RBCC Red Blood Cell Collection

ETFB [Confidence: low (only semi-automatic identification from reviews)]
Electron transfer flavoprotein subunit beta; Beta-ETF
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P38117
ID ETFB_HUMAN Reviewed; 255 AA.
AC P38117; B3KNY2; Q6IBH7; Q71RF6; Q9Y3S7;
DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Electron transfer flavoprotein subunit beta;
DE Short=Beta-ETF;
GN Name=ETFB; ORFNames=FP585;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fetal liver;
RX PubMed=8504797; DOI=10.1111/j.1432-1033.1993.tb17847.x;
RA Finocchiaro G., Colombo I., Garavaglia B., Gellera C., Valdameri G.,
RA Garbuglio N., Didonato S.;
RT "cDNA cloning and mitochondrial import of the beta-subunit of the
RT human electron-transfer flavoprotein.";
RL Eur. J. Biochem. 213:1003-1008(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GA2B ASN-128.
RX PubMed=12815589; DOI=10.1002/humu.10226;
RA Olsen R.K.J., Andresen B.S., Christensen E., Bross P., Skovby F.,
RA Gregersen N.;
RT "Clear relationship between ETF/ETFDH genotype and phenotype in
RT patients with multiple acyl-CoA dehydrogenation deficiency.";
RL Hum. Mutat. 22:12-23(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP MET-154.
RX PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
RA Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
RA Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
RA Gu J.;
RT "Large-scale cDNA transfection screening for genes related to cancer
RT development and progression.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 147-199, AND VARIANT GA2B
RP GLN-164.
RX PubMed=7912128; DOI=10.1093/hmg/3.3.429;
RA Colombo I., Finocchiaro G., Garavaglia B., Garbuglio N., Yamaguchi S.,
RA Frerman F., Berra B., Didonato S.;
RT "Mutations and polymorphisms of the gene encoding the beta-subunit of
RT the electron transfer flavoprotein in three patients with glutaric
RT acidemia type II.";
RL Hum. Mol. Genet. 3:429-435(1994).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
RX PubMed=8962055; DOI=10.1073/pnas.93.25.14355;
RA Roberts D.L., Frerman F.E., Kim J.-J.P.;
RT "Three-dimensional structure of human electron transfer flavoprotein
RT to 2.1-A resolution.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:14355-14360(1996).
RN [10]
RP VARIANT MET-154.
RX PubMed=10356313; DOI=10.1006/mgme.1999.2856;
RA Bross P., Pedersen P., Winter V., Nyholm M., Johansen B.N.,
RA Olsen R.K., Corydon M.J., Andresen B.S., Eiberg H., Kolvraa S.,
RA Gregersen N.;
RT "A polymorphic variant in the human electron transfer flavoprotein
RT alpha-chain (alpha-T171) displays decreased thermal stability and is
RT overrepresented in very-long-chain acyl-CoA dehydrogenase-deficient
RT patients with mild childhood presentation.";
RL Mol. Genet. Metab. 67:138-147(1999).
CC -!- FUNCTION: The electron transfer flavoprotein serves as a specific
CC electron acceptor for several dehydrogenases, including five acyl-
CC CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase. It
CC transfers the electrons to the main mitochondrial respiratory
CC chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase).
CC -!- COFACTOR: Binds 1 FAD per dimer.
CC -!- COFACTOR: Binds 1 AMP per subunit.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta subunit.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P38117-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P38117-2; Sequence=VSP_017850;
CC -!- TISSUE SPECIFICITY: Abundant in liver, heart and skeletal muscle.
CC A weak expression is seen in the brain, placenta, lung, kidney and
CC pancreas.
CC -!- DISEASE: Glutaric aciduria 2B (GA2B) [MIM:231680]: An autosomal
CC recessively inherited disorder of fatty acid, amino acid, and
CC choline metabolism. It is characterized by multiple acyl-CoA
CC dehydrogenase deficiencies resulting in large excretion not only
CC of glutaric acid, but also of lactic, ethylmalonic, butyric,
CC isobutyric, 2-methyl-butyric, and isovaleric acids. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the ETF beta-subunit/FixA family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ETFB";
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DR EMBL; X71129; CAA50441.1; -; mRNA.
DR EMBL; AF436663; AAN03713.1; -; Genomic_DNA.
DR EMBL; AF436658; AAN03713.1; JOINED; Genomic_DNA.
DR EMBL; AF436659; AAN03713.1; JOINED; Genomic_DNA.
DR EMBL; AF436660; AAN03713.1; JOINED; Genomic_DNA.
DR EMBL; AF436661; AAN03713.1; JOINED; Genomic_DNA.
DR EMBL; AF436662; AAN03713.1; JOINED; Genomic_DNA.
