Alternative titles; symbols
HGNC Approved Gene Symbol: ETFDH
Cytogenetic location: 4q32.1 Genomic coordinates (GRCh38) : 4:158,672,296-158,709,623 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q32.1 | Glutaric acidemia IIC | 231680 | Autosomal recessive | 3 |
Electron transfer flavoprotein (ETF) exists in the mitochondrial matrix as a heterodimer of 30-kD alpha subunits (ETFA; 608053) and 28-kD beta subunits (ETFB; 130410) and contains 1 flavin adenine dinucleotide (FAD) and 1 adenosine 5-prime monophosphate (AMP) per heterodimer. ETFDH, a 64-kD monomer integrated in the inner mitochondrial membrane, contains 1 molecule of FAD and a 4Fe-4S cluster. Both enzymes are required for electron transfer from at least 9 mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Multiple acyl-CoA dehydrogenation deficiency (MADD; 231680), also known as glutaric acidemia II or glutaric aciduria II, can be caused by mutation in any of the 3 ETF genes. The disorders resulting from defects in the ETFA, ETFB, and ETFDH genes are referred to as glutaric acidemia IIA, IIB, and IIC, respectively, although there appears to be no difference in the clinical phenotypes.
Olsen et al. (2003) determined that the ETFDH gene contains 13 exons.
By analysis of mouse/human and CHO/human hybrid panels and by in situ hybridization, Beard et al. (1993) demonstrated that the ETFDH gene is located on 4q32-qter. White et al. (1996) demonstrated that the corresponding gene is located on mouse chromosome 3.
In 4 patients with multiple acyl-CoA dehydrogenase deficiency (MADD; 231680), also known as glutaric acidemia IIC, Beard et al. (1993) identified 5 mutations in the ETFDH gene (see, e.g., 231675.0001). All 5 mutations were rare and caused total lack of enzyme activity and antigen.
In 4 Taiwanese patients from 3 unrelated families with MADD, Liang et al. (2009) identified homozygous or compound heterozygous mutations in the ETFDH gene (231675.0003-231675.0005). The A84T mutation (231675.0003) was present in all 4 patients.
In 7 patients from 5 families with late-onset of an isolated myopathy associated with coenzyme Q10 deficiency, Gempel et al. (2007) identified homozygous or compound heterozygous mutations in the ETFDH gene (see, e.g., 231675.0007 and 231675.0008). Two of the patients had previously been reported by Horvath et al. (2006) as having primary coenzyme Q10 deficiency (see, e.g., COQ10D1, 607426). All patients had increased levels of multiple acyl-CoA derivatives, and all showed marked improvement upon treatment with oral CoQ10 and/or riboflavin. Gempel et al. (2007) concluded that MADD due to ETFDH mutations can result in isolated myopathy with secondary coenzyme Q10 deficiency.
In a patient with late-onset glutaric acidemia IIC, who was originally reported by Lalani et al. (2005) with primary coenzyme Q10 deficiency (607426), Xiao et al. (2020) identified compound heterozygous mutations in the ETFDH gene (231675.0009-231675.0010). Western blot analysis in patient fibroblasts revealed decreased expression of the ETFHD, TFP-alpha (HADHA; 600890), and VLCAD (609575) proteins, and minimally reduced TFP-beta (HADHB 143450) protein compared to control samples. Mitochondrial superoxide was increased in patient fibroblasts, and steady-state ATP levels and maximal respiration-basal respiration were decreased. Xiao et al. (2020) concluded that these studies provided evidence for widespread mitochondrial dysfunction in this patient.
In a patient with type IIC glutaric acidemia, also known as multiple acyl-CoA dehydrogenase deficiency (231680), Beard et al. (1993) identified a T-to-C transition in the triplet encoding the initiator methionine of the ETFDH gene. The mutation resulted in total loss of enzyme activity and antigen.
In an infant with the neonatal-onset form of glutaric acidemia IIC with congenital anomalies (231680), Olsen et al. (2003) found homozygosity for a 1-bp deletion of 36A in the ETFDH gene, causing a frameshift beginning with ala12, introducing a stop codon at amino acid 19. The parents were consanguineous. The child died 1 hour after birth and showed Potter face, enlarged polycystic kidneys, symmetrical warty dysplasia of the cerebral cortex, bile duct hypoplasia, cholestasis, fatty degeneration of the liver, siderosis, lung hypoplasia, and steatosis of the myocardium. A second child in the family presented at birth with similar clinical and morphologic findings. The patient had been previously reported by Lehnert et al. (1982) and Bohm et al. (1982).
