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Pathway Description

Ethylmalonic Encephalopathy

Homo sapiens

Disease Pathway

Created: 2013-08-01

Last Updated: 2025-01-24

Ethylmalonic Encephalopathy (Epema Syndrome; EE) is a rare autosomal recessive disorder caused by a mutation in the ETHE1 gene which codes for protein ETHE1. A deficiency of this protein inhibits proper energy production in mitochondria and a deficiency in cytochrome c oxidase. This results in accumulation of 2-methylbutyrylglycine, N-butyrylglycine, isobutyrylglycine, isovalerylglycine, and methylsuccinic acid in urine. Concentrations of L-carnitine are reduced in plasma. Symptoms, which present at birth, include peripheral neuropathy, seizures, microcephaly, and hypotonia lead to premature death. Treatment includes riboflavin and L-carnitine.

References

Ethylmalonic Encephalopathy References

Wikipedia: Ethylmalonic encephalopathy

Uniprot: O95571

OMIM: Entry 602473

Engelke, U., van der Graaf, M., Heerschap, A., Hoenderop, S., Moolenaar, S., Morava, E., Wevers, R. Handbook of 1H-NMR spectroscopy in inborn errors of metabolism: body fluid NMR spectroscopy and in vivo MR spectroscopy (2nd ed) (2007) p.38 Heilbronn: SPS Verlagsgesellschaft

Burlina A, Zacchello F, Dionisi-Vici C, Bertini E, Sabetta G, Bennet MJ, Hale DE, Schmidt-Sommerfeld E, Rinaldo P: New clinical phenotype of branched-chain acyl-CoA oxidation defect. Lancet. 1991 Dec 14;338(8781):1522-3.

Pubmed: 1683940

Grosso S, Mostardini R, Farnetani MA, Molinelli M, Berardi R, Dionisi-Vici C, Rizzo C, Morgese G, Balestri P: Ethylmalonic encephalopathy: further clinical and neuroradiological characterization. J Neurol. 2002 Oct;249(10):1446-50. doi: 10.1007/s00415-002-0880-4.

Pubmed: 12382164

Mineri R, Rimoldi M, Burlina AB, Koskull S, Perletti C, Heese B, von Dobeln U, Mereghetti P, Di Meo I, Invernizzi F, Zeviani M, Uziel G, Tiranti V: Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. J Med Genet. 2008 Jul;45(7):473-8. doi: 10.1136/jmg.2008.058271.

Pubmed: 18593870

Ozand PT, Rashed M, Millington DS, Sakati N, Hazzaa S, Rahbeeni Z, al Odaib A, Youssef N, Mazrou A, Gascon GG, et al.: Ethylmalonic aciduria: an organic acidemia with CNS involvement and vasculopathy. Brain Dev. 1994 Nov;16 Suppl:12-22.

Pubmed: 7726376

Tiranti V, D'Adamo P, Briem E, Ferrari G, Mineri R, Lamantea E, Mandel H, Balestri P, Garcia-Silva MT, Vollmer B, Rinaldo P, Hahn SH, Leonard J, Rahman S, Dionisi-Vici C, Garavaglia B, Gasparini P, Zeviani M: Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am J Hum Genet. 2004 Feb;74(2):239-52. doi: 10.1086/381653. Epub 2004 Jan 19.

Pubmed: 14732903

Di Meo I, Lamperti C, Tiranti V: Ethylmalonic Encephalopathy

Pubmed: 28933811

Di Meo I, Auricchio A, Lamperti C, Burlina A, Viscomi C, Zeviani M: Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy. EMBO Mol Med. 2012 Sep;4(9):1008-14. doi: 10.1002/emmm.201201433. Epub 2012 Aug 20.

Pubmed: 22903887

Fatty Acid Metabolism References

Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.

Lodish, H. et al. Molecular cell biology. (2004) New York: W.H Freeman.

Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.

Vance, D.E., and Vance, J.E. Biochemistry of lipids, lipoproteins, and membranes (4th ed.) (2002) Amsterdam; Boston: Elsevier.

Wakil SJ, Abu-Elheiga LA: Fatty acid metabolism: target for metabolic syndrome. J Lipid Res. 2009 Apr;50 Suppl:S138-43. doi: 10.1194/jlr.R800079-JLR200. Epub 2008 Dec 1.

Pubmed: 19047759

Wataya K, Akanuma J, Cavadini P, Aoki Y, Kure S, Invernizzi F, Yoshida I, Kira J, Taroni F, Matsubara Y, Narisawa K: Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: functional analysis and association with polymorphic haplotypes and two clinical phenotypes. Hum Mutat. 1998;11(5):377-86. doi: 10.1002/(SICI)1098-1004(1998)11:5<377::AID-HUMU5>3.0.CO;2-E.