DR EMBL; AF370381; AAQ15217.1; -; mRNA.
DR EMBL; CR456827; CAG33108.1; -; mRNA.
DR EMBL; AK055285; BAG51494.1; -; mRNA.
DR EMBL; BC093961; AAH93961.1; -; mRNA.
DR EMBL; BC093963; AAH93963.1; -; mRNA.
DR EMBL; X76067; CAB37832.1; -; Genomic_DNA.
DR PIR; S32482; S32482.
DR RefSeq; NP_001014763.1; NM_001014763.1.
DR RefSeq; NP_001976.1; NM_001985.2.
DR UniGene; Hs.348531; -.
DR PDB; 1EFV; X-ray; 2.10 A; B=1-255.
DR PDB; 1T9G; X-ray; 2.90 A; S=1-255.
DR PDB; 2A1T; X-ray; 2.80 A; S=1-255.
DR PDB; 2A1U; X-ray; 2.11 A; B=1-255.
DR PDBsum; 1EFV; -.
DR PDBsum; 1T9G; -.
DR PDBsum; 2A1T; -.
DR PDBsum; 2A1U; -.
DR ProteinModelPortal; P38117; -.
DR SMR; P38117; 4-255.
DR DIP; DIP-6162N; -.
DR IntAct; P38117; 2.
DR MINT; MINT-1520912; -.
DR STRING; 9606.ENSP00000346173; -.
DR PhosphoSite; P38117; -.
DR DMDM; 585110; -.
DR REPRODUCTION-2DPAGE; IPI00004902; -.
DR UCD-2DPAGE; P38117; -.
DR PaxDb; P38117; -.
DR PeptideAtlas; P38117; -.
DR PRIDE; P38117; -.
DR Ensembl; ENST00000309244; ENSP00000311930; ENSG00000105379.
DR Ensembl; ENST00000354232; ENSP00000346173; ENSG00000105379.
DR GeneID; 2109; -.
DR KEGG; hsa:2109; -.
DR UCSC; uc002pwh.3; human.
DR CTD; 2109; -.
DR GeneCards; GC19M051848; -.
DR HGNC; HGNC:3482; ETFB.
DR HPA; HPA018910; -.
DR HPA; HPA018921; -.
DR HPA; HPA018923; -.
DR MIM; 130410; gene.
DR MIM; 231680; phenotype.
DR neXtProt; NX_P38117; -.
DR Orphanet; 26791; Glutaric acidemia type 2.
DR PharmGKB; PA27898; -.
DR eggNOG; COG2086; -.
DR HOGENOM; HOG000247877; -.
DR HOVERGEN; HBG005614; -.
DR KO; K03521; -.
DR OMA; EDPPVRQ; -.
DR OrthoDB; EOG7X3QS5; -.
DR PhylomeDB; P38117; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; P38117; -.
DR GeneWiki; ETFB; -.
DR GenomeRNAi; 2109; -.
DR NextBio; 8527; -.
DR PRO; PR:P38117; -.
DR ArrayExpress; P38117; -.
DR Bgee; P38117; -.
DR CleanEx; HS_ETFB; -.
DR Genevestigator; P38117; -.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0009055; F:electron carrier activity; TAS:ProtInc.
DR GO; GO:0022904; P:respiratory electron transport chain; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.40.50.620; -; 1.
DR InterPro; IPR000049; ET-Flavoprotein_bsu_CS.
DR InterPro; IPR014730; ETF_a/b_N.
DR InterPro; IPR012255; ETF_b.
DR InterPro; IPR014729; Rossmann-like_a/b/a_fold.
DR PANTHER; PTHR21294; PTHR21294; 1.
DR Pfam; PF01012; ETF; 1.
DR PIRSF; PIRSF000090; Beta-ETF; 1.
DR SMART; SM00893; ETF; 1.
DR PROSITE; PS01065; ETF_BETA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Disease mutation; Electron transport; FAD; Flavoprotein;
KW Glutaricaciduria; Mitochondrion; Polymorphism; Reference proteome;
KW Transport.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 255 Electron transfer flavoprotein subunit
FT beta.
FT /FTId=PRO_0000167870.
FT MOD_RES 2 2 N-acetylalanine (By similarity).
FT MOD_RES 19 19 N6-acetyllysine (By similarity).
FT MOD_RES 35 35 N6-acetyllysine (By similarity).
FT MOD_RES 56 56 N6-acetyllysine (By similarity).
FT MOD_RES 59 59 N6-acetyllysine (By similarity).
FT MOD_RES 110 110 N6-acetyllysine (By similarity).
FT MOD_RES 114 114 N6-acetyllysine (By similarity).
FT MOD_RES 116 116 N6-acetyllysine (By similarity).
FT MOD_RES 200 200 N6-acetyllysine (By similarity).
FT MOD_RES 210 210 N6-acetyllysine (By similarity).
FT MOD_RES 238 238 N6-acetyllysine (By similarity).
FT MOD_RES 248 248 N6-acetyllysine (By similarity).
FT VAR_SEQ 1 19 MAELRVLVAVKRVIDYAVK -> MYLSLWVTINTVNLRNTL
FT SGLRGAVTTVGMIKSDVPGTQEWLDERRRQGDLPLPTNSNP
FT VLSLELCDPGQGPAPFQAVVVLIQPGRGLALRPPPSCLFPP
FT DPTPSPPAGQ (in isoform 2).
FT /FTId=VSP_017850.
FT VARIANT 128 128 D -> N (in GA2B).
FT /FTId=VAR_025804.
FT VARIANT 154 154 T -> M (in dbSNP:rs1130426).
FT /FTId=VAR_008548.
FT VARIANT 164 164 R -> Q (in GA2B; dbSNP:rs104894677).
FT /FTId=VAR_002369.
FT CONFLICT 198 198 I -> S (in Ref. 7; CAB37832).
FT STRAND 5 9
FT STRAND 12 14
FT STRAND 16 18
FT STRAND 26 29
FT STRAND 36 38
FT HELIX 40 54
FT STRAND 59 68
FT HELIX 71 81
FT STRAND 84 90
FT HELIX 93 96
FT HELIX 101 115
FT STRAND 118 124
FT TURN 127 129
FT HELIX 134 142
FT STRAND 146 156
FT STRAND 159 166
FT STRAND 169 183
FT HELIX 185 187
FT HELIX 195 200
FT TURN 201 203
FT STRAND 206 209
FT HELIX 211 214
FT STRAND 221 228
FT HELIX 242 251
SQ SEQUENCE 255 AA; 27844 MW; 47E6EAEF50EB2C80 CRC64;
MAELRVLVAV KRVIDYAVKI RVKPDRTGVV TDGVKHSMNP FCEIAVEEAV RLKEKKLVKE
VIAVSCGPAQ CQETIRTALA MGADRGIHVE VPPAEAERLG PLQVARVLAK LAEKEKVDLV
LLGKQAIDDD CNQTGQMTAG FLDWPQGTFA SQVTLEGDKL KVEREIDGGL ETLRLKLPAV
VTADLRLNEP RYATLPNIMK AKKKKIEVIK PGDLGVDLTS KLSVISVEDP PQRTAGVKVE
TTEDLVAKLK EIGRI
//

