Multiple acyl-CoA dehydrogenase deficiency

General Information (adopted from Orphanet):

Synonyms, Signs: MADD
GA II
Glutaric acidemia type 2
Electron transfer flavoprotein ubiquinone oxidoreductase deficiency
Ethylmalonic-Adipicaciduria
ETFB deficiency, included
ETFDH deficiency
Glutaric Acidemia IIC, included
ETFB deficiency
EMA Glutaric Acidemia IIA, included
Glutaric Acidemia II
Glutaric aciduria type 2
Glutaric Acidemia IIB, included
MAD deficiency
ETFA deficiency
ETFDH deficiency, included
Glutaric Acidemia II
ETFA deficiency, included
Electron transfer flavoprotein deficiency
Multiple FAD dehydrogenase deficiency
Number of Symptoms 131
OrphanetNr: 26791
OMIM Id: 231680
ICD-10: E71.3
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: <= 0.9 of 100 000
Inheritance: Autosomal recessive
17912479 [IBIS]
Age of onset: All ages
25200064 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Acyl-CoA dehydrogenase deficiency
 -Rare genetic disease
Fatty acid oxidation and ketogenesis disorder with hypertrophic cardiomyopathy
 -Rare cardiac disease
 -Rare genetic disease
Muscular lipidosis
 -Rare genetic disease
 -Rare neurologic disease

Comment:

Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia Type II, is a rare autosomal recessive defect of the electron transfer flavoprotein or ubiquinone oxidoreductase, resulting in abnormal fatty acid, amino acid, and choline metabolism. This leads to the impaired metabolism and excretion of glutaric, lactic, ethylmalonic, and other organic acids leading to metabolic acidosis, hypoglycemia, and ‘‘sweaty-feet’’ odor. Neonatal-onset MADD is a rare disease, with poor prognosis (PMID:17912479). Patients with MADD fall into 3 broad clinical phenotypes: 1) neonatal onset with congenital anomalies, 2) neonatal onset without anomalies, 3) mild and/or late onset (Orphanet, May 2016). The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases. Mean age at onset was 19.2 years. The mean delay between onset of symptoms and diagnosis was 3.9 years. Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). 20% had both acute and chronic symptoms. 5% of patients had died at a mean age of 5.8 years, while 3% of patients have remained asymptomatic until a maximum age of 14 years. The vast majority of patients carry mutations in the ETFDH gene (93%), while mutations in the ETFA (5%) and ETFB (2%) genes are the exceptions (PMID:25200064). Involved genes: ETFDH (MADD) (PMID:25200064); ETFA (MADD) (PMID:25200064); ETFB (MADD) (PMID:25200064);

