RBCC Red Blood Cell Collection

HADHA (HADH) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Trifunctional enzyme subunit alpha, mitochondrial (78 kDa gastrin-binding protein; TP-alpha; Long-chain enoyl-CoA hydratase; 4.2.1.17; Long chain 3-hydroxyacyl-CoA dehydrogenase; 1.1.1.211; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P40939
ID ECHA_HUMAN Reviewed; 763 AA.
AC P40939; B2R7L4; Q16679; Q53T69; Q53TA2; Q96GT7;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 03-APR-2002, sequence version 2.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Trifunctional enzyme subunit alpha, mitochondrial;
DE AltName: Full=78 kDa gastrin-binding protein;
DE AltName: Full=TP-alpha;
DE Includes:
DE RecName: Full=Long-chain enoyl-CoA hydratase;
DE EC=4.2.1.17;
DE Includes:
DE RecName: Full=Long chain 3-hydroxyacyl-CoA dehydrogenase;
DE EC=1.1.1.211;
DE Flags: Precursor;
GN Name=HADHA; Synonyms=HADH;
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].
RX PubMed=8135828; DOI=10.1006/bbrc.1994.1302;
RA Kamijo T., Aoyama T., Komiyama A., Hashimoto T.;
RT "Structural analysis of cDNAs for subunits of human mitochondrial
RT fatty acid beta-oxidation trifunctional protein.";
RL Biochem. Biophys. Res. Commun. 199:818-825(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7918661; DOI=10.1016/0167-4781(94)90091-4;
RA Zhang Q.X., Baldwin G.S.;
RT "Structures of the human cDNA and gene encoding the 78 kDa gastrin-
RT binding protein and of a related pseudogene.";
RL Biochim. Biophys. Acta 1219:567-575(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Amygdala;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 SUBUNIT.
RX PubMed=8163672; DOI=10.1172/JCI117158;
RA Kamijo T., Wanders R.J., Saudubray J.-M., Aoyama T., Komiyama A.,
RA Hashimoto T.;
RT "Mitochondrial trifunctional protein deficiency. Catalytic
RT heterogeneity of the mutant enzyme in two patients.";
RL J. Clin. Invest. 93:1740-1747(1994).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-295; LYS-303; LYS-406;
RP LYS-505; LYS-540 AND LYS-644, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
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 [10]
RP VARIANT LCHAD DEFICIENCY GLN-510.
RX PubMed=7811722; DOI=10.1016/0005-2760(94)90064-7;
RA Ijlst L., Wanders R.J.A., Ushikubo S., Kamijo T., Hashimoto T.;
RT "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase
RT deficiency: identification of the major disease-causing mutation in
RT the alpha-subunit of the mitochondrial trifunctional protein.";
RL Biochim. Biophys. Acta 1215:347-350(1994).
RN [11]
RP VARIANT AFLP GLN-510.
RX PubMed=7846063; DOI=10.1073/pnas.92.3.841;
RA Sims H.F., Brackett J.C., Powell C.K., Treem W.R., Hale D.E.,
RA Bennett M.J., Gibson B., Shapiro S., Strauss A.W.;
RT "The molecular basis of pediatric long chain 3-hydroxyacyl-CoA
RT dehydrogenase deficiency associated with maternal acute fatty liver of
RT pregnancy.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:841-845(1995).
RN [12]
RP CHARACTERIZATION OF VARIANT LCHAD DEFICIENCY GLN-510.
RX PubMed=8770876; DOI=10.1172/JCI118863;
RA Ijlst L., Ruiter J.P.N., Hoovers J.M.N., Jakobs M.E., Wanders R.J.A.;
RT "Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA
RT dehydrogenase deficiency. Characterization and expression of the
RT mutant protein, mutation analysis on genomic DNA and chromosomal
RT localization of the mitochondrial trifunctional protein alpha subunit
RT gene.";
RL J. Clin. Invest. 98:1028-1033(1996).
RN [13]
RP VARIANTS LCHAD DEFICIENCY PRO-342 AND GLN-510.
RX PubMed=9266371; DOI=10.1023/A:1005310903004;
RA Ijlst L., Oostheim W., Ruiter J.P.N., Wanders R.J.A.;
RT "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase
RT deficiency: identification of two new mutations.";
RL J. Inherit. Metab. Dis. 20:420-422(1997).
RN [14]
RP VARIANTS TFP DEFICIENCY ASP-282 AND ASN-305.
RX PubMed=9739053; DOI=10.1172/JCI2091;
RA Ibdah J.A., Tein I., Dionisi-Vici C., Bennett M.J., Ijlst L.,
RA Gibson B., Wanders R.J.A., Strauss A.W.;
RT "Mild trifunctional protein deficiency is associated with progressive
RT neuropathy and myopathy and suggests a novel genotype-phenotype
RT correlation.";
RL J. Clin. Invest. 102:1193-1199(1998).
CC -!- FUNCTION: Bifunctional subunit.
CC -!- CATALYTIC ACTIVITY: (3S)-3-hydroxyacyl-CoA = trans-2(or 3)-enoyl-
CC CoA + H(2)O.
CC -!- CATALYTIC ACTIVITY: A long-chain (S)-3-hydroxyacyl-CoA + NAD(+) =
CC a long-chain 3-oxoacyl-CoA + NADH.
CC -!- PATHWAY: Lipid metabolism; fatty acid beta-oxidation.
CC -!- SUBUNIT: Octamer of 4 alpha (HADHA) and 4 beta (HADHB) subunits.
CC -!- INTERACTION:
CC O95166:GABARAP; NbExp=5; IntAct=EBI-356720, EBI-712001;
CC Q9H0R8:GABARAPL1; NbExp=4; IntAct=EBI-356720, EBI-746969;
CC P60520:GABARAPL2; NbExp=4; IntAct=EBI-356720, EBI-720116;
CC Q9GZQ8:MAP1LC3B; NbExp=4; IntAct=EBI-356720, EBI-373144;
CC -!- SUBCELLULAR LOCATION: Mitochondrion.
CC -!- DISEASE: Trifunctional protein deficiency (TFP deficiency)
CC [MIM:609015]: The clinical manifestations are very variable and
CC include hypoglycemia, cardiomyopathy and sudden death. Phenotypes
CC with mainly hepatic and neuromyopathic involvement can also be
CC distinguished. Biochemically, TFP deficiency is defined by the
CC loss of all three enzyme activities of the TFP complex. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD
CC deficiency) [MIM:609016]: The clinical features are very similar
CC to TFP deficiency. Biochemically, LCHAD deficiency is
CC characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase
CC activity, while the other enzyme activities of the TFP complex are
CC normal or only slightly reduced. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Maternal acute fatty liver of pregnancy (AFLP)
CC [MIM:609016]: Severe maternal illness occurring during pregnancies
CC with affected fetuses. This disease is associated with LCHAD
CC deficiency and characterized by sudden unexplained infant death or
CC hypoglycemia and abnormal liver enzymes (Reye-like syndrome).
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: In the N-terminal section; belongs to the enoyl-CoA
CC hydratase/isomerase family.
CC -!- SIMILARITY: In the central section; belongs to the 3-hydroxyacyl-
CC CoA dehydrogenase family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HADHA";
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DR EMBL; D16480; BAA03941.1; -; mRNA.
DR EMBL; U04627; AAA56664.1; -; mRNA.
DR EMBL; AK313027; BAG35861.1; -; mRNA.
DR EMBL; AC010896; AAY14643.1; -; Genomic_DNA.
DR EMBL; AC011742; AAX93141.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00703.1; -; Genomic_DNA.
DR EMBL; BC009235; AAH09235.1; -; mRNA.
DR PIR; JC2108; JC2108.
DR RefSeq; NP_000173.2; NM_000182.4.
DR UniGene; Hs.516032; -.
DR ProteinModelPortal; P40939; -.