MIM 130410
*RECORD*
*FIELD* NO
130410
*FIELD* TI
*130410 ELECTRON TRANSFER FLAVOPROTEIN, BETA POLYPEPTIDE; ETFB
*FIELD* TX

DESCRIPTION
read more
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) and contains 1 flavin adenine dinucleotide (FAD) and 1
adenosine 5-prime monophosphate (AMP) per heterodimer. ETFDH (231675), 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.

CLONING

Finocchiaro et al. (1989) cloned the gene for the beta subunit of human
electron transfer flavoprotein.

GENE STRUCTURE

Olsen et al. (2003) determined that the ETFB gene contains 6 exons.

MAPPING

Finocchiaro et al. (1989) mapped the ETFB gene to chromosome 19 by
Southern analysis of somatic cell hybrid DNAs. Antonacci et al. (1994)
assigned the ETFB gene to 19q13.3 by Southern analysis of somatic cell
hybrids and fluorescence in situ hybridization. White et al. (1996)
mapped the corresponding gene to mouse chromosome 7.

MOLECULAR GENETICS

Royal et al. (1991) demonstrated a 2-allele RFLP of the ETFB gene; the
frequencies of the alternative alleles were 0.51 and 0.49.

Colombo et al. (1994) identified mutations in the ETFB gene in patients
with glutaric acidemia IIB (e.g., 130410.0001).

In a series of 9 patients with glutaric acidemia II, Olsen et al. (2003)
identified a defect in the ETFB gene in each of 3 patients representing
the 3 different clinical forms of the disorder: the neonatal-onset form
with congenital anomalies (type I), the neonatal-onset form without
congenital anomalies (type II), and the late-onset form (type III).

*FIELD* AV
.0001
GLUTARIC ACIDEMIA IIB
ETFB, ARG164GLN

In 2 Japanese brothers with glutaric acidemia IIB (231680), Colombo et
al. (1994) demonstrated compound heterozygosity for mutations at the
ETFB gene. One allele carried a G-to-A transition at nucleotide 518,
causing a change of codon 164 from arginine to glutamine. The other
allele carried a G-to-C transversion at the first nucleotide of the
intron donor site, downstream of an exon that is skipped during the
splicing event, and a deletion of 159 bp, spanning nucleotides 466
through 624 and leading to the removal of 53 amino acids and no
interruption of the open reading frame.

.0002
GLUTARIC ACIDEMIA IIB
ETFB, 1-EX DEL, IVSDS, +1, G-C

See 130410.0001 and Colombo et al. (1994).

.0003
GLUTARIC ACIDEMIA IIB
ETFB, ASP128ASN

In a patient with the late-onset form (type III) of MADD (231680), Olsen
et al. (2003) found homozygosity for an asp128-to-asn (D128N) mutation
in exon 4 of the ETFB gene. The patient was born of consanguineous
Kurdish parents and had been reported by Lundemose et al. (1997). Both
parents were heterozygous for the mutation. The child died in its first
episode during varicella infection at 21 months of age. A previous child
had died unexpectedly at the age of 6 months. Slight stasis and edema of
the lungs and notable fatty infiltration in the liver were found at
autopsy.

*FIELD* RF
1. Antonacci, R.; Colombo, I.; Archidiacono, N.; Volta, M.; DiDonato,
S.; Finocchiaro, G.; Rocchi, M.: Assignment of the gene encoding
the beta-subunit of the electron-transfer flavoprotein (ETFB) to human
chromosome 19q13.3. Genomics 19: 177-179, 1994.

2. Colombo, I.; Finocchiaro, G.; Garavaglia, B.; Garbuglio, N.; Yamaguchi,
S.; Frerman, F. E.; Berra, B.; DiDonato, S.: Mutations and polymorphisms
of the gene encoding the beta-subunit of the electron transfer flavoprotein
in three patients with glutaric acidemia type II. Hum. Molec. Genet. 3:
429-435, 1994.

3. Finocchiaro, G.; Archidiacono, N.; Gellera, C.; Bloisi, W.; Colombo,
I.; Valdameri, G.; Romeo, G.; Tanaka, K.; Di Donato, S.: Molecular
cloning and chromosomal localization of the beta-subunit of human
electron transfer flavoprotein (ETF). (Abstract) Am. J. Hum. Genet. 45:
A185, 1989.

4. Lundemose, J. B.; Kolvraa, S.; Gregersen, N.; Christensen, E.;
Gregersen, M.: Fatty acid oxidation disorders as primary cause of
sudden and unexpected death in infants and young children: an investigation
performed on cultured fibroblasts from 79 children who died aged between
0-4 years. Molec. Path. 50: 212-217, 1997.

5. 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.

6. Royal, V.; Alberts, M. J.; Pericak-Vance, M. A.; Finocchiaro, G.;
Bebout, J.; Yamaoka, L.; Hung, W.-Y.; Gaskell, P. C.; Roses, A. D.
: RsaI RFLP for electron transport flavoprotein-beta (ETFB). Nucleic
Acids Res. 19: 14, 1991.

7. 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.

*FIELD* CN
Victor A. McKusick - updated: 8/18/2003

*FIELD* CD
Victor A. McKusick: 9/9/1990

*FIELD* ED
carol: 07/27/2011
carol: 4/6/2005
terry: 3/16/2005
mgross: 8/19/2003
terry: 8/18/2003
carol: 12/13/1998
alopez: 6/17/1998
joanna: 6/11/1997
mark: 4/17/1996
terry: 4/10/1996
carol: 4/13/1994
warfield: 4/8/1994
carol: 10/11/1993
carol: 5/21/1993
supermim: 3/16/1992
carol: 11/26/1991

MIM 231680
*RECORD*
*FIELD* NO
231680
*FIELD* TI
#231680 MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD
;;GLUTARIC ACIDEMIA II;;
GLUTARIC ACIDURIA II;;
read moreGA II;;
ETHYLMALONIC-ADIPICACIDURIA; EMA
GLUTARIC ACIDEMIA IIA, INCLUDED;;
ETFA DEFICIENCY, INCLUDED;;
GLUTARIC ACIDEMIA IIB, INCLUDED;;
ETFB DEFICIENCY, INCLUDED;;
GLUTARIC ACIDEMIA IIC, INCLUDED;;
ETFDH DEFICIENCY, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because MADD, also known as
glutaric acidemia II or glutaric aciduria II, can be caused by mutations
in at least 3 different genes: ETFA (608053), ETFB (130410), and ETFDH
(231675). These genes are all involved in electron transfer in the
mitochondrial respiratory chain. The disorders resulting from defects in
these 3 genes are referred to as glutaric acidemia IIA, IIB, and IIC,
respectively, although there appears to be no difference in the clinical
phenotypes.