Pubmed: 9600456

Finocchiaro G, Taroni F, Rocchi M, Martin AL, Colombo I, Tarelli GT, DiDonato S: cDNA cloning, sequence analysis, and chromosomal localization of the gene for human carnitine palmitoyltransferase. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):661-5. doi: 10.1073/pnas.88.2.661.

Pubmed: 1988962

Finocchiaro G, Taroni F, Rocchi M, Liras Martin A, Colombo I, Tarelli GT, DiDonato S: cDNA cloning, sequence analysis, and chromosomal localization of human carnitine palmitoyltransferase. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10981. doi: 10.1073/pnas.88.23.10981.

Pubmed: 1961767

Janssen U, Davis EM, Le Beau MM, Stoffel W: Human mitochondrial enoyl-CoA hydratase gene (ECHS1): structural organization and assignment to chromosome 10q26.2-q26.3. Genomics. 1997 Mar 15;40(3):470-5. doi: 10.1006/geno.1996.4597.

Pubmed: 9073515

Peters H, Buck N, Wanders R, Ruiter J, Waterham H, Koster J, Yaplito-Lee J, Ferdinandusse S, Pitt J: ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain. 2014 Nov;137(Pt 11):2903-8. doi: 10.1093/brain/awu216. Epub 2014 Aug 14.

Pubmed: 25125611

Haack TB, Jackson CB, Murayama K, Kremer LS, Schaller A, Kotzaeridou U, de Vries MC, Schottmann G, Santra S, Buchner B, Wieland T, Graf E, Freisinger P, Eggimann S, Ohtake A, Okazaki Y, Kohda M, Kishita Y, Tokuzawa Y, Sauer S, Memari Y, Kolb-Kokocinski A, Durbin R, Hasselmann O, Cremer K, Albrecht B, Wieczorek D, Engels H, Hahn D, Zink AM, Alston CL, Taylor RW, Rodenburg RJ, Trollmann R, Sperl W, Strom TM, Hoffmann GF, Mayr JA, Meitinger T, Bolognini R, Schuelke M, Nuoffer JM, Kolker S, Prokisch H, Klopstock T: Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann Clin Transl Neurol. 2015 May;2(5):492-509. doi: 10.1002/acn3.189. Epub 2015 Mar 13.

Pubmed: 26000322

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. 1994 Mar 15;199(2):818-25. doi: 10.1006/bbrc.1994.1302.

Pubmed: 8135828

Zhang QX, Baldwin GS: Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene. Biochim Biophys Acta. 1994 Oct 18;1219(2):567-75. doi: 10.1016/0167-4781(94)90091-4.

Pubmed: 7918661

Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.

Pubmed: 14702039

Orii KE, 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 Mol Genet. 1997 Aug;6(8):1215-24. doi: 10.1093/hmg/6.8.1215.

Pubmed: 9259266

Abe H, Ohtake A, Yamamoto S, Satoh Y, Takayanagi M, Amaya Y, Takiguchi M, Sakuraba H, Suzuki Y, Mori M, et al.: Cloning and sequence analysis of a full length cDNA encoding human mitochondrial 3-oxoacyl-CoA thiolase. Biochim Biophys Acta. 1993 Nov 16;1216(2):304-6. doi: 10.1016/0167-4781(93)90160-f.

Pubmed: 8241273

Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.

Pubmed: 15489334

Aboulaich N, Vainonen JP, Stralfors P, Vener AV: Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes. Biochem J. 2004 Oct 15;383(Pt 2):237-48. doi: 10.1042/BJ20040647.

Pubmed: 15242332

Gobin S, Bonnefont JP, Prip-Buus C, Mugnier C, Ferrec M, Demaugre F, Saudubray JM, Rostane H, Djouadi F, Wilcox W, Cederbaum S, Haas R, Nyhan WL, Green A, Gray G, Girard J, Thuillier L: Organization of the human liver carnitine palmitoyltransferase 1 gene ( CPT1A) and identification of novel mutations in hypoketotic hypoglycaemia. Hum Genet. 2002 Aug;111(2):179-89. doi: 10.1007/s00439-002-0752-0. Epub 2002 Jul 16.

Pubmed: 12189492

Britton CH, Schultz RA, Zhang B, Esser V, Foster DW, McGarry JD: Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):1984-8. doi: 10.1073/pnas.92.6.1984.

Pubmed: 7892212

Abe T, Fujino T, Fukuyama R, Minoshima S, Shimizu N, Toh H, Suzuki H, Yamamoto T: Human long-chain acyl-CoA synthetase: structure and chromosomal location. J Biochem. 1992 Jan;111(1):123-8. doi: 10.1093/oxfordjournals.jbchem.a123707.

Pubmed: 1607358

Ghosh B, Barbosa E, Singh I: Molecular cloning and sequencing of human palmitoyl-CoA ligase and its tissue specific expression. Mol Cell Biochem. 1995 Oct 4;151(1):77-81. doi: 10.1007/bf01076899.