In 4 Taiwanese patients from 3 unrelated families with glutaric acidemia IIC (MADD; 231680), Liang et al. (2009) identified a 250G-A transition in exon 3 of the ETFDH gene, resulting in an ala84-to-thr (A84T) substitution. One patient was homozygous for the mutation, whereas the other 3 were compound heterozygous for A84T and either a 524G-T transversion, resulting in an arg175-to-leu (R175L; 231675.0004) substitution (2 sibs) or a 380T-A transversion, resulting in a leu127-to-his (L127H; 231675.0005) substitution. All 3 mutations affected highly conserved residues in the FAD-binding domain. The R175L and L127H mutations were not identified in 200 Taiwanese control chromosomes. The A84T variant was identified in 1 of 200 Taiwanese control chromosomes but not in 100 Japanese, 100 Korean, and 100 Thai control chromosomes. No specific haplotype could be linked to the A84T variant.
Lan et al. (2010) identified homozygosity for the A84T mutation in 6 of 7 Han Taiwanese patients with MADD. The patients had a variable phenotype. The age at diagnosis ranged from 7 to 43 years, and the patients' ages at the time of the report were between 22 and 44 years. All had a history of episodic myalgia and limb weakness predominantly affecting the proximal muscles during an acute stage of myopathy. Four had dysphagia and 2 had respiratory failure. Serum creatine kinase was increased during the acute attacks. Three had 1 episode, whereas 4 had recurrent episodes. Four patients had extramuscular features. All except 1 regained normal muscle strength after the acute stage. Trigger factors in some patients included prolonged fasting and exercise. Blood analysis showed increased acylcarnitines ranging from C8 to C16. A seventh Han Taiwanese patient with the disorder was compound heterozygous for A84T and a 524G-A transition in the ETFDH gene, resulting in an arg175-to-his (R175H; 231675.0006) substitution in a highly conserved residue in the FAD-binding domain.
For discussion of the arg175-to-leu (R175L) mutation in the ETFDH gene that was found in compound heterozygous state in a patient with glutaric acidemia IIC (MADD; 231680) by Liang et al. (2009), see 231675.0003.
For discussion of the leu127-to-his (L127H) mutation in the ETFDH gene that was found in compound heterozygous state in a patient with glutaric acidemia IIC (MADD; 231680) by Liang et al. (2009), see 231675.0003.
For discussion of the arg175-to-his (R175H) mutation in the ETFDH gene that was found in compound heterozygous state in a patient with glutaric acidemia IIC (MADD; 231680) by Liang et al. (2009), see 231675.0003.
In 5 patients from 3 unrelated consanguineous families with MADD (231680), Gempel et al. (2007) identified a homozygous 1130T-C transition in the ETFDH gene, resulting in a leu377-to-pro (L377P) substitution in a conserved residue in the C terminus. The mutation was not found in 50 normal controls. Two of the families were of Turkish origin and 1 was Kurdish. The phenotype was homogeneous, with an age of onset ranging from early teens to young adulthood. All patients had exercise intolerance and proximal muscle weakness, often with cramping, hyporeflexia, and increased serum creatine kinase. Muscle biopsies showed myopathy with small vacuoles in most type I fibers, lipid droplets, and decreased levels of coenzyme Q10. There was also decreased activity of respiratory complex I+III and II+III. Laboratory studies showed increased levels of multiple acyl-CoA derivatives. All patients had a favorable response to treatment with CoQ10 and/or riboflavin. One of the patients had previously been reported by Horvath et al. (2006) as having myopathic coenzyme Q deficiency (see, e.g., COQ10D1, 607426).
In a 13-year-old girl, born of consanguineous Turkish parents, with MADD (231680), Gempel et al. (2007) identified a homozygous 1448C-T transition in the ETFDH gene, resulting in a pro483-to-leu (P483L) substitution in a conserved residue. The patient presented at age 12 years with muscle weakness, myalgia, and loss of ambulation associated with increased serum creatine kinase. Muscle biopsy showed myopathy with small vacuoles in most type I fibers, lipid droplets, and decreased levels of coenzyme Q10. There was also decreased activity of respiratory complex I+III and II+III. Laboratory studies showed accumulation of acyl-CoA derivatives. Treatment with riboflavin resulted in complete resolution of muscle symptoms.