DESCRIPTION

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 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).

CLINICAL FEATURES

- 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
acid were found in the blood and urine. The defect was tentatively
located to the metabolism of a range of acyl-CoA compounds. A possibly
identically affected child died earlier.

Lehnert et al. (1982), Bohm et al. (1982), and others described
malformations with multiple acyl-CoA dehydrogenation deficiency:
congenital polycystic kidneys, characteristic facies, etc.

Typical clinical features of the disorder are respiratory distress,
muscular hypotonia, sweaty feet odor, hepatomegaly, and death often in
the neonatal period. Of the 12 previously reported cases reviewed by
Niederwieser et al. (1983), 7 died in the first 5 days of life and only
2 patients survived to ages 5 and 19 years.

Harkin et al. (1986) described apparently characteristic and perhaps
pathognomonic, cytoplasmic, homogeneous, and moderately electron-dense
membrane-limited bodies in the central nervous system and renal tissues
of a female patient who died at age 5 days. The kidneys were enlarged
with numerous cortical cysts. Selective proximal tubular damage leads to
glycosuria and generalized amino aciduria. The patient came from an
inbred Louisiana Cajun community and had a sib who also died in the
newborn period.

Patients with severe deficiency of the ETF dehydrogenase type have
distinctive congenital malformations, whereas those with ETF deficiency
do not; the severity of the metabolic block, rather than its location,
and the resulting profound acidosis in utero may disturb normal
morphogenesis. Colevas et al. (1988) described the pathologic findings
in 2 cases. The pattern of lesions, in particular the striking
localization of renal dysplasia to the medulla, suggested that the
malformations may be the consequence of an accumulation of toxic
metabolites that is not corrected by placental transfer. Other
malformations included cerebral pachygyria, pulmonary hypoplasia, and
facial dysmorphism. Lipid accumulation was demonstrated in the liver,
heart, and renal tubular epithelium, all tissues that use fatty acids as
a primary source of energy.

Wilson et al. (1989) found reports of malformations in 8 of 16 cases.
The anomalies included macrocephaly, large anterior fontanel, high
forehead, flat nasal bridge, telecanthus, and malformed ears.
Abnormalities such as hypotonia, cerebral gliosis, heterotopias,
hepatomegaly, hepatic periportal necrosis, polycystic kidneys, and
genital defects were considered reminiscent of the anomalies in
Zellweger syndrome, but elevations of glutaric, ethylmalonic, adipic,
and isovaleric acids were considered distinctive for glutaric aciduria
type II. Wilson et al. (1989) described a unique ultrastructural change
in the glomerular basement membrane which they suggested may represent
an early stage in renal cyst formation and provide a diagnostic
criterion for glutaric aciduria II when enzyme studies are unavailable.

Poplawski et al. (1999) reported a family in which an unexplained
neonatal death had occurred. Twelve years after the death, they
retrospectively diagnosed multiple acyl-CoA-dehydrogenase deficiency by
demonstrating an abnormal acyl-carnitine profile in the child's archived
neonatal screening card, using tandem mass spectrometry.

Angle and Burton (2008) reported 3 unrelated infants with genetically
confirmed MADD who experienced sudden acute life-threatening events in
the first year of life, resulting in death in 2 infants. All had been
correctly diagnosed via a newborn screening protocol. Each developed
cardiopulmonary arrest concurrent with metabolic stress or limited
caloric intake, including vomiting, upper respiratory infection, and
rotaviral diarrhea. Although only 1 patient had a documented arrhythmia,
Angle and Burton (2008) suggested that an intrinsic abnormality of
myocardial function due to altered energy production may have played a
role. The authors emphasized the importance of aggressive nutritional
management in infants with MADD.

- Later Onset

Hypoglycemia caused by inborn errors of metabolism, including
disturbances of organic-acid metabolism, usually appear during infancy
or childhood. Thus, the case reported by Dusheiko et al. (1979) was
unusual. A 19-year-old woman had episodic vomiting, severe hypoglycemia,
and fatty infiltration of the liver. The parents were not related. One
of her sisters, at age 7, developed nausea, vomiting, and a 'stale' odor
to the breath, and died after 3 days in hypoglycemic coma. At age 10, a
second sister was found to have jaundice, hepatomegaly, and hypoglycemia
after an acute febrile illness. She recovered from that illness but died
'in her sleep' 2 years later. Excess amounts of glutaric and
ethylmalonic acids were found in the urine, consistent with defective
dehydrogenation of isovaleryl CoA and butyryl CoA, respectively. These
organic acids plus others are excreted in the urine in excess in
Jamaican vomiting sickness, caused by the ingestion of unripe akee.
Unripe akee contains the toxin hypoglycin, which inhibits several acyl
CoA dehydrogenases. Cultured fibroblasts in the patient of Dusheiko et
al. (1979) showed reduced ability to oxidize radiolabeled butyrate and
lysine.

Mongini et al. (1992) reported a 25-year-old woman who complained of
episodes of muscle weakness, nausea and vomiting since the age of 10
years. She had been born with bilateral cataracts and strabismus. Muscle
biopsy showed free fatty acid accumulation. Low-fat diet reduced the
episodes of muscle weakness.

Horvath et al. (2006) reported 3 unrelated patients with myopathy
associated with coenzyme Q10 deficiency: a 32-year-old German woman who
developed proximal muscle weakness during pregnancy; a 29-year-old
Turkish man who developed difficulty walking and premature fatigue; and
a 6-year-old Hungarian boy who had exercise intolerance and generalized
hypotonia. All patients had significantly increased serum creatine
kinase, increased serum lactate, myopathic changes on EMG, and hypo- or
areflexia. None had myoglobinuria, ataxia, or seizures. Muscle biopsies
showed lipid storage myopathy, respiratory chain complex deficiencies,
and CoQ10 levels below 50% of normal. All 3 patients showed marked
improvement after 3 to 6 months of oral CoQ10 supplementation. Gempel et
al. (2007) reported follow-up on the patients reported by Horvath et al.
(2006). The German woman had developed abnormal liver enzymes and
recurrence of muscle weakness, and laboratory studies showed increased
multiple acyl-CoA derivatives in serum. The Turkish man had proximal
muscle weakness with scapular winging and waddling gait, and laboratory
studies were consistent with MADD. Gempel et al. (2007) also reported 5
patients from 3 additional consanguineous families with late-onset MADD
manifest as childhood-onset muscle weakness, muscle pain, and increased
serum creatine kinase. All 7 patients responded favorably to riboflavin
and/or coenzyme Q supplementation. Muscle biopsies showed a myopathy
with lipid accumulation and small vacuoles; only 2 patients had
ragged-red fibers. All had a decrease of respiratory complex I+III and
II+III activity, and all had decreased muscle CoQ10 levels. Molecular
analysis identified biallelic pathogenic mutations in the ETFDH gene in
all patients (see, e.g., 231675.0007 and 231675.0008), thus confirming
the diagnosis of MADD. Gempel et al. (2007) concluded that MADD due to
ETFDH mutations can result in isolated myopathy with secondary coenzyme
Q10 deficiency.