Symptom Information: Sort by abundance 

1
 (HPO:0030198) Fatigable weakness of distal limb muscles Rare [IBIS] 0.6% (n=350) 25200064 IBIS 1 / 7739
2
 (HPO:0006543) Cardiorespiratory arrest Rare [IBIS] 0.3% (n=350) 25200064 IBIS 11 / 7739
3
 (HPO:0005943) Respiratory arrest Rare [IBIS] 0.3% (n=350) 25200064 IBIS 5 / 7739
4
 (HPO:0001288) Gait disturbance Rare [IBIS] 0.3% (n=350) 25200064 IBIS 318 / 7739
5
 (HPO:0001958) Nonketotic hypoglycemia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 4 / 7739
6
 (HPO:0001638) Cardiomyopathy Rare [IBIS] 1.2% (n=350) 25200064 IBIS 192 / 7739
7
 (HPO:0002273) Tetraparesis Rare [IBIS] 0.6% (n=350) 25200064 IBIS 15 / 7739
8
 (HPO:0001262) Somnolence Rare [IBIS] 0.3% (n=350) 25200064 IBIS 20 / 7739
9
 (HPO:0001733) Pancreatitis Rare [IBIS] 0.6% (n=350) 25200064 IBIS 46 / 7739
10
 (HPO:0001639) Hypertrophic cardiomyopathy Rare [IBIS] 0.6% (n=350) 25200064 IBIS 137 / 7739
11
 (HPO:0002524) Cataplexy Rare [IBIS] 0.3% (n=350) 25200064 IBIS 8 / 7739
12
 (HPO:0030050) Narcolepsy Rare [IBIS] 0.3% (n=350) 25200064 IBIS 6 / 7739
13
 (HPO:0001946) Ketosis Rare [IBIS] 0.3% (n=350) 25200064 IBIS 17 / 7739
14
 (HPO:0001273) Abnormality of the corpus callosum Rare [IBIS] 0.3% (n=350) 25200064 IBIS 20 / 7739
15
 (HPO:0002500) Abnormality of the cerebral white matter Rare [IBIS] 0.3% (n=350) 25200064 IBIS 73 / 7739
16
 (HPO:0000969) Edema Rare [IBIS] 0.3% (n=350) 25200064 IBIS 117 / 7739
17
 (HPO:0002329) Drowsiness Rare [IBIS] 0.3% (n=350) 25200064 IBIS 19 / 7739
18
 (HPO:0002301) Hemiplegia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 42 / 7739
19
 (HPO:0012734) Ketotic hypoglycemia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 3 / 7739
20
 (HPO:0004386) Gastrointestinal inflammation Rare [IBIS] 0.9% (n=350) 25200064 IBIS 5 / 7739
21
 (HPO:0001712) Left ventricular hypertrophy Rare [IBIS] 0.3% (n=350) 25200064 IBIS 76 / 7739
22
 (HPO:0001644) Dilated cardiomyopathy Rare [IBIS] 0.3% (n=350) 25200064 IBIS 141 / 7739
23
 (HPO:0002415) Leukodystrophy Rare [IBIS] 0.3% (n=350) 25200064 IBIS 30 / 7739
24
 (HPO:0002478) Progressive spastic quadriplegia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 7 / 7739
25
 (HPO:0002169) Clonus Rare [IBIS] 0.3% (n=350) 25200064 IBIS 37 / 7739
26
 (HPO:0001257) Spasticity Rare [IBIS] 0.3% (n=350) 25200064 IBIS 251 / 7739
27
 (HPO:0010307) Stridor Rare [IBIS] 0.3% (n=350) 25200064 IBIS 19 / 7739
28
 (HPO:0005543) Reduced protein C activity Rare [IBIS] 0.3% (n=350) 25200064 IBIS 4 / 7739
29
 (HPO:0100651) Type I diabetes mellitus Rare [IBIS] 0.6% (n=350) 25200064 IBIS 44 / 7739
30
 (HPO:0002910) Elevated hepatic transaminases Rare [IBIS] 0.9% (n=350) 25200064 IBIS 158 / 7739
31
 (HPO:0000486) Strabismus Rare [IBIS] 0.3% (n=350) 25200064 IBIS 576 / 7739
32
 (HPO:0002300) Mutism Rare [IBIS] 0.3% (n=350) 25200064 IBIS 28 / 7739
33
 (MedDRA:10051093) Cardiopulmonary failure Rare [IBIS] 0.3% (n=350) 25200064 IBIS 1 / 7739
34
 (HPO:0002014) Diarrhea Occasional [IBIS] 21.1% (n=350) 25200064 IBIS 225 / 7739
35
 (HPO:0001824) Weight loss Rare [IBIS] 4.3% (n=350) 25200064 IBIS 42 / 7739
36
 (HPO:0009073) Progressive proximal muscle weakness Rare [IBIS] 0.6% (n=350) 25200064 IBIS 8 / 7739
37
 (HPO:0003128) Lactic acidosis Rare [IBIS] 0.6% (n=350) 25200064 IBIS 116 / 7739
38
 (HPO:0002878) Respiratory failure Rare [IBIS] 1.7% (n=350) 25200064 IBIS 57 / 7739
39
 (HPO:0001635) Congestive heart failure Rare [IBIS] 0.6% (n=350) 25200064 IBIS 232 / 7739
40
 (HPO:0003690) Limb muscle weakness Rare [IBIS] 2% (n=350) 25200064 IBIS 41 / 7739
41
 (HPO:0001410) Decreased liver function Rare [IBIS] 1.2% (n=350) 25200064 IBIS 59 / 7739
42
 (HPO:0002829) Arthralgia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 79 / 7739