In a patient with glutaric acidemia IIC (MADD; 231680), Xiao et al. (2020) identified compound heterozygous mutations in the ETFDH gene, a previously reported c.665A-C transversion, resulting in a gln222-to-pro (Q222P) substitution, and a c.946G-T transversion, resulting in a gly322-to-cys (G322C; 231675.0010) substitution at a highly conserved residue. The mutations were identified by direct sequencing of the ETFDH gene. The G322C mutation was not present in the gnomAD database. and the Q222P was previously reported as pathogenic in MADD. The Q222P is predicted to be in the FAD-binding domain, and the G322C is predicted to be in the ubiquinone-binding domain. Western blot analysis in patient fibroblasts revealed decreased expression of the ETFHD, TFP-alpha (600890), and VLCAD (609575) proteins.
For discussion of the c.946G-T transversion in the ETFHD gene, resulting in a gly322-to-cys (G322C) substitution, that was found in compound heterozygous state in a patient with glutaric acidemia II (MADD; 231680) by Xiao et al. (2020), see 231675.0009.
Beard, S. E., Spector, E. B., Seltzer, W. K., Frerman, F. E., Goodman, S. I. Mutations in electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) in glutaric acidemia type II (GA2). (Abstract) Clin. Res. 41: 271A, 1993.
Bohm, N., Uy, J., Kiebling, M., Lehnert, W. Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers. II. Morphology and pathogenesis. Europ. J. Pediat. 139: 60-65, 1982. [PubMed: 7173260] [Full Text: https://doi.org/10.1007/BF00442082]
Gempel, K., Topaloglu, H., Talim, B., Schneiderat, P., Schoser, B. G. H., Hans, V. H., Palmafy, B., Kale, G., Tokatli, A., Quinzii, C., Hirano, M., Naini, A., DiMauro, S., Prokisch, H., Lochmuller, H., Horvath, R. The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain 130: 2037-2044, 2007. [PubMed: 17412732] [Full Text: https://doi.org/10.1093/brain/awm054]
Horvath, R., Schneiderat, P., Schoser, B. G. H., Gempel, K., Neuen-Jacob, E., Ploger, H., Muller-Hocker, J., Pongratz, D. E., Naini, A., DiMauro, S., Lochmuller, H. Coenzyme Q10 deficiency and isolated myopathy. Neurology 66: 253-255, 2006. [PubMed: 16434667] [Full Text: https://doi.org/10.1212/01.wnl.0000194241.35115.7c]
Lalani, S. R., Vladutiu, G. D., Plunkett, K., Lotze, T. E., Adesina, A. M., Scaglia, F. Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch. Neurol. 62: 317-320, 2005. [PubMed: 15710863] [Full Text: https://doi.org/10.1001/archneur.62.2.317]
Lan, M.-Y., Fu, M.-H., Liu, Y.-F., Huang, C.-C., Chang, Y.-Y., Liu, J.-S., Peng, C.-H., Chen, S.-S. High frequency of ETFDH c.250G-A mutation in Taiwanese patients with late-onset lipid storage myopathy. Clin. Genet. 78: 565-569, 2010. [PubMed: 20370797] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01421.x]
Lehnert, W., Wendel, U., Lindenmaier, S., Bohm, N. Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two brothers. I. Clinical, metabolical, and biochemical findings Europ. J. Pediat. 139: 56-59, 1982. [PubMed: 7173259] [Full Text: https://doi.org/10.1007/BF00442081]
Liang, W.-C., Ohkuma, A., Hayashi, Y. K., Lopez, L. C., Hirano, M., Nonaka, I., Noguchi, S., Chen, L.-H., Jong, Y.-J., Nishino, I. ETFDH mutations, CoQ-10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromusc. Disord. 19: 212-216, 2009. [PubMed: 19249206] [Full Text: https://doi.org/10.1016/j.nmd.2009.01.008]
Olsen, R. K. J., Andresen, B. S., Christensen, E., Bross, P., Skovby, F., Gregersen, N. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum. Mutat. 22: 12-23, 2003. [PubMed: 12815589] [Full Text: https://doi.org/10.1002/humu.10226]
White, R. A., Dowler, L. L., Angeloni, S. V., Koeller, D. M. Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and 13: the mouse homologs of genes responsible for glutaric acidemia type II in human. Genomics 33: 131-134, 1996. [PubMed: 8617498] [Full Text: https://doi.org/10.1006/geno.1996.0170]
Xiao, C., Astiazaran-Symonds, E., Basu, S., Kisling, M., Scaglia, F., Chapman, K. A., Wang, Y., Vockley, J., Ferreira, C. R. Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia type 2. Am. J. Med. Genet. 182A: 2426-2431, 2020. [PubMed: 32804429] [Full Text: https://doi.org/10.1002/ajmg.a.61786]