Liang et al. (2009) reported 4 Taiwanese patients from 3 unrelated
families with MADD due to mutations in the ETFDH gene
(231675.0003-231675.0005). There was marked phenotypic variability, even
between 2 affected sibs with the same genotype. The first patient was a
27-year-old woman who had exercise intolerance since early childhood. In
her teens, she developed several episodes of acute pancreatitis. At age
19, she developed dysphagia with progressive weakness of neck and
proximal limb muscles, and later had a more severe episode of muscle
weakness with acute respiratory failure, but no metabolic acidosis and
hypoketotic hypoglycemia. Serum creatine kinase was elevated, and muscle
biopsy showed increased lipid droplets predominantly in type 1 fibers.
Urinary profile was consistent with MADD. Her older sister had a milder
phenotype, with 2 bouts of muscle weakness and difficulty climbing
stairs and combing her hair. She never had metabolic crisis, hypoketotic
hypoglycemia, or respiratory failure. Laboratory studies showed low
serum carnitine, increased serum acylcarnitine levels, and elevated
glutaric, ethylmalonic, 2-hydroxylglutaric, 3-methylglutaconic, and
lactic acids in urine. Both patients responded well to riboflavin and
carnitine treatment. The third patient developed exercise intolerance,
dysphagia, poor head control, and limb weakness at age 14 years, and was
wheelchair-bound by age 16. He had neck and proximal muscle weakness
with wasting, lordosis, winged scapula, and absent tendon reflexes. He
did not have metabolic acidosis or hypoketotic hypoglycemia. Pulmonary
function tests demonstrated a severe restrictive ventilatory defect.
Muscle biopsy showed increased lipid droplets predominantly in type 1
fibers. He also responded well to riboflavin and carnitine treatment.
The last patient was a 10-year-old girl who was a slow runner since
childhood. She had an upper respiratory tract infection followed by
progressive proximal muscle weakness. A few days after discharge from
the hospital, her condition rapidly deteriorated and she developed fatal
cardiopulmonary failure associated with marked metabolic acidosis,
hyperammonemia, and hypoglycemia.

Lan et al. (2010) reported 7 Han Taiwanese patients with genetically
confirmed MADD. The patients were identified retrospectively by review
of muscle biopsies ascertained for lipid storage myopathy, and all were
asymptomatic when recruited. 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, including encephalopathy, seizures,
hypoglycemia, and heart failure in 1; vomiting and cardiac arrhythmia in
1; encephalopathy, liver function impairment and lactic acidosis in 1;
and vomiting and liver function impairment in 1. 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. Genetic analysis showed
that 6 of the patients were homozygous for an A84T mutation in the ETFDH
gene (231675.0003), and 1 was compound heterozygous for A84T and R175H
(231675.0006). This patient also had a heterozygous substitution in the
PNPLA2 gene (609059), which was not thought to contribute to the
phenotype.

BIOCHEMICAL FEATURES

By fusion of isovaleric acidemia (243500) cells with those of GA II,
Dubiel et al. (1983) showed that these disorders are genetically
distinct, since complementation was observed. In both disorders,
isovaleryl-CoA dehydrogenation is blocked. The defect in GA II is in one
of the proteins involved in the transfer of electrons from acyl-CoA
dehydrogenases to coenzyme Q of the mitochondrial electron transport
chain. Sarcosinemia and sarcosinuria are also observed in this disorder
(Goodman et al., 1980; Gregersen et al., 1980).

Ikeda et al. (1985) concluded that defective synthesis of ETFA was the
fundamental defect in 3 cell lines from patients with severe MADD.

Moon and Rhead (1987) detected 2 complementation groups in cell lines
from patients with severe multiple acyl-CoA dehydrogenation disorder.
This was consistent with the different defects in glutaric aciduria IIA
and glutaric aciduria IIB. The metabolic block in the cell lines from
the latter disorder was 3 times more severe than the former, as assayed
by oxidation of radiolabelled palmitate. No intragenic complementation
was observed within either group. Complementation was started after
polyethylene glycol fusion.

Onkenhout et al. (2001) determined the fatty acid composition of liver,
skeletal muscle, and heart obtained postmortem from patients with
deficiency of 1 of 3 types of acyl-CoA dehydrogenase: medium-chain
(MCAD; 607008), multiple (MADD), and very long-chain (VLCADD; 201475).
Increased amounts of multiple unsaturated fatty acids were found
exclusively in the triglyceride fraction. They could not be detected in
the free fatty acid or phospholipid fractions. Onkenhout et al. (2001)
concluded that intermediates of unsaturated fatty acid oxidation that
accumulate as a consequence of MCADD, MADD, and VLCADD are transported
to the endoplasmic reticulum for esterification into neutral
glycerolipids. The pattern of accumulation is characteristic for each
disease, which makes fatty acid analysis of total lipid of postmortem
tissues a useful tool in the detection of mitochondrial fatty acid
oxidation defects in patients who have died unexpectedly.