43
 (HPO:0003551) Difficulty climbing stairs Rare [IBIS] 0.3% (n=350) 25200064 IBIS 23 / 7739
44
 (HPO:0011675) Arrhythmia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 226 / 7739
45
 (HPO:0003236) Elevated serum creatine phosphokinase Rare [IBIS] 7.1% (n=350) 25200064 IBIS 214 / 7739
46
 (HPO:0001663) Ventricular fibrillation Rare [IBIS] 0.3% (n=350) 25200064 IBIS 35 / 7739
47
 (HPO:0001249) Intellectual disability Rare [IBIS] 0.3% (n=350) 25200064 IBIS 1089 / 7739
48
 (HPO:0002885) Medulloblastoma Rare [IBIS] 0.3% (n=350) 25200064 IBIS 20 / 7739
49
 (HPO:0001508) Failure to thrive Rare [IBIS] 1.2% (n=350) 25200064 IBIS 454 / 7739
50
 (HPO:0001337) Tremor Rare [IBIS] 0.6% (n=350) 25200064 IBIS 200 / 7739
51
 (OMIM) Febrile illness Rare [IBIS] 0.3% (n=350) 25200064 IBIS 2 / 7739
52
 (HPO:0001945) Fever Rare [IBIS] 1.2% (n=350) 25200064 IBIS 218 / 7739
53
 (HPO:0001263) Global developmental delay Rare [IBIS] 1.7% (n=350) 25200064 IBIS 853 / 7739
54
 (OMIM) Hyperexcitability Rare [IBIS] 0.3% (n=350) 25200064 IBIS 2 / 7739
55
 (HPO:0001254) Lethargy Rare [IBIS] 1.7% (n=350) 25200064 IBIS 104 / 7739
56
 (HPO:0005216) Chewing difficulties Rare [IBIS] 0.3% (n=350) 25200064 IBIS 6 / 7739
57
 (HPO:0002094) Dyspnea Rare [IBIS] 1.2% (n=350) 25200064 IBIS 132 / 7739
58
 (HPO:0003394) Muscle cramps Rare [IBIS] 1.2% (n=350) 25200064 IBIS 106 / 7739
59
 (HPO:0002017) Nausea and vomiting Rare [IBIS] 1.2% (n=350) 25200064 IBIS 134 / 7739
60
 (HPO:0012075) Personality disorder Rare [IBIS] 0.3% (n=350) 25200064 IBIS 4 / 7739
61
 (HPO:0002315) Headache Rare [IBIS] 0.6% (n=350) 25200064 IBIS 175 / 7739
62
 (HPO:0000708) Behavioral abnormality Rare [IBIS] 0.3% (n=350) 25200064 IBIS 212 / 7739
63
 (HPO:0001250) Seizures Rare [IBIS] 0.9% (n=350) 25200064 IBIS 1245 / 7739
64
 (HPO:0006957) Loss of ability to walk Rare [IBIS] 0.3% (n=350) 25200064 IBIS 7 / 7739
65
 (HPO:0001350) Slurred speech Rare [IBIS] 0.6% (n=350) 25200064 IBIS 16 / 7739
66
 (HPO:0002066) Gait ataxia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 327 / 7739
67
 (HPO:0200085) Limb tremor Rare [IBIS] 0.3% (n=350) 25200064 IBIS 6 / 7739
68
 (HPO:0000716) Depression Rare [IBIS] 0.6% (n=350) 25200064 IBIS 99 / 7739
69
 (HPO:0002445) Tetraplegia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 26 / 7739
70
 (HPO:0009058) Increased muscle lipid content Rare [IBIS] 3.1% (n=350) 25200064 IBIS 6 / 7739
71
 (OMIM) Lipid storage myopathy Rare [IBIS] 3.4% (n=350) 25200064 IBIS 4 / 7739
72
 (HPO:0001270) Motor delay Rare [IBIS] 0.6% (n=350) 25200064 IBIS 322 / 7739
73
 (HPO:0001259) Coma Rare [IBIS] 4.6% (n=350) 25200064 IBIS 65 / 7739
74
 (HPO:0003738) Exercise-induced myalgia Rare [IBIS] 0.3% (n=350) 25200064 IBIS 19 / 7739
75
 (MedDRA:10002523) Anion gap abnormal Rare [IBIS] 0.6% (n=350) 25200064 IBIS 1 / 7739
76
 (HPO:0001695) Cardiac arrest Rare [IBIS] 0.6% (n=350) 25200064 IBIS 87 / 7739
77
 (HPO:0002015) Dysphagia Rare [IBIS] 6% (n=350) 25200064 IBIS 301 / 7739
78
 (HPO:0003198) Myopathy Rare [IBIS] 5.4% (n=350) 25200064 IBIS 151 / 7739
79
 (HPO:0003324) Generalized muscle weakness Rare [IBIS] 1.4% (n=350) 25200064 IBIS 48 / 7739
80
 (HPO:0003546) Exercise intolerance Occasional [IBIS] 16.6% (n=350) 25200064 IBIS 62 / 7739
81
 (HPO:0002093) Respiratory insufficiency Rare [IBIS] 0.9% (n=350) 25200064 IBIS 410 / 7739
82
 (HPO:0003201) Rhabdomyolysis Rare [IBIS] 1.4% (n=350) 25200064 IBIS 27 / 7739
83
 (HPO:0002039) Anorexia Rare [IBIS] 0.6% (n=350) 25200064 IBIS 62 / 7739
84
 (HPO:0003365) Arthralgia of the hip Rare [IBIS] 0.3% (n=350) 25200064 IBIS 10 / 7739
85
 (HPO:0003418) Back pain Rare [IBIS] 0.3% (n=350) 25200064 IBIS 17 / 7739
86
