-296. Epub 2022 Jun 23 doi: 10.4274/balkanmedj.galenos.2022.2022-1-127. PMID: 35734957Free PMC Article
Zhou D, Ye M, Hu Z, Zhang Y, Zhu L, Yang R, Huang X
Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 Aug 25;50(4):454-462. doi: 10.3724/zdxbyxb-2021-0261. PMID: 34704421Free PMC Article
Plantone D, Pardini M, Rinaldi G
Clin Drug Investig 2021 Jun;41(6):513-527. Epub 2021 Apr 22 doi: 10.1007/s40261-021-01038-1. PMID: 33886098
Macchione F, Salviati L, Bordugo A, Vincenzi M, Camilot M, Teofoli F, Pancheri E, Zordan R, Bertolin C, Rossi S, Vattemi G, Tonin P
J Neurol 2020 May;267(5):1414-1419. Epub 2020 Jan 29 doi: 10.1007/s00415-020-09729-z. PMID: 31997039

Therapy

Rao NN, Burns K, Manolikos C, Hodge S
BMJ Case Rep 2023 May 22;16(5) doi: 10.1136/bcr-2022-252668. PMID: 37217231Free PMC Article
Zhang J, Han J, Wang Y, Wu Y, Ma L, Song X, Ji G
Balkan Med J 2022 Jul 22;39(4):290-296. Epub 2022 Jun 23 doi: 10.4274/balkanmedj.galenos.2022.2022-1-127. PMID: 35734957Free PMC Article
Plantone D, Pardini M, Rinaldi G
Clin Drug Investig 2021 Jun;41(6):513-527. Epub 2021 Apr 22 doi: 10.1007/s40261-021-01038-1. PMID: 33886098
Huang K, Duan HQ, Li QX, Luo YB, Yang H
Neuropathology 2020 Dec;40(6):531-539. Epub 2020 Jun 30 doi: 10.1111/neup.12667. PMID: 32608139
Yıldız Y, Talim B, Haliloglu G, Topaloglu H, Akçören Z, Dursun A, Sivri HS, Coşkun T, Tokatlı A
Pediatr Neurol 2019 Oct;99:69-75. Epub 2019 Jun 28 doi: 10.1016/j.pediatrneurol.2019.06.015. PMID: 31331668

Prognosis

Lin Y, Zheng W, Chen Y, Huang C, Fu Q, Chen D, Peng W
Clin Chim Acta 2022 Dec 1;537:181-187. Epub 2022 Nov 5 doi: 10.1016/j.cca.2022.10.024. PMID: 36334790
Zhou D, Ye M, Hu Z, Zhang Y, Zhu L, Yang R, Huang X
Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 Aug 25;50(4):454-462. doi: 10.3724/zdxbyxb-2021-0261. PMID: 34704421Free PMC Article
Plantone D, Pardini M, Rinaldi G
Clin Drug Investig 2021 Jun;41(6):513-527. Epub 2021 Apr 22 doi: 10.1007/s40261-021-01038-1. PMID: 33886098
Missaglia S, Tavian D, Angelini C
Crit Rev Biochem Mol Biol 2021 Aug;56(4):360-372. Epub 2021 Apr 7 doi: 10.1080/10409238.2021.1908952. PMID: 33823724
Lin Y, Zhang W, Chen Z, Lin C, Lin W, Fu Q, Peng W, Chen D
J Pediatr Endocrinol Metab 2021 May 26;34(5):649-652. Epub 2021 Apr 7 doi: 10.1515/jpem-2020-0694. PMID: 33823107

Clinical prediction guides

Lin Y, Zheng W, Chen Y, Huang C, Fu Q, Chen D, Peng W
Clin Chim Acta 2022 Dec 1;537:181-187. Epub 2022 Nov 5 doi: 10.1016/j.cca.2022.10.024. PMID: 36334790
Missaglia S, Tavian D, Angelini C
Crit Rev Biochem Mol Biol 2021 Aug;56(4):360-372. Epub 2021 Apr 7 doi: 10.1080/10409238.2021.1908952. PMID: 33823724
van Rijt WJ, Ferdinandusse S, Giannopoulos P, Ruiter JPN, de Boer L, Bosch AM, Huidekoper HH, Rubio-Gozalbo ME, Visser G, Williams M, Wanders RJA, Derks TGJ
J Inherit Metab Dis 2019 Sep;42(5):878-889. Epub 2019 Jul 17 doi: 10.1002/jimd.12147. PMID: 31268564
Béhin A, Acquaviva-Bourdain C, Souvannanorath S, Streichenberger N, Attarian S, Bassez G, Brivet M, Fouilhoux A, Labarre-Villa A, Laquerrière A, Pérard L, Kaminsky P, Pouget J, Rigal O, Vanhulle C, Eymard B, Vianey-Saban C, Laforêt P
Rev Neurol (Paris) 2016 Mar;172(3):231-41. Epub 2016 Mar 30 doi: 10.1016/j.neurol.2015.11.008. PMID: 27038534
Desbats MA, Lunardi G, Doimo M, Trevisson E, Salviati L
J Inherit Metab Dis 2015 Jan;38(1):145-56. Epub 2014 Aug 5 doi: 10.1007/s10545-014-9749-9. PMID: 25091424

Recent systematic reviews

Ma J, Zhang H, Liang F, Li G, Pang X, Zhao R, Wang J, Chang X, Guo J, Zhang W
Orphanet J Rare Dis 2024 Feb 16;19(1):72. doi: 10.1186/s13023-024-03072-6. PMID: 38365830Free PMC Article
Manta A, Spendiff S, Lochmüller H, Thompson R
J Neuromuscul Dis 2021;8(3):401-417. doi: 10.3233/JND-200621. PMID: 33720849Free PMC Article
van Rijt WJ, Jager EA, Allersma DP, Aktuğlu Zeybek AÇ, Bhattacharya K, Debray FG, Ellaway CJ, Gautschi M, Geraghty MT, Gil-Ortega D, Larson AA, Moore F, Morava E, Morris AA, Oishi K, Schiff M, Scholl-Bürgi S, Tchan MC, Vockley J, Witters P, Wortmann SB, van Spronsen F, Van Hove JLK, Derks TGJ
Genet Med 2020 May;22(5):908-916. Epub 2020 Jan 6 doi: 10.1038/s41436-019-0739-z. PMID: 31904027Free PMC Article

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, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C4 and C5 +/- Other Acylcarnitines, Glutaric Acidemia II (GA-II) (MADD), 2022
    • ACMG Algorithm,
      American College of Medical Genetics and Genomics, Algorithm, Glutaric Acidemia II (GA-II)/ MADD, Riboflavin Metabolism Disorder, Ethylmalonic Encephalopathy: C4 and C5 elevated +/- other elevated acylcarnitines (AC), 2022
    • 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

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...