DR SMR; P40939; 45-761.
DR IntAct; P40939; 31.
DR MINT; MINT-1159893; -.
DR STRING; 9606.ENSP00000370023; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P40939; -.
DR DMDM; 20141376; -.
DR REPRODUCTION-2DPAGE; IPI00031522; -.
DR UCD-2DPAGE; P40939; -.
DR PaxDb; P40939; -.
DR PeptideAtlas; P40939; -.
DR PRIDE; P40939; -.
DR DNASU; 3030; -.
DR Ensembl; ENST00000380649; ENSP00000370023; ENSG00000084754.
DR GeneID; 3030; -.
DR KEGG; hsa:3030; -.
DR UCSC; uc002rgy.3; human.
DR CTD; 3030; -.
DR GeneCards; GC02M026413; -.
DR HGNC; HGNC:4801; HADHA.
DR HPA; HPA015536; -.
DR MIM; 600890; gene.
DR MIM; 609015; phenotype.
DR MIM; 609016; phenotype.
DR neXtProt; NX_P40939; -.
DR Orphanet; 243367; Acute fatty liver of pregnancy.
DR Orphanet; 5; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency.
DR Orphanet; 746; Mitochondrial trifunctional protein deficiency.
DR PharmGKB; PA29175; -.
DR eggNOG; COG1250; -.
DR HOGENOM; HOG000261346; -.
DR HOVERGEN; HBG005557; -.
DR InParanoid; P40939; -.
DR KO; K07515; -.
DR OMA; MMLNEAA; -.
DR OrthoDB; EOG7P2XRF; -.
DR PhylomeDB; P40939; -.
DR BioCyc; MetaCyc:HS01481-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P40939; -.
DR UniPathway; UPA00659; -.
DR ChiTaRS; HADHA; human.
DR GenomeRNAi; 3030; -.
DR NextBio; 11996; -.
DR PRO; PR:P40939; -.
DR ArrayExpress; P40939; -.
DR Bgee; P40939; -.
DR CleanEx; HS_HADH; -.
DR CleanEx; HS_HADHA; -.
DR Genevestigator; P40939; -.
DR GO; GO:0016507; C:mitochondrial fatty acid beta-oxidation multienzyme complex; IEA:Ensembl.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0003857; F:3-hydroxyacyl-CoA dehydrogenase activity; TAS:ProtInc.
DR GO; GO:0003985; F:acetyl-CoA C-acetyltransferase activity; TAS:ProtInc.
DR GO; GO:0004300; F:enoyl-CoA hydratase activity; TAS:ProtInc.
DR GO; GO:0000062; F:fatty-acyl-CoA binding; IEA:Ensembl.
DR GO; GO:0016509; F:long-chain-3-hydroxyacyl-CoA dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0016508; F:long-chain-enoyl-CoA hydratase activity; IEA:Ensembl.
DR GO; GO:0051287; F:NAD binding; IEA:Ensembl.
DR GO; GO:0035965; P:cardiolipin acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0006635; P:fatty acid beta-oxidation; TAS:Reactome.
DR GO; GO:0046474; P:glycerophospholipid biosynthetic process; TAS:Reactome.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0032868; P:response to insulin stimulus; IEA:Ensembl.
DR Gene3D; 1.10.1040.10; -; 2.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR006180; 3-OHacyl-CoA_DH_CS.
DR InterPro; IPR006176; 3-OHacyl-CoA_DH_NAD-bd.
DR InterPro; IPR006108; 3HC_DH_C.
DR InterPro; IPR008927; 6-PGluconate_DH_C-like.
DR InterPro; IPR001753; Crotonase_core_superfam.
DR InterPro; IPR013328; DH_multihelical.
DR InterPro; IPR018376; Enoyl-CoA_hyd/isom_CS.
DR InterPro; IPR012803; Fa_ox_alpha_mit.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR Pfam; PF00725; 3HCDH; 2.
DR Pfam; PF02737; 3HCDH_N; 1.
DR Pfam; PF00378; ECH; 1.
DR SUPFAM; SSF48179; SSF48179; 2.
DR TIGRFAMs; TIGR02441; fa_ox_alpha_mit; 1.
DR PROSITE; PS00067; 3HCDH; 1.
DR PROSITE; PS00166; ENOYL_COA_HYDRATASE; 1.
PE 1: Evidence at protein level;
KW Acetylation; Complete proteome; Disease mutation;
KW Fatty acid metabolism; Lipid metabolism; Lyase; Mitochondrion;
KW Multifunctional enzyme; NAD; Oxidoreductase; Polymorphism;
KW Reference proteome; Transit peptide.
FT TRANSIT 1 36 Mitochondrion (Potential).
FT CHAIN 37 763 Trifunctional enzyme subunit alpha,
FT mitochondrial.
FT /FTId=PRO_0000007403.
FT SITE 151 151 Important for catalytic activity (By
FT similarity).
FT SITE 173 173 Important for catalytic activity (By
FT similarity).
FT MOD_RES 46 46 N6-acetyllysine (By similarity).
FT MOD_RES 60 60 N6-acetyllysine (By similarity).
FT MOD_RES 129 129 N6-acetyllysine (By similarity).
FT MOD_RES 166 166 N6-acetyllysine (By similarity).
FT MOD_RES 214 214 N6-acetyllysine (By similarity).
FT MOD_RES 249 249 N6-acetyllysine (By similarity).
FT MOD_RES 289 289 N6-acetyllysine (By similarity).
FT MOD_RES 295 295 N6-acetyllysine.
FT MOD_RES 303 303 N6-acetyllysine.
FT MOD_RES 326 326 N6-acetyllysine (By similarity).
FT MOD_RES 334 334 N6-acetyllysine (By similarity).
FT MOD_RES 350 350 N6-acetyllysine (By similarity).
FT MOD_RES 353 353 N6-acetyllysine (By similarity).
FT MOD_RES 386 386 N6-acetyllysine (By similarity).
FT MOD_RES 406 406 N6-acetyllysine.
FT MOD_RES 411 411 N6-acetyllysine (By similarity).
FT MOD_RES 460 460 N6-acetyllysine (By similarity).
FT MOD_RES 505 505 N6-acetyllysine.
FT MOD_RES 519 519 N6-acetyllysine (By similarity).
FT MOD_RES 540 540 N6-acetyllysine.
FT MOD_RES 569 569 N6-acetyllysine (By similarity).
FT MOD_RES 644 644 N6-acetyllysine.
FT MOD_RES 664 664 N6-acetyllysine (By similarity).
FT MOD_RES 728 728 N6-acetyllysine (By similarity).
FT MOD_RES 735 735 N6-acetyllysine (By similarity).
FT MOD_RES 759 759 N6-acetyllysine (By similarity).
FT VARIANT 282 282 V -> D (in TFP deficiency; mild phenotype
FT with slowly progressive myopathy and
FT sensorimotor polyneuropathy).
FT /FTId=VAR_021125.
FT VARIANT 305 305 I -> N (in TFP deficiency; mild phenotype
FT with slowly progressive myopathy and
FT sensorimotor polyneuropathy).
FT /FTId=VAR_021126.
FT VARIANT 342 342 L -> P (in LCHAD deficiency).
FT /FTId=VAR_021127.
FT VARIANT 358 358 Q -> K (in dbSNP:rs10200182).
FT /FTId=VAR_048908.
FT VARIANT 510 510 E -> Q (in AFLP and LCHAD deficiency;
FT loss of activity; dbSNP:rs137852769).
FT /FTId=VAR_002273.
FT CONFLICT 146 146 L -> V (in Ref. 1; BAA03941).
FT CONFLICT 152 152 V -> L (in Ref. 2; AAA56664).
FT CONFLICT 171 171 T -> A (in Ref. 2; AAA56664).
FT CONFLICT 178 178 A -> I (in Ref. 2; AAA56664).
FT CONFLICT 197 198 AL -> VF (in Ref. 2; AAA56664).
FT CONFLICT 206 206 S -> N (in Ref. 2; AAA56664).
FT CONFLICT 211 211 R -> S (in Ref. 2; AAA56664).
FT CONFLICT 576 576 T -> P (in Ref. 2; AAA56664).
FT CONFLICT 694 694 L -> S (in Ref. 1; BAA03941).
SQ SEQUENCE 763 AA; 83000 MW; 247FF7B4E48FB484 CRC64;
MVACRAIGIL SRFSAFRILR SRGYICRNFT GSSALLTRTH INYGVKGDVA VVRINSPNSK
VNTLSKELHS EFSEVMNEIW ASDQIRSAVL ISSKPGCFIA GADINMLAAC KTLQEVTQLS
QEAQRIVEKL EKSTKPIVAA INGSCLGGGL EVAISCQYRI ATKDRKTVLG TPEVLLGALP
GAGGTQRLPK MVGVPAALDM MLTGRSIRAD RAKKMGLVDQ LVEPLGPGLK PPEERTIEYL
EEVAITFAKG LADKKISPKR DKGLVEKLTA YAMTIPFVRQ QVYKKVEEKV RKQTKGLYPA
PLKIIDVVKT GIEQGSDAGY LCESQKFGEL VMTKESKALM GLYHGQVLCK KNKFGAPQKD
VKHLAILGAG LMGAGIAQVS VDKGLKTILK DATLTALDRG QQQVFKGLND KVKKKALTSF
ERDSIFSNLT GQLDYQGFEK ADMVIEAVFE DLSLKHRVLK EVEAVIPDHC IFASNTSALP
ISEIAAVSKR PEKVIGMHYF SPVDKMQLLE IITTEKTSKD TSASAVAVGL KQGKVIIVVK
DGPGFYTTRC LAPMMSEVIR ILQEGVDPKK LDSLTTSFGF PVGAATLVDE VGVDVAKHVA
EDLGKVFGER FGGGNPELLT QMVSKGFLGR KSGKGFYIYQ EGVKRKDLNS DMDSILASLK
LPPKSEVSSD EDIQFRLVTR FVNEAVMCLQ EGILATPAEG DIGAVFGLGF PPCLGGPFRF
VDLYGAQKIV DRLKKYEAAY GKQFTPCQLL ADHANSPNKK FYQ
//