Pubmed: 8584017

Highlighted elements will appear in red.

Highlight Compounds

	(2E)-Decenoyl-CoA
	(2E)-Hexadecenoyl-CoA
	(2E)-Hexenoyl-CoA
	(2E)-Octenoyl-CoA
	(2E)-Tetradecenoyl-CoA
	3-Hydroxybutyryl-CoA
	3-Hydroxydecanoyl-CoA
	3-Hydroxydodecanoyl-CoA
	3-Hydroxyhexadecanoyl-CoA
	3-Hydroxyhexanoyl-CoA
	3-hydroxyoctanoyl-CoA
	3-Hydroxytetradecanoyl-CoA
	3-oxodecanoyl-CoA
	3-oxododecanoyl-CoA
	3-oxohexadecanoyl-CoA
	3-oxohexanoyl-CoA
	3-oxooctanoyl-CoA
	3-oxotetradecanoyl-CoA
	Acetoacetyl-CoA
	Acetyl-CoA
	Adenosine monophosphate
	Adenosine triphosphate
	Butyryl-CoA
	Carbon dioxide
	Coenzyme A
	Crotonoyl-CoA
	Decanoyl-CoA
	FAD
	Glutaryl-CoA
	Hexanoyl-CoA
	Hydrogen Ion
	L-Carnitine
	L-Palmitoylcarnitine
	Lauroyl-CoA
	Magnesium
	NAD
	NADH
	Octanoyl-CoA
	Palmitic acid
	Palmitoyl-CoA
	Pyrophosphate
	Tetradecanoyl-CoA
	Water

Highlight Proteins

	3-ketoacyl-CoA thiolase, mitochondrial
	Acetyl-CoA acetyltransferase, mitochondrial
	Carnitine O-palmitoyltransferase 1, liver isoform
	Carnitine O-palmitoyltransferase 2, mitochondrial
	Enoyl-CoA hydratase, mitochondrial
	Glutaryl-CoA dehydrogenase, mitochondrial
	Long-chain specific acyl-CoA dehydrogenase, mitochondrial
	Long-chain-fatty-acid--CoA ligase 1
	Medium-chain specific acyl-CoA dehydrogenase, mitochondrial
	Short-chain specific acyl-CoA dehydrogenase, mitochondrial
	Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial
	Trifunctional enzyme subunit alpha, mitochondrial
	Trifunctional enzyme subunit beta, mitochondrial
	Very long-chain specific acyl-CoA dehydrogenase, mitochondrial

Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.

Visualize Compound Data

		(2E)-Decenoyl-CoA
		(2E)-Hexadecenoyl-CoA
		(2E)-Hexenoyl-CoA
		(2E)-Octenoyl-CoA
		(2E)-Tetradecenoyl-CoA
		3-Hydroxybutyryl-CoA
		3-Hydroxydecanoyl-CoA
		3-Hydroxydodecanoyl-CoA
		3-Hydroxyhexadecanoyl-CoA
		3-Hydroxyhexanoyl-CoA
		3-hydroxyoctanoyl-CoA
		3-Hydroxytetradecanoyl-CoA
		3-oxodecanoyl-CoA
		3-oxododecanoyl-CoA
		3-oxohexadecanoyl-CoA
		3-oxohexanoyl-CoA
		3-oxooctanoyl-CoA
		3-oxotetradecanoyl-CoA
		Acetoacetyl-CoA
		Acetyl-CoA
		Adenosine monophosphate
		Adenosine triphosphate
		Butyryl-CoA
		Carbon dioxide
		Coenzyme A
		Crotonoyl-CoA
		Decanoyl-CoA
		FAD
		Glutaryl-CoA
		Hexanoyl-CoA
		Hydrogen Ion
		L-Carnitine
		L-Palmitoylcarnitine
		Lauroyl-CoA
		Magnesium
		NAD
		NADH
		Octanoyl-CoA
		Palmitic acid
		Palmitoyl-CoA
		Pyrophosphate
		Tetradecanoyl-CoA
		Water

Visualize Protein Data

		3-ketoacyl-CoA thiolase, mitochondrial
		Acetyl-CoA acetyltransferase, mitochondrial
		Carnitine O-palmitoyltransferase 1, liver isoform
		Carnitine O-palmitoyltransferase 2, mitochondrial
		Enoyl-CoA hydratase, mitochondrial
		Glutaryl-CoA dehydrogenase, mitochondrial
		Long-chain specific acyl-CoA dehydrogenase, mitochondrial
		Long-chain-fatty-acid--CoA ligase 1
		Medium-chain specific acyl-CoA dehydrogenase, mitochondrial
		Short-chain specific acyl-CoA dehydrogenase, mitochondrial
		Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial
		Trifunctional enzyme subunit alpha, mitochondrial
		Trifunctional enzyme subunit beta, mitochondrial
		Very long-chain specific acyl-CoA dehydrogenase, mitochondrial

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