 (HPO:0003473) Fatigable weakness Rare [IBIS] 0.9% (n=350) 25200064 IBIS 39 / 7739
87
 (HPO:0030199) Fatigable weakness of neck muscles Rare [IBIS] 0.3% (n=350) 25200064 IBIS 1 / 7739
88
 (HPO:0003388) Easy fatigability Rare [IBIS] 1.4% (n=350) 25200064 IBIS 34 / 7739
89
 (HPO:0045045) Elevated plasma acylcarnitine levels Very frequent [IBIS] 93.9% (n=214) 25200064 IBIS 3 / 7739
90
 (HPO:0003326) Myalgia Occasional [IBIS] 17.1% (n=350) 25200064 IBIS 143 / 7739
91
 (HPO:0012432) Chronic fatigue Rare [IBIS] 0.3% (n=350) 25200064 IBIS 5 / 7739
92
 (HPO:0005692) Joint hyperflexibility Rare [IBIS] 0.3% (n=350) 25200064 IBIS 20 / 7739
93
 (HPO:0001985) Hypoketotic hypoglycemia Rare [IBIS] 0.9% (n=350) 25200064 IBIS 11 / 7739
94
 (HPO:0001298) Encephalopathy Rare [IBIS] 4.6% (n=350) 25200064 IBIS 72 / 7739
95
 (HPO:0001919) Acute kidney injury 22041377 IBIS 21 / 7739
96
 (OMIM) Acute metabolic decompensation Rare [IBIS] 0.3% (n=350) 25200064 IBIS 2 / 7739
97
 (HPO:0002572) Episodic vomiting Rare [IBIS] 9.4% (n=350) 25200064 IBIS 12 / 7739
98
 (HPO:0002018) Nausea Rare [IBIS] 2.4% (n=350) 25200064 IBIS 44 / 7739
99
 (HPO:0002013) Vomiting Occasional [IBIS] 37.1% (n=350) 25200064 IBIS 191 / 7739
100
 (HPO:0002089) Pulmonary hypoplasia 11746129 IBIS 80 / 7739
101
 (HPO:0002098) Respiratory distress Rare [IBIS] 0.6% (n=350) 11746129 IBIS 75 / 7739
102
 (HPO:0003530) Glutaric acidemia Very frequent [IBIS] 17912479 IBIS 2 / 7739
103
 (HPO:0001942) Metabolic acidosis Frequent [IBIS] 17912479 IBIS 81 / 7739
104
 (HPO:0011015) Abnormality of blood glucose concentration Rare [IBIS] 0.9% (n=350) 25200064 IBIS 1 / 7739
105
 (HPO:0001943) Hypoglycemia Occasional [IBIS] 7.7% (n=350) 25200064 IBIS 131 / 7739
106
 (HPO:0010892) Abnormality of branched chain family amino acid metabolism Frequent [IBIS] 11746129 IBIS 2 / 7739
107
 (HPO:0003490) Defective dehydrogenation of isovaleryl CoA and butyryl CoA 11746129 IBIS 1 / 7739
108
 (HPO:0003219) Ethylmalonic aciduria Frequent [IBIS] 25200064 IBIS 5 / 7739
109
 (HPO:0003150) Glutaric aciduria Frequent [IBIS] 25200064 IBIS 7 / 7739
110
 (HPO:0001640) Cardiomegaly 17912479 IBIS 81 / 7739
111
 (HPO:0003647) Electron transfer flavoprotein-ubiquinone oxidoreductase defect Very frequent [IBIS] 17912479 IBIS 2 / 7739
112
 (HPO:0001397) Hepatic steatosis 17912479 IBIS 75 / 7739
113
 (HPO:0001987) Hyperammonemia Rare [IBIS] 3.4% (n=350) 25200064 IBIS 50 / 7739
114
 (HPO:0001252) Muscular hypotonia 6862997 IBIS 990 / 7739
115
 (HPO:0001290) Generalized hypotonia 25200064 IBIS 51 / 7739
116
 (HPO:0001324) Muscle weakness Frequent [IBIS] 45.4% (n=350) 25200064 IBIS 859 / 7739
117
 (HPO:0001325) Hypoglycemic coma Rare [IBIS] 0.9% (n=350) 25200064 IBIS 9 / 7739
118
 (HPO:0000348) High forehead 11420420 IBIS 157 / 7739
119
 (HPO:0000260) Wide anterior fontanel 11420420 IBIS 55 / 7739
120
 (HPO:0002240) Hepatomegaly Occasional [IBIS] 8.6% (n=350) 25200064 IBIS 467 / 7739
121
 (HPO:0006582) Reye syndrome-like episodes Rare [IBIS] 2.3% (n=350) 25200064 IBIS 5 / 7739
122
 (HPO:0000078) Abnormality of the genital system 11420420 IBIS 33 / 7739
123
 (HPO:0001999) Abnormal facial shape 11420420 IBIS 169 / 7739
124
 (HPO:0000091) Abnormality of the renal tubule 17912479 IBIS 15 / 7739
125
 (HPO:0000107) Renal cyst 11746129 IBIS 126 / 7739
126
 (HPO:0000113) Polycystic kidney dysplasia 17912479 IBIS 75 / 7739
127
 (HPO:0100520) Oliguria Rare [IBIS] 0.3% (n=350) 25200064 IBIS 14 / 7739
128
 (HPO:0002919) Ketonuria Rare [IBIS] 0.3% (n=350) 25200064 IBIS 18 / 7739
129
 (HPO:0003811) Neonatal death 17912479 IBIS 44 / 7739
130
 (MedDRA:10005555) Blood glucose decreased Rare [IBIS] 0.9% (n=350) 25200064 IBIS 1 / 7739
131
 (OMIM) Neonatal acidosis 17912479 IBIS 1 / 7739