MIM 600890
*RECORD*
*FIELD* NO
600890
*FIELD* TI
*600890 HYDROXYACYL-CoA DEHYDROGENASE/3-KETOACYL-CoA THIOLASE/ENOYL-CoA HYDRATASE,
read moreALPHA SUBUNIT; HADHA
;;TRIFUNCTIONAL PROTEIN, ALPHA SUBUNIT;;
MITOCHONDRIAL TRIFUNCTIONAL PROTEIN, ALPHA SUBUNIT; MTPA;;
LONG-CHAIN HYDROXYACYL-CoA DEHYDROGENASE; LCHAD;;
ECHA
*FIELD* TX

DESCRIPTION

The HADHA and HADHB (143450) genes encode the alpha and beta subunits of
the mitochondrial trifunctional protein, respectively. The heterocomplex
contains 4 alpha and 4 beta subunits and catalyzes 3 steps in
mitochondrial beta-oxidation of fatty acids, including the long-chain
3-hydroxyacyl-CoA dehydrogenase (LCHAD) step. The alpha subunit harbors
the 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.211) and enoyl-CoA
hydratase activities (EC 4.2.1.27) (Kamijo et al., 1994).

CLONING

Kamijo et al. (1994) identified cDNAs for the genes encoding the alpha
and beta subunits of the holoenzyme. The alpha-subunit cDNA encodes an
82.598-kD precursor, which ultimately becomes the 78.969-kD mature
subunit.

Using rat Hadha to screen a human heart cDNA library, Sims et al. (1995)
cloned HADHA, which encodes a 763-amino acid full-length protein,
consisting of a 36-amino acid transit peptide and a 727-amino acid
mature protein. HADHA shares 89% amino acid identity with its rat
homolog.

Orii et al. (1999) determined that the HADHA and HADHB genes are linked
in a head-to-head arrangement on opposite strands and that they have in
common a 350-bp 5-prime flanking region. This region has bidirectional
promoter activity with 2 critical cis elements that are activated by
transcription factor SP1 (189906) binding. The authors concluded that
expression of trifunctional protein subunits is probably coordinately
regulated by a common promoter and by SP1.

GENE STRUCTURE

Sims et al. (1995) determined that the HADHA gene contains 20 exons
spanning over 52 kb.

MAPPING

By somatic cell hybrid studies, Craig et al. (1976) tentatively assigned
the structural gene for trifunctional protein to chromosome 7. However,
IJlst et al. (1996) localized the gene for the alpha subunit of the
mitochondrial trifunctional protein to 2p24.1-p23.3 by fluorescence in
situ hybridization (FISH). Yang et al. (1996) mapped both the HADHA and
HADHB genes to 2p23 by FISH.

MOLECULAR GENETICS

- Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency

In LCHAD deficiency (609016), there is an isolated deficiency of the
dehydrogenase activity with normal hydratase activity and moderately
decreased thiolase activity (59% of control) (IJlst et al., 1996). In 24
of 26 unrelated Dutch patients with long-chain 3-hydroxyacyl-CoA
dehydrogenase deficiency, IJlst et al. (1994) identified a homozygous
1528G-C transversion in exon 15 of the HADHA gene, resulting in an E510Q
substitution (600890.0001), based on numbering from the start codon. Two
patients were compound heterozygous for E510Q and another pathogenic
mutation in the HADHA gene (see, e.g., 600890.0006-600890.0007). IJlst
et al. (1996) used S. cerevisiae for expression of wildtype and mutant
protein to show that the E510Q mutation is directly responsible for the
loss of LCHAD activity. Furthermore, they described a newly developed
method allowing identification of the mutation in genomic DNA. The
finding of an 87% allele frequency of this mutation in 34
LCHAD-deficient patients made this a valuable test for prenatal
diagnosis. Sims et al. (1995) designated the 1528G-C mutation as E474Q
based on numbering of the mature HADHA protein.

Ibdah et al. (1999) identified mutations in the HADHA gene in 19
children with LCHAD deficiency who presented with hypoketotic
hypoglycemia and fatty liver. Eight children were homozygous for the
E474Q mutation, while 11 were compound heterozygous for E474Q and
another pathogenic mutation. While carrying fetuses with the E474Q
mutation, 79% of the heterozygous mothers had fatty liver of pregnancy
or the HELLP syndrome (hemolysis, elevated liver enzymes, and low
platelets).

- Mitochondrial Trifunctional Protein Deficiency

In mitochondrial trifunctional protein deficiency (MTP deficiency;
609105), all 3 activities of the protein are deficient: dehydrogenase,
hydratase, and thiolase (IJlst et al., 1996).

In a patient with MTP deficiency, Brackett et al. (1995) identified
compound heterozygosity for 2 mutations in the HADHA gene (600890.0003
and 600890.0004). The patient presented in the neonatal period with
hypoglycemia and cardiomyopathy and later died unexpectedly at the age
of 18 months.

In 2 patients with MTP deficiency, Ibdah et al. (1998) identified
biallelic mutations in the HADHA gene (600890.0008-600890.0010). The
phenotype was characterized by slowly progressive chronic polyneuropathy
and myopathy without hepatic or cardiac involvement. All 3 mutations
were located in exon 9, which encodes a linker domain between the
NH2-terminal hydratase and the COOH-terminal 3-hydroxyacyl-CoA
dehydrogenase.

Ibdah et al. (1999) reported 5 children with complete MTP deficiency who
presented with neonatal dilated cardiomyopathy or progressive
neuromyopathy. None had the E474Q mutation common in isolated LCHAD
deficiency, and none of their mothers had liver disease during
pregnancy.

In 2 unrelated patients with lethal deficiency of trifunctional protein,
Spiekerkoetter et al. (2002) delineated apparently homozygous
alpha-subunit mutations that were present in heterozygous form in both
mothers, but not in either biologic father. They performed a
microsatellite repeat analysis of both patients and their parents using
7 chromosome 2-specific polymorphic DNA markers and 4 non-chromosome 2
markers. In both patients, 2 chromosome 2-specific markers demonstrated
maternal isodisomy of chromosome 2. The other 5 chromosome 2-specific
markers were noninformative in each patient. Inheritance of alleles from
chromosomes 4, 5, and 7 was consistent with paternity. Spiekerkoetter et
al. (2002) stated that 6 of 12 trifunctional protein-deficient patients
with alpha-subunit mutations had disease due to homozygosity of
mutations, and 2 of these 6 via the mechanism of uniparental disomy
(UPD). For very rare autosomal recessive diseases, UPD greatly alters
the empiric risk for the disorder from the 25% normally used.
Spiekerkoetter et al. (2002) noted reports of 6 cases of maternal UPD of
chromosome 2 and 2 cases of paternal UPD of chromosome 2.

ANIMAL MODEL

Ibdah et al. (2001) found that Mtpa-null mouse fetuses accumulated
long-chain fatty acid metabolites and had low birth weight. Mtpa-null
mice exhibited neonatal hypoglycemia, and all died suddenly within 6 to
36 hours after birth. Histopathologic analysis showed rapid development
of hepatic steatosis after birth, and later showed significant necrosis
and acute degeneration of the cardiac and diaphragmatic myocytes. The
findings were similar to those observed in human trifunctional protein
deficiency, indicating that long-chain fatty acid oxidation is essential
for fetal development and survival after birth.

*FIELD* AV
.0001
LCHAD DEFICIENCY
LCHAD DEFICIENCY WITH MATERNAL ACUTE FATTY LIVER OF PREGNANCY, INCLUDED
HADHA, GLU510GLN

Based on numbering from the start codon, which was used by IJlst et al.
(1994), this mutation is designated glu510-to-gln. Sims et al. (1995)
had designated the mutation GLU474GLN based on numbering of the mature
protein.

IJlst et al. (1994) identified a 1528G-C transversion in exon 15 of the
HADHA gene, resulting in a glu510-to-gln (E510Q) substitution, in
approximately 87% of the chromosomes in patients with LCHAD deficiency
(609015).

Sims et al. (1995) used single-strand conformation variance (SSCV)
analysis of the alpha subunit of long-chain 3-hydroxyacyl-CoA
dehydrogenase to determine the molecular basis of LCHAD deficiency in 3
families in which children presented with sudden unexplained death or
hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all
families, the mother had acute fatty liver and associated severe
complications during pregnancy. The analysis in 2 affected children
demonstrated homozygosity for the E474Q mutation. The third child was
compound heterozygous for E474Q and Q342X (600890.0002).

IJlst et al. (1996) developed a PCR-RFLP method to identify the E474Q
mutation in genomic DNA. Functional expression studies in S. cerevisiae
showed that the mutation is directly responsible for the loss of LCHAD
activity.

Tyni et al. (1997) discussed the clinical presentation of 13 patients
with LCHAD deficiency due to a homozygous E474Q mutation. The patients
had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly
during the first 2 years of life. Recurrent metabolic crises had
occurred in 7 patients; the other 6 had a steadily progressive course.
Cholestatic liver disease, which is uncommon in beta-oxidation defects,
was found in 2 patients. One patient had peripheral neuropathy, and 6
had retinopathy with focal pigmentary aggregations or retinal
hypopigmentation. Radiologically, there was bilateral periventricular or
focal cortical lesions in 3 patients and brain atrophy in 1. Only 1
patient, who had dietary treatment for 9 years, was alive at the age of
14 years; all others died before they were 2 years of age. The
experience indicated the importance of recognizing the clinical features
of LCHAD deficiency for the early institution of dietary management,
which can alter the otherwise invariably poor prognosis.

Ibdah et al. (1999) reported a patient who presented at 2 months of age
with generalized tonic-clonic seizure due to an acute infantile
hypocalcemia and vitamin D deficiency. He also had occult, unexplained
cholestatic liver disease and impairment of 25-hydroxylation of vitamin
D secondary to hepatic steatosis. Sudden unexpected death occurred at 8
months. Molecular analysis revealed homozygosity for the E474Q mutation.
The mother had preeclampsia during the third trimester of her pregnancy.

.0002
LCHAD DEFICIENCY
HADHA, GLN342TER

In 1 family studied by Sims et al. (1995), a child with LCHAD deficiency
(09015) was a compound heterozygote for 2 mutations in the HADHA gene:
E474Q (600890.0001) and a 1132C-T transition, resulting in a
gln342-to-ter (Q342X) substitution within the cofactor NAD-binding
domain of the mature protein. A truncated alpha subunit produced by this
mutant allele would not contain the LCHAD active site.

.0003
TRIFUNCTIONAL PROTEIN DEFICIENCY
HADHA, IVS3, G-A, +1

In an infant with neonatal presentation of hypoglycemia and lactic
aciduria and sudden unexplained death (609015) at the age of 18 months,
Brackett et al. (1995) demonstrated compound heterozygosity for 2
different mutations in the 5-prime donor splice site following exon 3: a
paternally inherited G-to-A transition at the invariant position +1 and
a maternally inherited A-to-G mutation at position +3 (600890.0004).
Both allelic mutations apparently caused skipping of exon 3 (71 bp),
resulting in universal deletion of exon 3 in the patient's mRNA,
undetectable levels of alpha-subunit protein, and complete loss of
trifunctional protein.