Riboflavin-responsive multiple acylcoenzyme A dehydrogenase deficiency
is characterized by, among other features, a decrease in fatty acid
beta-oxidation capacity. Muscle uncoupling protein-3 (UCP3; 602044) is
upregulated under conditions that either increase the levels of
circulating free fatty acid and/or decrease fatty acid beta-oxidation.
Using a relatively large cohort of 7 MADD patients, Russell et al.
(2003) studied the metabolic disturbances of this disease and determined
if they might increase UCP3 expression. Biochemical and molecular tests
demonstrated decreases in fatty acid beta-oxidation and in the
activities of respiratory chain complexes I (see 157655) and II (see
600857). These metabolic alterations were associated with increases of
3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All
parameters were restored to control values after riboflavin treatment.
The authors postulated that upregulation of UCP3 in MADD is due to the
accumulation of muscle fatty acid/acylCoA. The authors considered MADD
an optimal model to study the hypothesis that UCP3 is involved in the
outward translocation of an excess of fatty acid from the mitochondria
and to show that, in humans, the effects of fatty acid on UCP3
expression are direct and independent of fatty acid beta-oxidation.

INHERITANCE

Mantagos et al. (1979) proved autosomal recessive inheritance of MADD by
demonstration of partial enzyme deficiency in each parent of a female
patient.

Niederwieser et al. (1983) reported the case of the son of
consanguineous Jewish parents who died at age 7 months. In a note added
in proof, they described the prenatal diagnosis of an affected female of
the same parentage, indicating autosomal recessive inheritance.

DIAGNOSIS

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 in the beta-oxidation
pathway or a profile reminiscent of glutaric aciduria type II, a
possible digestive disorder should be ruled out.

- Prenatal Diagnosis

Yamaguchi et al. (1990, 1991) described type II glutaric aciduria due to
deficiency of ETFB. The patient had a neonatal onset of intermittent
illness without congenital anomalies. The diagnosis was made at the age
of 10 months. Subsequently, the parents of the patient of Yamaguchi et
al. (1991) had another pregnancy and Yamaguchi et al. (1991) performed
prenatal diagnosis by immunochemical procedures on cultured amniocytes
and by organic acid analysis of amniotic fluid, using a stable isotope
dilution method. They also described the monitoring of the clinical
course and metabolite excretion in early infancy when the patient had no
symptoms. Glutarate concentration was increased in the cell-free
supernatant of the amniotic fluid.

CLINICAL MANAGEMENT

Gregersen et al. (1982) reported successful treatment of a 5 year old
with riboflavin.

Riboflavin-responsive glutaric aciduria type II was reported by Uziel et
al. (1995) in a boy who developed gradually progressive spastic ataxia
and a leukodystrophy without ever having experienced episodic metabolic
crises.

MOLECULAR GENETICS

- 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

Colombo et al. (1994) identified mutations in the ETFB gene in patients
with GA IIB (e.g., 130410.0001).

- Glutaric aciduria IIC

Beard et al. (1993) identified 5 mutations in the ETFDH gene (e.g.,
231675.0001) in 4 patients with GA IIC. All 5 mutations were rare and
caused total lack of enzyme activity and antigen.

In 4 Taiwanese patients from 3 unrelated families with relatively
late-onset 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.

GENOTYPE/PHENOTYPE CORRELATIONS

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 in 9 patients
representing the phenotypic spectrum of MADD. They identified and
characterized 7 novel and 3 previously reported disease-causing
mutations. Studies of these 9 patients yielded results consistent with 3
clinical forms of MADD showing a clear relationship between the nature
of the mutations and the severity of the disease. Homozygosity for 2
null mutations caused fetal development of congenital anomalies,
resulting in a type I disease phenotype. Even minute amounts of residual
ETF/ETFDH activity seemed to be sufficient to prevent embryonic
development of congenital anomalies, giving rise to type II disease.
Studies of an asp128-to-asn mutation of the ETFB gene (D128N;
130410.0003), identified in a patient with type III disease, showed that
the residual activity of the enzyme could be rescued up to 59% of that
of wildtype activity when ETFB(D128N)-transformed E. coli cells were
grown at low temperature. This suggested that the effect of the
ETF/ETFDH genotype in patients with milder forms of MADD, in whom
residual enzyme activity allows modulation of the enzymatic phenotype,
may be influenced by environmental factors such as cellular temperature.

HISTORY

A neonatal lethal form, called 'GA IIA' by Coude et al. (1981), was
thought possibly to be X-linked. Coude et al. (1981) reported a pedigree
supportive of X-linked inheritance because of the occurrence of a total
of 5 proved or presumed cases in 3 sibships related through 5
presumptive carrier females. ('GA IIB' was the designation used by Coude
et al. (1981) for a mild form that presented as recurrent hypoglycemia
without ketosis and showed a less severe evolution with survival to
adulthood.)

*FIELD* SA
Amendt and Rhead (1986); Gregersen (1985); Jakobs et al. (1984);
Mitchell et al. (1983)
*FIELD* RF
1. Amendt, B. A.; Rhead, W. J.: The multiple acyl-coenzyme A dehydrogenation
disorders, glutaric aciduria type II and ethylmalonic-adipic aciduria:
mitochondrial fatty acid oxidation, acyl-coenzyme A dehydrogenase,
and electron transfer flavoprotein activities in fibroblasts. J.
Clin. Invest. 78: 205-213, 1986.

2. Angle, B.; Burton, B. K.: Risk of sudden death and acute life-threatening
events in patients with glutaric acidemia type II. Molec. Genet.
Metab. 93: 36-39, 2008.

3. 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.

4. 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.

5. Colevas, A. D.; Edwards, J. L.; Hruban, R. H.; Mitchell, G. A.;
Valle, D.; Hutchins, G. M.: Glutaric acidemia type II: comparison
of pathologic features in two infants. Arch. Path. Lab. Med. 112:
1133-1139, 1988.

6. Colombo, I.; Finocchiaro, G.; Garavaglia, B.; Garbuglio, N.; Yamaguchi,
S.; Frerman, F. E.; Berra, B.; DiDonato, S.: Mutations and polymorphisms
of the gene encoding the beta-subunit of the electron transfer flavoprotein
in three patients with glutaricacidemia type II. Hum. Molec. Genet. 3:
429-435, 1994.

7. Costa, C. G.; Verhoeven, N. M.; Kneepkens, C. M. F.; Douwes, A.
C.; Wanders, R. J. A.; Tavares De Almeida, I.; Duran, M.; Jakobs,
C.: Organic acid profiles resembling a beta-oxidation defect in two
patients with coeliac disease. J. Inherit. Metab. Dis. 19: 177-180,
1996.