Associated genes:

ETFDH; ETFA; ETFB;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
ETFA rs119458969 pathogenic RCV000002711.2
ETFA rs119458970 pathogenic RCV000002712.2
ETFA rs119458971 pathogenic RCV000002713.2
ETFB rs104894677 pathogenic RCV000018200.28
ETFB rs104894678 pathogenic RCV000018202.24
ETFDH rs121964953 pathogenic RCV000012806.15
ETFDH rs121964954 pathogenic RCV000012808.22
ETFDH rs121964955 pathogenic RCV000024282.24
ETFDH rs121964955 pathogenic RCV000012809.24
ETFDH rs121964956 pathogenic RCV000012810.24
ETFDH rs377656387 pathogenic RCV000024306.16
ETFDH rs377686388 pathogenic RCV000180601.1
ETFDH rs387907170 pathogenic RCV000024305.22
ETFDH rs398124151 pathogenic RCV000173803.1
ETFDH rs398124152 pathogenic RCV000198866.1
ETFDH rs398124152 pathogenic RCV000174102.1
ETFDH rs398124153 pathogenic RCV000174536.1
ETFDH rs727503919 pathogenic RCV000174332.1
ETFDH rs796051964 pathogenic RCV000175781.1

Additional Information:

Description: (OMIM) Glutaric aciduria II (GA II) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of ...
Diagnosis OMIM Costa et al. (1996) noted that a number of subclinical deficiencies caused by malabsorption could be misdiagnosed as inherited mitochondrial fatty acid oxidation defects. They suggested that in the presence of organic acid profiles reminiscent of a defect ...
Clinical Description OMIM - Neonatal Onset

In the son of healthy parents from the same small town in Turkey, Przyrembel et al. (1976) described fatal neonatal acidosis and hypoglycemia with a strong 'sweaty feet' odor. Large amounts of glutaric ...
Genotype-Phenotype Correlations OMIM To examine whether the different clinical forms of MADD can be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, Olsen et al. (2003) investigated the molecular genetic basis for disease development ...
Molecular genetics OMIM - Glutaric aciduria IIA

Indo et al. (1991), Rhead et al. (1992), and Freneaux et al. (1992) identified mutations in the ETFA gene in patients with GA IIA (e.g., 608053.0001).

- Glutaric aciduria IIB ...