.0004
TRIFUNCTIONAL PROTEIN DEFICIENCY
HADHA, IVS3, A-G, +3

See 600890.0003 and Brackett et al. (1995).

.0005
TRIFUNCTIONAL PROTEIN DEFICIENCY
HADHA, ARG524TER

Isaacs et al. (1996) described an infant with trifunctional protein
deficiency (609015) who was compound heterozygous for the common E474Q
mutation (600890.0001) causing LCHAD deficiency (609016) and a novel
1678C-T transition in exon 16 of the HADHA gene that results in an
arg524-to-ter (R524X) substitution of the mature protein. The mother was
heterozygous for the R524X mutation, and the infant's father and 2
phenotypically normal brothers were heterozygous for the E474Q mutation.
Pregnancies were normal with the heterozygous sons but complicated by
acute fatty liver of pregnancy with the affected son. The exon 16
mutation was confirmed by SSCV and nucleotide sequencing while both
mutations were evident by ASO analysis. Quantification of the mRNA
transcript from the premature termination codon mutation in exon 16
showed greatly reduced cytoplasmic levels as expected. The authors
suggested that any child born to a mother with acute fatty liver of
pregnancy should be screened for LCHAD or MTP deficiency.

.0006
LCHAD DEFICIENCY
HADHA, 1-BP INS, 2129C

Most patients with a defect in the mitochondrial trifunctional protein
complex have an isolated deficiency of LCHAD activity (609016). In a
group of 46 LCHAD-deficient patients studied enzymatically, IJlst et al.
(1997) found 12 to be compound heterozygous for the common 1528G-C
mutation (600890.0001) and another mutation in HADHA. IJlst et al.
(1997) described 2 new mutations found in this compound heterozygous
group. One was an insertion of a C at position 2129, changing the
reading frame for the alpha subunit and creating a premature stop codon
at residue 733, resulting in a truncated protein that was presumed to be
unstable. The second was a 1025T-C transition, resulting in a
leu342-to-pro (L342P; 600890.0007) substitution.

.0007
LCHAD DEFICIENCY
HADHA, LEU342PRO

See 600890.0006 and IJlst et al. (1997).

.0008
TRIFUNCTIONAL PROTEIN DEFICIENCY WITH MYOPATHY AND NEUROPATHY
HADHA, VAL246ASP

In a patient with trifunctional protein deficiency with myopathy and
neuropathy (see 609015), Ibdah et al. (1998) identified a homozygous
845T-A transversion in exon 9 of the HADHA gene, resulting in a
val246-to-asp (V246D) substitution of the mature protein. The patient
was a 13-year-old boy who was born to asymptomatic first-cousin parents.
He had delayed gross motor milestones and, beginning at age 20 months,
he had the first of many episodes of profound weakness precipitated by
fever, vomiting, or dehydration. His subsequent clinical course was
characterized by slowly progressive limb-girdle myopathy with mild
facial weakness and a symmetric peripheral sensorimotor axonopathy with
secondary demyelination. In addition, the patient had recurrent episodes
of myoglobinuria (up to 5 times per year) precipitated by prolonged
exertion, infection, cold exposure, fasting, and/or stress. Muscle
biopsy revealed a mild lipid-accumulative myopathy. With the
introduction of frequent feeding, a high-carbohydrate low-fat diet, and
preventive fatty acid oxidation measures at age 7.5 years, there was a
marked reduction in the frequency of myoglobinuric episodes. There was,
however, no improvement in power or endurance, and these continued to
deteriorate. A trial of prednisone resulted in significant improvement
in the limb-girdle myopathy, which had been sustained over 5 years, as
well as a transient improvement in his peripheral neuropathy.
Myoglobinuric episodes were reduced to once every 1 to 2 years and were
less severe.

.0009
TRIFUNCTIONAL PROTEIN DEFICIENCY WITH MYOPATHY AND NEUROPATHY
HADHA, ILE269ASN

In a patient with trifunctional protein deficiency with myopathy and
neuropathy (see 609015), Ibdah et al. (1998) identified compound
heterozygosity for 2 mutations in the HADHA gene: an ile269-to-asn
(I269N) substitution and an arg255-to-ter substitution (600890.0010) in
the mature protein. Both mutations were in exon 9. The patient was a
12-year-old boy who was born to unrelated healthy parents. The first
episode of muscle weakness occurred at 13 months of age, precipitated by
an upper respiratory tract infection. Thereafter there were recurrent
episodes of muscle weakness and myoglobinuria precipitated by infection,
fasting, exertion, or cold exposure. At long-term follow-up, the patient
had slowly progressive sensorimotor polyneuropathy characterized by
bilateral foot drop, contracture of the Achilles tendons, and symmetric
weakness in wrist and finger extension. He did not have pigmentary
retinopathy or cardiomyopathy. A high-carbohydrate/low-fat diet failed
to prevent the progression of the neuromuscular manifestations. This
patient had previously been reported by Dionisi-Vici et al. (1991). In
that report it was stated that a sister had died at the age of 3 years,
probably of the same disorder.

.0010
TRIFUNCTIONAL PROTEIN DEFICIENCY WITH MYOPATHY AND NEUROPATHY
HADHA, ARG255TER

See 600890.0009 and Ibdah et al. (1998).

*FIELD* SA
Jackson et al. (1992); Tyni et al. (2002); Wanders et al. (1989)
*FIELD* RF
1. Brackett, J. C.; Sims, H. F.; Rinaldo, P.; Shapiro, S.; Powell,
C. K.; Bennett, M. J.; Strauss, A. W.: Two alpha subunit donor splice
site mutations cause human trifunctional protein deficiency. J. Clin.
Invest. 95: 2076-2082, 1995.

2. Craig, I.; Tolley, E.; Bobrow, M.: A preliminary analysis of the
segregation of human hydroxyacyl coenzyme A dehydrogenase in human-mouse
somatic cell hybrids. Birth Defects Orig. Art. Ser. XII(7): 114-117,
1976.

3. Dionisi Vici, C.; Burlina, A. B.; Bertini, E.; Bachmann, C.; Mazziotta,
M. R. M.; Zacchello, F.; Sabetta, G.; Hale, D. E.: Progressive neuropathy
and recurrent myoglobinuria in a child with long-chain 3-hydroxyacyl-coenzyme
A dehydrogenase deficiency. J. Pediat. 118: 744-746, 1991.

4. Ibdah, J. A.; Bennett, M. J.; Rinaldo, P.; Zhao, Y.; Gibson, B.;
Sims, H. F.; Strauss, A. W.: A fetal fatty-acid oxidation disorder
as a cause of liver disease in pregnant women. New Eng. J. Med. 340:
1723-1731, 1999.

5. Ibdah, J. A.; Dasouki, M. J.; Strauss, A. W.: Long-chain 3-hydroxyacyl-CoA
dehydrogenase deficiency: variable expressivity of maternal illness
during pregnancy and unusual presentation with infantile cholestasis
and hypocalcaemia. J. Inherit. Metab. Dis. 22: 811-814, 1999.

6. Ibdah, J. A.; Paul, H.; Zhao, Y.; Binford, S.; Salleng, K.; Cline,
M.; Matern, D.; Bennett, M. J.; Rinaldo, P.; Strauss, A. W.: Lack
of mitochondrial trifunctional protein im mice causes neonatal hypoglycemia
and sudden death. J. Clin. Invest. 107: 1403-1409, 2001.

7. Ibdah, J. A.; Tein, I.; Dionisi-Vici, C.; Bennett, M. J.; IJlst,
L.; Gibson, B.; Wanders, R. J. A.; Strauss, A. W.: Mild trifunctional
protein deficiency is associated with progressive neuropathy and myopathy
and suggests a novel genotype-phenotype correlation. J. Clin. Invest. 102:
1193-1199, 1998.

8. IJlst, L.; Oostheim, W.; Ruiter, J. P. N.; Wanders, R. J. A.:
Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency:
identification of two new mutations. J. Inherit. Metab. Dis. 20:
420-422, 1997.

9. IJlst, L.; Ruiter, J. P. N.; Hoovers, J. M. N.; Jakobs, M. E.;
Wanders, R. J. A.: Common missense mutation G1528C in long-chain
3-hydroxyacyl-CoA dehydrogenase deficiency: characterization and expression
of the mutant protein, mutation analysis on genomic DNA and chromosomal
localization of the mitochondrial trifunctional protein alpha subunit
gene. J. Clin. Invest. 98: 1028-1033, 1996.

10. IJlst, L.; Wanders, R. J. A.; Ushikubo, S.; Kamijo, T.; Hashimoto,
T.: Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase
deficiency: identification of the major disease-causing mutation in
the alpha-subunit of the mitochondrial trifunctional protein. Biochim.
Biophys. Acta 1215: 347-350, 1994.

11. Isaacs, J. D.; Sims, H. F.; Powell, C. K.; Bennett, M. J.; Hale,
D. E.; Treem, W. R.; Strauss, A. W.: Maternal acute fatty liver of
pregnancy associated with fetal trifunctional protein deficiency:
molecular characterization of a novel maternal mutant allele. Pediat.
Res. 40: 393-398, 1996.

12. Jackson, S.; Kler, R. S.; Bartlett, K.; Briggs, H.; Bindoff, L.
A.; Pourfarzam, M.; Gardner-Medwin, D.; Turnbull, D. M.: Combined
enzyme defect of mitochondrial fatty acid oxidation. J. Clin. Invest. 90:
1219-1225, 1992.