8. Coude, F. X.; Ogier, H.; Charpentier, C.; Thomassin, G.; Checoury,
A.; Amedee-Manesme, O.; Saudubray, J. M.; Frezal, J.: Neonatal glutaric
aciduria type II: an X-linked recessive inherited disorder. Hum.
Genet. 59: 263-265, 1981.

9. Dubiel, B.; Dabrowski, C.; Wetts, R.; Tanaka, K.: Complementation
studies of isovaleric acidemia and glutaric aciduria type II using
cultured skin fibroblasts. J. Clin. Invest. 72: 1543-1552, 1983.

10. Dusheiko, G.; Kew, M. C.; Joffe, B. I.; Lewin, J. R.; Mantagos,
S.; Tanaka, K.: Recurrent hypoglycemia associated with glutaric aciduria
type II in an adult. New Eng. J. Med. 301: 1405-1409, 1979.

11. Freneaux, E.; Sheffield, V. C.; Molin, L.; Shires, A.; Rhead,
W. J.: Glutaric acidemia type II: heterogeneity in beta-oxidation
flux, polypeptide synthesis, and complementary DNA mutations in the
alpha-subunit of electron transfer flavoprotein in eight patients. J.
Clin. Invest. 90: 1679-1686, 1992.

12. Frerman, F. E.; Goodman, S. I.: Defects of electron transfer
flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase:
glutaric acidemia type II.In: Scriver, C. R.; Beaudet, A. L.; Sly,
W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited
Disease. New York: McGraw-Hill (8th Ed.): 2001. Pp. 2357-2365.

13. 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.

14. Goodman, S. I.: Personal Communication. Denver, Colorado 5/20/1993.

15. Goodman, S. I.; McCabe, E. R. B.; Fennessey, P. V.; Mace, J. W.
: Multiple acyl Co-A dehydrogenase deficiency (glutaric aciduria type
II) with transient hypersarcosinemia and sarcosinuria; possible inherited
deficiency of an electron transfer flavoprotein. Pediat. Res. 14:
12-17, 1980.

16. Gregersen, N.: Acyl-CoA dehydrogenation disorders. Scand. J.
Clin. Lab. Invest. 45 (suppl. 174): 1-60, 1985.

17. Gregersen, N.; Kolvraa, S.; Rasmussen, K.; Christensen, E.; Brandt,
N. J.; Ebbesen, F.; Hansen, F. H.: Biochemical studies in a patient
with defects in the metabolism of acyl-CoA and sarcosine: another
possible case of glutaric aciduria type II. J. Inherit. Metab. Dis. 3:
67-72, 1980.

18. Gregersen, N.; Wintzensen, H.; Christensen, S. K. E.; Christensen,
M. F.; Brandt, N. J.; Rasmussen, K.: C(6)-C(10)-dicarboxylic aciduria:
investigations of a patient with riboflavin responsive multiple acyl-CoA
dehydrogenation defects. Pediat. Res. 16: 861-868, 1982.

19. Harkin, J. C.; Gill, W. L.; Shapira, E.: Glutaric acidemia type
II: phenotypic findings and ultrastructural studies of brain and kidney. Arch.
Path. Lab. Med. 110: 399-401, 1986.

20. 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.

21. Ikeda, Y.; Keese, S.; Tanaka, K.: Molecular heterogeneity of
electron transfer flavoprotein (ETF) in glutaric acidemia type II
due to an ETF deficiency. (Abstract) Pediat. Res. 19: 249A, 1985.

22. Indo, Y.; Glassberg, R.; Yokota, I.; Tanaka, K.: Molecular characterization
of variant alpha-subunit of electron transfer flavoprotein in three
patients with glutaric acidemia type II--and identification of glycine
substitution for valine-157 in the sequence of the precursor, producing
an unstable mature protein in a patient. Am. J. Hum. Genet. 49:
575-580, 1991.

23. Jakobs, C.; Sweetman, L.; Wadman, S. K.; Duran, M.; Saudubray,
J.-M.; Nyhan, W. L.: Prenatal diagnosis of glutaric aciduria type
II by direct chemical analysis of dicarboxylic acids in amniotic fluid. Europ.
J. Pediat. 141: 153-157, 1984.

24. 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.

25. 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 newborn brothers. II. Morphology and pathogenesis. Europ.
J. Pediat. 139: 56-59, 1982.

26. 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.

27. Mantagos, S.; Genel, M.; Tanaka, K.: Ethylmalonic-adipic aciduria:
in vivo and in vitro studies indicating deficiency of activities of
multiple acyl-CoA dehydrogenases. J. Clin. Invest. 64: 1580-1589,
1979.

28. Mitchell, G.; Saudubray, J. M.; Benoit, Y.; Rocchiccioli, F.;
Charpentier, C.; Ogier, H.; Boue, J.: Antenatal diagnosis of glutaricaciduria
type II. (Letter) Lancet 321: 1099 only, 1983. Note: Originally
Volume I.

29. Mongini, T.; Doriguzzi, C.; Palmucci, L.; De Francesco, A.; Bet,
L.; Manfredi, L.; Ponzetto, C.; Bresolin, N.: Lipid storage myopathy
in multiple acyl-CoA dehydrogenase deficiency: an adult case. Europ.
Neurol. 32: 170-176, 1992.

30. Moon, A.; Rhead, W. J.: Complementation analysis of fatty acid
oxidation disorders. J. Clin. Invest. 79: 59-64, 1987.

31. Niederwieser, A.; Steinmann, B.; Exner, U.; Neuheiser, F.; Redweik,
U.; Wang, M.; Rampini, S.; Wendel, U.: Multiple acyl-CoA dehydrogenation
deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly,
muscle hypotonia and cardiomyopathy: detection of N-isovalerylglutamic
acid and its monoamide. Helv. Paediat. Acta 38: 9-26, 1983.

32. 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.

33. Onkenhout, W.; Venizelos, V.; Scholte, H. R.; De Klerk, J. B.
C.; Poorthuis, B. J. H. M.: Intermediates of unsaturated fatty acid
oxidation are incorporated in triglycerides but not in phospholipids
in tissues from patients with mitochondrial beta-oxidation defects. J.
Inherit. Metab. Dis. 24: 337-344, 2001.