13. Kamijo, T.; Aoyama, T.; Komiyama, A.; Hashimoto, T.: Structural
analysis of cDNAs for subunits of human mitochondrial fatty acid beta-oxidation
trifunctional protein. Biochem. Biophys. Res. Commun. 199: 818-825,
1994.

14. Orii, K. E.; Orii, K. O.; Souri, M.; Orii, T.; Kondo, N.; Hashimoto,
T.; Aoyama, T.: Genes for the human mitochondrial trifunctional protein
alpha- and beta-subunits are divergently transcribed from a common
promoter region. J. Biol. Chem. 274: 8077-8084, 1999.

15. Sims, H. F.; Brackett, J. C.; Powell, C. K.; Treem, W. R.; Hale,
D. E.; Bennett, M. J.; Gibson, B.; Shapiro, S.; Strauss, A. W.: The
molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase
deficiency associated with maternal acute fatty liver of pregnancy. Proc.
Nat. Acad. Sci. 92: 841-845, 1995.

16. Spiekerkoetter, U.; Eeds, A.; Yue, Z.; Haines, J.; Strauss, A.
W.; Summar, M.: Uniparental disomy of chromosome 2 resulting in lethal
trifunctional protein deficiency due to homozygous alpha-subunit mutations. Hum.
Mutat. 20: 447-451, 2002.

17. Tyni, T.; Johnson, M.; Eaton, S.; Pourfarzam, M.; Andrews, R.;
Turnbull, D. M.: Mitochondrial fatty acid beta-oxidation in the retinal
pigment epithelium. Pediat. Res. 52: 595-600, 2002.

18. Tyni, T.; Palotie, A.; Viinikka, L.; Valanne, L.; Salo, M. K.;
von Dobeln, U.; Jackson, S.; Wanders, R.; Venizelos, N.; Pihko, H.
: Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with
the G1528C mutation: clinical presentation of thirteen patients. J.
Pediat. 130: 67-76, 1997.

19. Wanders, R. J. A.; Duran, M.; IJlst, L.; de Jager, J. P.; van
Gennip, A. H.; Jakobs, C.; Dorland, L.; van Sprang, F. J.: Sudden
infant death and long-chain 3-hydroxyacyl-CoA dehydrogenase. Lancet 334:
52-53, 1989. Note: Originally Volume 2.

20. Yang, B.-Z.; Heng, H. H. Q.; Ding, J.-H.; Roe, C. R.: The genes
for the alpha and beta subunits of the mitochondrial trifunctional
protein are both located in the same region on human chromosome 2p23. Genomics 37:
141-143, 1996.

*FIELD* CN
Cassandra L. Kniffin - updated: 12/14/2007
Ada Hamosh - reorganized: 11/10/2004
Natalie E. Krasikov - updated: 2/4/2004
Victor A. McKusick - updated: 2/26/2003
Victor A. McKusick - updated: 1/2/2003
Patricia A. Hartz - updated: 11/4/2002
Ada Hamosh - updated: 4/26/2001
Victor A. McKusick - updated: 2/6/2001
Ada Hamosh - updated: 10/31/2000
Wilson H. Y. Lo - updated: 11/17/1999
Victor A. McKusick - updated: 6/4/1999
Victor A. McKusick - updated: 10/6/1998
Victor A. McKusick - updated: 3/24/1998
Victor A. McKusick - updated: 2/25/1998
Victor A. McKusick - updated: 2/12/1998
Victor A. McKusick - updated: 8/22/1997
Victor A. McKusick - updated: 6/21/1997
Mark H. Paalman - updated: 10/17/1996
Cynthia K. Ewing - updated: 10/6/1996

*FIELD* CD
Victor A. McKusick: 10/25/1995

*FIELD* ED
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mimadm: 11/3/1995
mark: 10/25/1995

MIM 609015
*RECORD*
*FIELD* NO
609015
*FIELD* TI
#609015 TRIFUNCTIONAL PROTEIN DEFICIENCY
;;MITOCHONDRIAL TRIFUNCTIONAL PROTEIN DEFICIENCY
read moreTRIFUNCTIONAL PROTEIN DEFICIENCY WITH MYOPATHY AND NEUROPATHY, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because mitochondrial
trifunctional protein (MTP) deficiency can be caused by mutation in the
genes encoding either the alpha (HADHA; 600890) or beta (HADHB; 143450)
subunits of the mitochondrial trifunctional protein.

DESCRIPTION

The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta
subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty
acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain
enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional
protein deficiency is characterized by decreased activity of all 3
enzymes. Clinically, classic trifunctional protein deficiency can be
classified into 3 main clinical phenotypes: neonatal onset of a severe,
lethal condition resulting in sudden unexplained infant death (SIDS;
272120), infantile onset of a hepatic Reye-like syndrome, and
late-adolescent onset of primarily a skeletal myopathy (Spiekerkoetter
et al., 2003).

Some patients with MTP deficiency show a protracted progressive course
associated with myopathy, recurrent rhabdomyolysis, and sensorimotor
axonal neuropathy. These patients tend to survive into adolescence and
adulthood (den Boer et al., 2003).

See also isolated LCHAD deficiency (609016), which is caused by mutation
in the HADHA gene.

CLINICAL FEATURES

Wanders et al. (1992) reported an infant, born of first-cousin parents,
who presented with hypoglycemia and major hypotonia at 2 days of age.
The infant developed respiratory failure and showed poor spontaneous
motility and absence of suckling and archaic reflexes on day 8, had
acute cardiac failure on day 28 related to a hypokinetic cardiomyopathy
with distended wall, and died on day 30. Studies of fibroblasts from the
patient demonstrated deficiency of all 3 activities of trifunctional
protein.

Jackson et al. (1992) reported a young girl who presented with recurrent
episodes of muscle weakness culminating in a severe attack of
generalized muscle weakness. Muscle mitochondria from the patient
demonstrated an abnormal pattern of intermediates of beta-oxidation with
an accumulation of 3-hydroxyacyl- and 2-enoyl-CoA and carnitine esters,
and 3-oxoacylcarnitines. The patient was shown to have a combined defect
of long-chain 3-hydroxyacyl-CoA dehydrogenase, long-chain 3-oxoacyl-CoA
thiolase, and long-chain 2-enoyl-CoA hydratase. In fibroblasts from both
parents, intermediate levels of enzyme activity were found. The proband
died at age 4.5 years after a brief illness. An earlier-born brother had
died at the age of 2.5 years, probably of the same disorder. He showed
terminally low-output cardiac failure with an enlarged dilated heart and
generalized weakness.

Dionisi-Vici et al. (1996) described the clinical course of a girl
diagnosed at the age of 15 months with a history of recurrent vomiting
at birth. The patient presented with severe hypotonia, respiratory
failure requiring assisted ventilation, and severe dilated
cardiomyopathy. Urine organic acids were strongly suggestive of a fatty
acid oxidation defect by characteristic excretion of
3-hydroxydicarboxylic acid; additional laboratory findings were
consistent with hypoparathyroidism. Fibroblast analysis showed that all
3 MTP enzyme activities were affected, albeit to different degrees. In
follow-up, additional episodes of metabolic decompensation were induced
by intercurrent febrile illnesses.

Den Boer et al. (2003) found that 9 (42%) of 21 patients with MTP
deficiency presented with rapidly progressive clinical deterioration.
Eight of these patients died of cardiac complications within 8 weeks;
the ninth patient died of liver failure within 4 weeks. Six of the 9 had
hypoketotic hypoglycemia. Other clinical features of the rapidly
progressive group included hypotonia, lethargy, liver disease, and
peripheral neuropathy. One of 7 tested had pigmentary retinopathy. Two
patients who were diagnosed prenatally died despite treatment; 1 of
these patients had hydrops fetalis. Two (11%) of 19 pregnancies on which
information was available were complicated by HELLP syndrome (hemolysis,
elevated liver enzymes, and low platelets).

Purevsuren et al. (2009) reported the clinical and molecular features of
5 Japanese patients with MTP deficiency, including 3 who had previously
been reported. Two had an early lethal phenotype, 2 had an intermediate
hepatic phenotype, and 1 had a late-onset myopathic phenotype. The first
2 patients had onset within the first days of life of lactic acidosis,
hyperketotic hypoglycemia, and hyperammonemia. Both died of cardiac
arrest at ages 8 days and 3 months, respectively. The 2 patients with
hepatic involvement had onset at ages 9 and 13 months, respectively.
Both had delayed psychomotor development. One had increased liver
enzymes, lactic acidemia, and recurrent rhabdomyolysis. The other had
lethargy, hypotonia, recurrent respiratory infections, and liver
dysfunction. The last patient, previously reported by Miyajima et al.
(1997), had onset at age 15 years of muscle pain and weakness associated
with rhabdomyolysis.

- MTP Deficiency with Myopathy and Neuropathy

Dionisi Vici et al. (1991) described slowly progressive neuropathy and
recurrent myoglobinuria in a boy whose sister had died at the age of 3
years, presumably of the same disorder.

Schaefer et al. (1996) reported 3 adults from a family with symptoms of
recurrent exercise-induced rhabdomyolysis associated with peripheral
neuropathy. Investigation of fatty acid oxidation in the patients
revealed a deficiency of the mitochondrial trifunctional enzyme of
beta-oxidation. The patients appeared to represent a novel phenotype of
MTP deficiency characterized by recurrent rhabdomyolysis and peripheral
neuropathy, but without involvement of other organs. This phenotype was
associated with prolonged survival beyond the fourth decade. A
low-fat/high-carbohydrate diet proved beneficial in one of the patients,
drastically reducing the frequency of rhabdomyolytic episodes. Schaefer
et al. (1996) noted that MTP deficiency should be considered in patients
with recurrent episodes of myoglobinuria and peripheral neuropathy
presenting in later life.

Miyajima et al. (1997) reported a 23-year-old man with recurrent
myoglobinuria, low muscle-free carnitine levels, and deficient fasting
ketogenesis. Urinary organic acid analysis showed large amounts of
C6-C14 3-hydroxydicarboxylic acids. The 3 activities of the
mitochondrial trifunctional protein were markedly decreased, and the
protein content was less than 2% of normal controls. Miyajima et al.
(1997) concluded that MTP deficiency can also present in adolescence
with recurrent myoglobinuria.

Den Boer et al. (2003) found that 12 (57%) of 21 patients with MTP
deficiency presented with a slow, insidious disease characterized by
hypotonia, muscle cramps, decreased tendon reflexes, and peripheral
neuropathy. Other features included cardiomyopathy, liver disease, and
feeding difficulties with failure to thrive. Seven of these patients
died: 5 from progressive cardiomyopathy, 1 from severe infection and
metabolic derangement, and 1 suddenly almost 14 years after onset. The 5
surviving patients were in relatively good clinical condition without
cardiomyopathy. Three had developmental delay. Some had episodic
rhabdomyolysis and/or myoglobinuria.

CLINICAL MANAGEMENT

Although the mortality rate among children with deficiency of LCHAD or
complete deficiency of the trifunctional protein had been reported to be
75 to 90%, Ibdah et al. (1999) found that 67% of the affected children
in their study were alive and receiving dietary treatment at the most
recent follow-up, and most were able to attend school. Dietary treatment
of children with fatty acid oxidation disorders dramatically reduced
morbidity and mortality.

MOLECULAR GENETICS

In a patient with MTP deficiency, Brackett et al. (1995) identified
compound heterozygosity for 2 mutations in the HADHA gene (600890.0003
and 600890.0004). The patient presented in the neonatal period with
hypoglycemia and cardiomyopathy and later died unexpectedly at the age
of 18 months.

In 2 unrelated patients with trifunctional protein deficiency, Ushikubo
et al. (1996) identified homozygous or compound heterozygous mutations
in the HADHB gene (143450.0001-143450.0003). This was the first
demonstration of disease-causing mutations in the beta subunit. Using a
vaccinia virus system and gel filtration analysis for cDNA expression
experiments in patients' fibroblasts, Ushikubo et al. (1996) found that
both normal alpha and beta subunits, and possibly their association, are
important for stabilizing the trifunctional protein.

Orii et al. (1997) identified 2 Japanese patients in whom the 3 enzyme
activities of the trifunctional protein were undetectable in
fibroblasts. The patients were homozygous or compound heterozygous for
mutations in the HADHB gene (143450.0004; 143450.0005).

GENOTYPE/PHENOTYPE CORRELATIONS

In 2 unrelated patients with slowly progressive neuropathy and recurrent
myoglobinuria, Ibdah et al. (1998) confirmed MTP deficiency and
identified biallelic mutations in exon 9 of the HADHA gene
(600890.0008-600890.0010). One of the patients had been reported by
Dionisi Vici et al. (1991); both patients survived into their early
teens. Ibdah et al. (1998) suggested that the relatively milder
phenotype in these patients may be correlated with mutations in exon 9
of the HADHA gene, which encodes a linker domain between 2 regions of
enzyme activity.

Ibdah et al. (1999) reported 5 children with complete MTP deficiency who
presented with neonatal dilated cardiomyopathy or progressive
neuromyopathy. None had the common HADHA mutation (E474Q; 600890.0001)
often seen in isolated LCHAD deficiency, and none of their mothers had
liver disease during pregnancy. Similarly, Chakrapani et al. (2000)
reported 5 families with trifunctional protein deficiency in which 3
mothers experienced significant hepatic disease while carrying an
affected fetus. Diagnoses were based on increased levels of long-chain
hydroxyacylcarnitines and deficiencies of 3-hydroxyacyl-CoA
dehydrogenase and 3-ketoacyl-CoA thiolase activity in fibroblasts. None
of these affected infants had the E474Q mutation.

Spiekerkoetter et al. (2003) characterized 15 patients from 13 families
with HADHB mutations of the mitochondrial trifunctional protein. Three
clinical phenotypes were apparent: a severe neonatal presentation with
cardiomyopathy, Reye-like symptoms, and early death in 4 patients; a
hepatic form with recurrent hypoketotic hypoglycemia in 2 patients; and
a milder, later-onset neuromyopathic phenotype with episodic
myoglobinuria in 9 patients. Maternal HELLP syndrome occurred in 2
mothers independently of the fetal phenotype. Mutation analysis revealed
16 different mutations, 12 of which were missense mutations. Based on
homology to yeast thiolase, which had been characterized structurally,
Spiekerkoetter et al. (2003) found that the location of the mutation
within the protein correlated with the clinical phenotype. Outer loop
mutations that were expected to alter protein stability were present
only in milder forms. The degree of reduction in thiolase antigen also
correlated with the severity of clinical presentation. Thus, although
MTP deficiency is highly heterogeneous, some genotype-phenotype
correlation could be established.

Purevsuren et al. (2009) reported 5 Japanese patients with trifunctional
protein deficiency due to homozygous or compound heterozygous mutations
in the HADHB gene (see, e.g., 143450.0004 and 143450.0006). In vitro
functional expression studies indicated a genotype/phenotype
correlation: patients whose mutations resulted in no residual protein
activity had a more severe phenotype than those whose mutations had
residual activity.

*FIELD* RF
1. Brackett, J. C.; Sims, H. F.; Rinaldo, P.; Shapiro, S.; Powell,
C. K.; Bennett, M. J.; Strauss, A. W.: Two alpha subunit donor splice
site mutations cause human trifunctional protein deficiency. J. Clin.
Invest. 95: 2076-2082, 1995.

2. Chakrapani, A.; Olpin, S.; Cleary, M.; Walter, J. H.; Wraith, J.
E.; Besley, G. T. N.: Trifunctional protein deficiency: three families
with significant maternal hepatic dysfunction in pregnancy not associated
with E474Q mutation. J. Inherit. Metab. Dis. 23: 826-834, 2000.

3. den Boer, M. E. J.; Dionisi-Vici, C.; Chakrapani, A.; van Thuijl,
A. O. J.; Wanders, R. J. A.; Wijburg, F. A.: Mitochondrial trifunctional
protein deficiency: a severe fatty acid oxidation disorder with cardiac
and neurologic involvement. J. Pediat. 142: 684-689, 2003.

4. Dionisi-Vici, C.; Garavaglia, B.; Burlina, A. B.; Bertini, E.;
Saponara, I.; Sabetta, G.; Taroni, F.: Hypoparathyroidism in mitochondrial
trifunctional protein deficiency. J. Pediat. 129: 159-162, 1996.

5. Dionisi Vici, C.; Burlina, A. B.; Bertini, E.; Bachmann, C.; Mazziotta,
M. R. M.; Zacchello, F.; Sabetta, G.; Hale, D. E.: Progressive neuropathy
and recurrent myoglobinuria in a child with long-chain 3-hydroxyacyl-coenzyme
A dehydrogenase deficiency. J. Pediat. 118: 744-746, 1991.

6. Ibdah, J. A.; Bennett, M. J.; Rinaldo, P.; Zhao, Y.; Gibson, B.;
Sims, H. F.; Strauss, A. W.: A fetal fatty-acid oxidation disorder
as a cause of liver disease in pregnant women. New Eng. J. Med. 340:
1723-1731, 1999.

7. Ibdah, J. A.; Tein, I.; Dionisi-Vici, C.; Bennett, M. J.; IJlst,
L.; Gibson, B.; Wanders, R. J. A.; Strauss, A. W.: Mild trifunctional
protein deficiency is associated with progressive neuropathy and myopathy
and suggests a novel genotype-phenotype correlation. J. Clin. Invest. 102:
1193-1199, 1998.

8. Jackson, S.; Singh Kler, R.; Bartlett, K.; Briggs, H.; Bindoff,
L. A.; Pourfarzam, M.; Gardner-Medwin, D.; Turnbull, D. M.: Combined
enzyme defect of mitochondrial fatty acid oxidation. J. Clin. Invest. 90:
1219-1225, 1992.

9. Miyajima, H.; Orii, K. E.; Shindo, Y.; Hashimoto, T.; Shinka, T.;
Kuhara, T.; Matsumoto, I.; Shimizu, H.; Kaneko, E.: Mitochondrial
trifunctional protein deficiency associated with recurrent myoglobinuria
in adolescence. Neurology 49: 833-837, 1997.

10. Orii, K. E.; Aoyama, T.; Wakui, K.; Fukushima, Y.; Miyajima, H.;
Yamaguchi, S.; Orii, T.; Kondo, N.; Hashimoto, T.: Genomic and mutational
analysis of the mitochondrial trifunctional protein beta-subunit (HADHB)
gene in patients with trifunctional protein deficiency. Hum. Molec.
Genet. 6: 1215-1224, 1997.

11. Purevsuren, J.; Fukao, T.; Hasegawa, Y.; Kobayashi, H.; Li, H.;
Mushimoto, Y.; Fukuda, S.; Yamaguchi, S.: Clinical and molecular
aspects of Japanese patients with mitochondrial trifunctional protein
deficiency. Molec. Genet. Metab. 98: 372-377, 2009.