34. Poplawski, N. K.; Ranieri, E.; Harrison, J. R.; Fletcher, J. M.
: Multiple acyl-coenzyme A dehydrogenase deficiency: diagnosis by
acyl-carnitine analysis of a 12-year-old newborn screening card. J.
Pediat. 134: 764-766, 1999.

35. Przyrembel, H.; Wendel, U.; Becker, K.; Bremer, H. J.; Bruinvis,
L.; Ketting, D.; Wadman, S. K.: Glutaric aciduria type II: report
on a previously undescribed metabolic disorder. Clin. Chim. Acta 66:
227-239, 1976.

36. Rhead, W. J.; Freneaux, E.; Sheffield, V. C.; Molin, L.; Shires,
A.: Glutaric acidemia type II (GAII): heterogeneity in beta-oxidation
flux, polypeptide synthesis and cDNA mutations in the alpha-subunit
of electron transfer flavoprotein in 8 patients. (Abstract) Am. J.
Hum. Genet. 51 (suppl.): A175, 1992.

37. Russell, A. P.; Schrauwen, P.; Somm, E.; Gastaldi, G.; Hesselink,
M. K. C.; Schaart, G.; Kornips, E.; Lo, S. K.; Bufano, D.; Giacobino,
J.-P.; Muzzin, P.; Ceccon, M.; Angelini, C.; Vergani, L.: Decreased
fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme
A dehydrogenase-deficient patients is associated with an increase
in uncoupling protein-3. J. Clin. Endocr. Metab. 88: 5921-5926,
2003.

38. Uziel, G.; Garavaglia, B.; Ciceri, E.; Moroni, I.; Rimoldi, M.
: Riboflavin-responsive glutaric aciduria type II presenting as a
leukodystrophy. Pediat. Neurol. 13: 333-335, 1995.

39. Wilson, G. N.; de Chadarevian, J.-P.; Kaplan, P.; Loehr, J. P.;
Frerman, F. E.; Goodman, S. I.: Glutaric aciduria type II: review
of the phenotype and report of an unusual glomerulopathy. Am. J.
Med. Genet. 32: 395-401, 1989.

40. Yamaguchi, S.; Orii, T.; Maeda, K.; Oshima, M.; Hashimoto, T.
: A new variant of glutaric aciduria type II: deficiency of beta-subunit
of electron transfer flavoprotein. J. Inherit. Metab. Dis. 13: 783-786,
1990.

41. Yamaguchi, S.; Orii, T.; Suzuki, Y.; Maeda, K.; Oshima, M.; Hashimoto,
T.: Newly identified forms of electron transfer flavoprotein deficiency
in two patients with glutaric aciduria type II. Pediat. Res. 29:
60-63, 1991.

42. Yamaguchi, S.; Shimizu, N.; Orii, T.; Fukao, T.; Suzuki, Y.; Maeda,
K.; Hashimoto, T.; Previs, S. F.; Rinaldo, P.: Prenatal diagnosis
and neonatal monitoring of a fetus with glutaric aciduria type II
due to electron transfer flavoprotein (beta-subunit) deficiency. Pediat.
Res. 30: 439-443, 1991.

*FIELD* CS

Metabolic:
Neonatal acidosis;
Hypoglycemia

Misc:
Sweaty feet odor;
Stale breath odor;
Neonatal death frequent

GI:
Nausea;
Vomiting;
Fatty infiltration of liver;
Hepatomegaly;
Hepatic periportal necrosis

Neuro:
Hypoglycemic coma;
Muscle weakness;
Muscular hypotonia

HEENT:
Facial dysmorphism;
Macrocephaly;
Cerebral pachygyria;
Cerebral gliosis;
Large anterior fontanel;
High forehead;
Flat nasal bridge;
Telecanthus;
Congenital cataract;
Malformed ears

Skin:
Jaundice

Respiratory:
Respiratory distress;
Pulmonary hypoplasia

GU:
Selective proximal tubular damage;
Renal cortical cysts;
Polycystic kidneys;
Genital defects

Lab:
Glutaric aciduria;
Glutaric acidemia;
Ethylmalonic aciduria;
Glycosuria;
Generalized aminoaciduria;
Defective dehydrogenation of isovaleryl CoA and butyryl CoA;
Electron transfer flavoprotein-ubiquinone oxidoreductase defect

Inheritance:
Autosomal recessive

*FIELD* CN
Cassandra L. Kniffin - updated: 5/23/2012
Cassandra L. Kniffin - updated: 5/17/2012
Cassandra L. Kniffin - updated: 3/19/2010
Cassandra L. Kniffin - updated: 11/3/2009
John A. Phillips, III - updated: 4/1/2005
Victor A. McKusick - updated: 8/18/2003
Ada Hamosh - updated: 8/30/2001
Victor A. McKusick - updated: 8/5/1999
Jon B. Obray - updated: 7/13/1996
Orest Hurko - updated: 3/26/1996

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
carol: 05/25/2012
terry: 5/25/2012
ckniffin: 5/23/2012
carol: 5/17/2012
ckniffin: 5/17/2012
carol: 7/27/2011
wwang: 3/29/2010
ckniffin: 3/19/2010
wwang: 11/19/2009
ckniffin: 11/3/2009
terry: 3/4/2009
carol: 5/10/2007
terry: 12/20/2005
terry: 4/20/2005
terry: 4/6/2005
alopez: 4/1/2005
carol: 7/22/2004
mgross: 8/25/2003
mgross: 8/20/2003
mgross: 8/19/2003
terry: 8/18/2003
ckniffin: 6/13/2002
cwells: 9/14/2001
cwells: 9/4/2001
terry: 8/30/2001
carol: 8/26/1999
jlewis: 8/26/1999
terry: 8/5/1999
carol: 12/13/1998
alopez: 6/16/1997
carol: 7/13/1996
mark: 4/17/1996
terry: 4/10/1996
mark: 3/26/1996
terry: 3/21/1996
warfield: 4/15/1994
mimadm: 4/14/1994
carol: 10/11/1993
carol: 5/21/1993
carol: 5/7/1993
carol: 12/17/1992