12. Schaefer, J.; Jackson, S.; Dick, D. J.; Turnbull, D. M.: Trifunctional
enzyme deficiency: adult presentation of a usually fatal beta-oxidation
defect. Ann. Neurol. 40: 597-602, 1996.

13. Spiekerkoetter, U.; Sun, B.; Khuchua, Z.; Bennett, M. J.; Strauss,
A. W.: Molecular and phenotypic heterogeneity in mitochondrial trifunctional
protein deficiency due to beta-subunit mutations. Hum. Mutat. 21:
598-607, 2003.

14. Ushikubo, S.; Aoyama, T.; Kamijo, T.; Wanders, R. J. A.; Rinaldo,
P.; Vockley, J.; Hashimoto, T.: Molecular characterization of mitochondrial
trifunctional protein deficiency: formation of the enzyme complex
is important for stabilization of both alpha- and beta-subunits. Am.
J. Hum. Genet. 58: 979-988, 1996.

15. Wanders, R. J. A.; IJlst, L.; Poggi, F.; Bonnefont, J. P.; Munnich,
A.; Brivet, M.; Rabier, D.; Saudubray, J. M.: Human trifunctional
protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Biochem.
Biophys. Res. Commun. 188: 1139-1145, 1992.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Small for gestational age;
Failure to thrive

HEAD AND NECK:
[Eyes];
Pigmentary retinopathy (rare)

CARDIOVASCULAR:
[Heart];
Low-output cardiomyopathy;
Dilated cardiomyopathy;
Cardiac failure

RESPIRATORY:
Respiratory failure

ABDOMEN:
[Liver];
Hepatic dysfunction

MUSCLE, SOFT TISSUE:
Hypotonia;
Generalized weakness;
Slowly progressive limb-girdle myopathy;
Muscle pain;
Rhabdomyolysis, episodic

NEUROLOGIC:
[Central nervous system];
Poor spontaneous movements;
Delayed psychomotor development;
[Peripheral nervous system];
Sensorimotor axonopathy

METABOLIC FEATURES:
Lactic acidosis

PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Hydrops fetalis;
[Maternal];
HELLP syndrome (hemolysis, elevated liver enzymes, low platelets)

LABORATORY ABNORMALITIES:
Hypoketotic hypoglycemia;
Decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase,
long-chain 3-oxoacyl-CoA thiolase, and long-chain 2-enoyl-CoA hydratase;
Increased serum acylcarnitines;
Hyperammonemia;
Myoglobinuria;
Abnormal liver enzymes

MISCELLANEOUS:
Three major clinical forms are apparent;
Rapidly progressive neonatal onset with early death;
Infantile onset with hepatic involvement;
Childhood or adolescent onset, protracted, with myopathy and neuropathy;
Sudden infant death may occur;
Symptoms may be aggravated by acute illness;
Most patients die from heart failure

MOLECULAR BASIS:
Caused by mutation in the alpha subunit of the hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA
thiolase/enoyl-CoA hydratase (HADHA, 600890.0003);
Caused by mutation in the beta subunit of the hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA
thiolase/enoyl-CoA hydratase (HADHB, 143450.0001)

*FIELD* CD
Cassandra L. Kniffin: 12/7/2007

*FIELD* ED
ckniffin: 07/20/2010
joanna: 3/19/2008
ckniffin: 12/13/2007

*FIELD* CN
Cassandra L. Kniffin - updated: 7/20/2010
Cassandra L. Kniffin - updated: 12/13/2007
Cassandra L. Kniffin - updated: 12/12/2007
Carol A. Bocchini - updated: 11/12/2004

*FIELD* CD
Ada Hamosh: 11/8/2004

*FIELD* ED
wwang: 07/27/2010
ckniffin: 7/20/2010
carol: 12/14/2007
ckniffin: 12/13/2007
ckniffin: 12/12/2007
carol: 7/14/2005
carol: 11/12/2004
carol: 11/10/2004

MIM 609016
*RECORD*
*FIELD* NO
609016
*FIELD* TI
#609016 LONG-CHAIN 3-HYDROXYACYL-CoA DEHYDROGENASE DEFICIENCY
;;LCHAD DEFICIENCY
*FIELD* TX
read moreA number sign (#) is used with this entry because LCHAD deficiency is
caused by homozygous or compound heterozygous mutations in the gene
encoding long-chain hydroxyacyl-CoA dehydrogenase (HADHA; 600890).

Complete mitochondrial trifunctional protein deficiency (609015) is a
less common disorder that is also caused by mutation in the HADHA gene.

DESCRIPTION

Isolated deficiency of long-chain 3-hydroxyl-CoA dehydrogenase (LCHAD)
is an autosomal recessive disorder characterized by early-onset
cardiomyopathy, hypoglycemia, neuropathy, and pigmentary retinopathy,
and sudden death (IJlst et al., 1996).

CLINICAL FEATURES

Wanders et al. (1989) described sudden infant death syndrome (SIDS) in a
3-day-old infant caused by deficiency of long-chain 3-hydroxyacyl-CoA
dehydrogenase. Duran et al. (1991) reported that the younger sister of
this patient began at the age of 5 months to have feeding problems,
lowered consciousness, and liver dysfunction. Plasma long-chain
acylcarnitine was increased. A clue to the diagnosis was given by the
results of a phenylpropionic acid loading test. On a diet enriched with
medium-chain triglycerides, the patient started to thrive, signs of
cardiomyopathy disappeared, and her liver function returned to normal.

Rocchiccioli et al. (1990) described an infant with LCHAD deficiency who
developed recurrent hypoglycemia in early infancy and died at 9 months
of age from a rapidly progressive myopathy and cardiomyopathy. The
activities of long-, medium-, and short-chain acyl-CoA dehydrogenases
(609576, 607008 and 606885, respectively) and 3-ketoacyl-CoA thiolase
(607809) were normal. The clinical features of this disorder bore
similarities to those of systemic carnitine deficiency (212140) as well
as with carnitine-palmitoyl-CoA transferase (255110 and 255120) and
long-chain acyl-CoA dehydrogenase deficiencies. The differential
diagnosis relies on the demonstration of long-chain urinary dicarboxylic
acids with a hydroxyl group in the 3-position and on the study of the
enzyme activity in cultured fibroblasts. Rocchiccioli et al. (1990)
diagrammed the pathway of fatty acyl-CoA beta-oxidation in mitochondria.

Jackson et al. (1991) described the cases of 2 unrelated children.
Recessive inheritance was supported by the finding of intermediate
levels of enzyme activity in the fibroblasts from the parents of one of
the children.

Bertini et al. (1992) reported the case of an 11-month-old girl with
LCHAD deficiency and a new phenotype of sensorimotor polyneuropathy,
pigmentary retinopathy, and fatal progressive cardiomyopathy.

Hagenfeldt et al. (1990) described 5 patients with a suspected defect in
the beta-oxidation of fatty acids characterized by massive excretion of
3-hydroxydicarboxylic acids in the urine and accumulation of 3-hydroxy
fatty acids in serum during acute illness. Long-chain and medium-chain
acyl-coenzyme A dehydrogenases in fibroblasts were normal in all
patients. Death due to cardiomyopathy and liver failure occurred in 4 of
the 5 at 3 to 14 months of age. Elder sibs of 2 of the patients had died
unexpectedly in early infancy. The parents of 1 of the patients were
second cousins. Long-chain 3-hydroxyacyl-CoA dehydrogenase may have been
the enzyme deficient in these cases.

Tyni et al. (1997) discussed the clinical presentation of 13 patients
with LCHAD deficiency. The patients had hypoglycemia, cardiomyopathy,
muscle hypotonia, and hepatomegaly during the first 2 years of life.
Recurrent metabolic crises had occurred in 7 patients; the other 6 had a
steadily progressive course. Cholestatic liver disease, which is
uncommon in beta-oxidation defects, was found in 2 patients. One patient
had peripheral neuropathy, and 6 had retinopathy with focal pigmentary
aggregations or retinal hypopigmentation. Radiologically, there was
bilateral periventricular or focal cortical lesions in 3 patients and
brain atrophy in 1. Only 1 patient, who had dietary treatment for 9
years, was alive at the age of 14 years; all others died before they
were 2 years of age. The experience indicated the importance of
recognizing the clinical features of LCHAD deficiency for the early
institution of dietary management, which can alter the otherwise
invariably poor prognosis.

Ibdah et al. (1999) reported a patient who presented at 2 months of age
with generalized tonic-clonic seizure due to an acute infantile
hypocalcemia and vitamin D deficiency. He also had occult, unexplained
cholestatic liver disease and impairment of 25-hydroxylation of vitamin
D secondary to hepatic steatosis. Sudden unexpected death occurred at 8
months. Molecular analysis identified a homozygous 1528G-C mutation
(E510Q; 600890.0001) in the HADHA gene. The mother had preeclampsia
during the third trimester of her pregnancy.

In 2 girls, aged 8 and 15 years, with LCHAD deficiency,
Schrijver-Wieling et al. (1997) observed extensive macular pigmentary
depositions and a 'salt and pepper' scattering of pigment in their
retinas. They had decreasing visual acuity. The investigators suggested
that testing for LCHAD deficiency should be included in the diagnostic
process in children with retinal dystrophy, in particular when other
clinical symptoms suggesting this disorder occur. Uusimaa et al. (1997)
reported 2 unrelated boys with pigmentary retinopathy in association
with a mild clinical presentation of LCHAD deficiency.

Tyni et al. (2002) noted that pigmentary retinopathy is an important
feature of LCHAD deficiency. In studies in cultured porcine retinal
pigment epithelium (RPE) cells, they presented strong in vitro evidence
for the presence of mitochondrial fatty acid beta-oxidation in RPE cells
and the expression of the MTP in the RPE and other layers of the retina.

Sewell et al. (1994) stated that most reported cases were diagnosed at
the age of several months and presented with fasting-induced hypoketotic
hypoglycemia and muscular hypotonia. Thiel et al. (1999) reported a
patient presenting 20 hours after birth with signs of tachypnea,
hypotonia, and mild retractions, and Carpenter and Wilcken (1999)
described a patient who developed hypoglycemia at birth; on dietary
treatment, both patients remained well.

Although the mortality rate among children with deficiency of LCHAD or
complete deficiency of the trifunctional protein had been reported to be
75 to 90%, Ibdah et al. (1999) found that 67% of the affected children
in their study were alive and receiving dietary treatment at the most
recent follow-up, and most were able to attend school. Dietary treatment
of children with fatty-acid oxidation disorders dramatically reduces
morbidity and mortality.

Van Hove et al. (2000) reviewed the acylcarnitines in plasma and blood
spots of patients with LCHAD deficiency. Long-chain
3-hydroxyacylcarnitines of C14:1, C14, C16, and C18:1 chain length, and
long-chain acylcarnitines of C12, C14:1, C14, C16, C18:2, and C18:1
chain length were elevated. Acetylcarnitine was decreased. In plasma,
elevation of hydroxy-C18:1 acylcarnitine over the 95th centile of
controls, in combination with an elevation of 2 of the 3 acylcarnitines
C14, C14:1, and hydroxy-C16, identified over 85% of patients with high
specificity (less the 0.1% false-positive rate). High endogenous levels
of long-chain acylcarnitines in normal erythrocytes reduced the
diagnostic specificity in blood spots compared with plasma samples. The
results were diagnostic in the asymptomatic patients. Treatment with a
diet low in fat and high in medium-chain triglyceride decreased all
disease-specific acylcarnitines, often to normal, suggesting that this
assay is useful in treatment monitoring.

Fryburg et al. (1994) suggested that LCHAD deficiency is responsible for
the lipid myopathy in Bannayan-Riley-Ruvalcaba syndrome (153480), an
autosomal dominant condition of macrocephaly in combination with
lipomas/hemangiomas and developmental delay.

- Acute Fatty Liver Pregnancy (AFLP) and Hypertension, Elevated
Liver Enzymes, and Low Platelet (HELLP) Syndromes

Wilcken et al. (1993) and Treem et al. (1994) noted that isolated LCHAD
deficiency in children may be associated with severe maternal illness
occurring during pregnancies with affected fetuses. These maternal
illnesses include the acute fatty liver pregnancy (AFLP) syndrome;
hypertension or hemolysis, elevated liver enzymes, and low platelets
(HELLP) syndrome; and hyperemesis gravidum. The AFLP syndrome is
characterized by anorexia, nausea, vomiting, abdominal pain, and
jaundice in the third trimester. Fulminant liver failure and death may
occur. HELLP syndrome is more common and may represent the severe end of
the spectrum of preeclampsia. In both syndromes, microvesicular fatty
infiltration of maternal liver occurs, a pathologic picture similar to
that in children with fatty acid oxidation defects. Thus, AFLP and HELLP
are genetic disorders due to a primary defect in the fetus.

Ibdah et al. (1999) stated that little is known about the mechanism of
the association between isolated deficiency of LCHAD in a fetus with the
common 1528G-C mutation (600890.0001) on at least one allele and liver
disease in the mother during the pregnancy. They hypothesized that in
the presence of the 1528G-C mutation, long-chain 3-hydroxyacyl
metabolites produced by the fetus or placenta accumulate in the mother
and are highly toxic to the liver; this reaction is perhaps exaggerated
by the decreased metabolic utilization of fatty acids during pregnancy.

Ibdah et al. (2001) performed molecular prenatal diagnosis in 9
pregnancies, 8 in 6 families with isolated LCHAD deficiency and 1 in a
family with complete trifunctional protein deficiency. Analyses were
performed on chorionic villus samples in 7 pregnancies and on amniocytes
in 2. Molecular prenatal diagnosis successfully identified the fetal
genotype in all 9 pregnancies. Two fetuses were affected, and the
pregnancies were terminated. Two other fetuses had normal genotype and 5
others were heterozygotes. All 7 pregnancies were uncomplicated and all
the offspring were liveborn and healthy. Ibdah et al. (2001) concluded
that women heterozygous for trifunctional protein alpha-subunit
mutations who carry fetuses with wildtype or heterozygous genotypes have
uncomplicated pregnancies.

CLINICAL MANAGEMENT

Jones et al. (2003) analyzed the effects of dietary treatment of LCHAD
deficiency in an in vitro model of cultured skin fibroblasts from 2
patients with LCHAD deficiency, 1 with MPT deficiency, and controls. The
results suggested that a medium-chain triglyceride preparation reduces
the accumulation of potentially toxic long-chain 3-hydroxy-fatty acids
in LCHAD deficiency and that a preparation with a higher ratio of
decanoate to octanoate may be most effective.

MOLECULAR GENETICS

To identify the molecular basis of the deficiency in 26 Dutch patients
with a deficiency in long-chain 3-hydroxyacyl-CoA dehydrogenase, IJlst
et al. (1994) sequenced the cDNAs encoding the alpha and beta subunits
of the trifunctional enzyme and identified a 1528G-C transversion in the
dehydrogenase-encoding region of the alpha subunit. The single base
change resulted in an glu510-to-gln (E510Q; 600890.0001) amino acid
substitution, based on numbering from the start codon. The base
substitution created a PstI restriction site. Using RFLP methods, they
found that in 24 of 26 unrelated patients, only the 1528C was expressed.
The other 2 patients were compound heterozygotes with 1 allele carrying
this mutation. IJlst et al. (1996) used S. cerevisiae for expression of
wildtype and mutant protein to show that the 1528G-C mutation is
directly responsible for the loss of LCHAD activity. Furthermore, they
described a newly developed method allowing identification of the
1528G-C mutation in genomic DNA. The finding of an 87% allele frequency
of this mutation in 34 LCHAD-deficient patients made this a valuable
test for prenatal diagnosis. IJlst et al. (1996) showed that the E510Q
mutation is directly responsible for the loss of dehydrogenase activity
without changing the structure of the enzyme complex.

Sims et al. (1995) used single-strand conformation variance (SSCV)
analysis of the exons encoding the alpha subunit of trifunctional
protein to elucidate the molecular defects (see, e.g.,
600890.0001-600890.0002) in 3 families with children with isolated LCHAD
deficiency and mothers with either AFLP syndrome or HELLP syndrome.
Based on numbering of the mature peptide, Sims et al. (1995) designated
the 1528G-C mutation as glu474-to-gln (E474Q).

INHERITANCE

LCHAD deficiency usually shows autosomal recessive inheritance. Baskin
et al. (2010) reported an unusual case of LCHAD deficiency due to
paternal isodisomy of chromosome 2. The patient was a 22-month-old child
identified by newborn screening. Molecular analysis showed homozygosity
for the common 1528G-C mutation (E510Q; 600890.0001), but only the
father was found to be heterozygous for the mutation; it was not present
in the mother. Genotype analysis of chromosome 2 using STR markers
demonstrated uniparental isodisomy. The patient did not have other
phenotypic abnormalities, suggesting that chromosome 2 is not imprinted.
The finding was important, as it reduced the recurrence risk of this
disease for this couple.

POPULATION GENETICS

Ibdah et al. (1999) found 17 different mutations among the 24 children
in their study. In the 19 children with isolated deficiency of LCHAD,
71% of alleles had the E510Q mutation, and none of the 10 alleles (all
of which were abnormal) in the 5 children with trifunctional protein
deficiency had this mutation. Among 351 normal subjects, they found that
2 were heterozygous for the E510Q mutation. If this group of subjects
was representative of the general population, then isolated deficiency
of LCHAD would occur once in every 62,000 pregnancies, and either
trifunctional protein or long-chain 3-hydroxyacyl-CoA dehydrogenase
deficiency would occur once in 38,000 pregnancies.

*FIELD* SA
Jackson et al. (1992); Wanders et al. (1992)
*FIELD* RF
1. Baskin, B.; Geraghty, M.; Ray, P. N.: Paternal isodisomy of chromosome
2 as a cause of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
deficiency. Am. J. Med. Genet. 152A: 1808-1811, 2010.

2. Bertini, E.; Dionisi-Vici, C.; Garavaglia, B.; Burlina, A. B.;
Sabatelli, M.; Rimoldi, M.; Bartuli, A.; Sabetta, G.; DiDonato, S.
: Peripheral sensory-motor polyneuropathy, pigmentary retinopathy,
and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase
deficiency. Europ. J. Pediat. 151: 121-126, 1992.

3. Carpenter, K. H.; Wilcken, B.: Neonatal diagnosis of long-chain
3-hydroxyacyl-CoA dehydrogenase deficiency and implications for newborn
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*FIELD* CN
Cassandra L. Kniffin - updated: 11/1/2010
Cassandra L. Kniffin - updated: 12/14/2007
Natalie E. Krasikov - updated: 8/2/2005

*FIELD* CD
Ada Hamosh: 11/8/2004

*FIELD* ED
carol: 03/04/2013
wwang: 11/10/2010
ckniffin: 11/1/2010
terry: 4/8/2009
carol: 12/14/2007
ckniffin: 12/13/2007
ckniffin: 9/22/2005
carol: 8/2/2005
carol: 11/12/2004
carol: 11/10/2004
carol: 11/8/2004