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Open Access 01-01-2012 | Branched-chain Amino Acids

The 3-methylglutaconic acidurias: what’s new?

Authors: Saskia B. Wortmann, Leo A. Kluijtmans, Udo F. H. Engelke, Ron A. Wevers, Eva Morava

Published in: Journal of Inherited Metabolic Disease | Issue 1/2012

Abstract

The heterogeneous group of 3-methylglutaconic aciduria (3-MGA-uria) syndromes includes several inborn errors of metabolism biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. Five distinct types have been recognized: 3-methylglutaconic aciduria type I is an inborn error of leucine catabolism; the additional four types all affect mitochondrial function through different pathomechanisms. We provide an overview of the expanding clinical spectrum of the 3-MGA-uria types and provide the newest insights into the underlying pathomechanisms. A diagnostic approach to the patient with 3-MGA-uria is presented, and we search for the connection between urinary 3-MGA excretion and mitochondrial dysfunction.

Adwani SS, Whitehead BF, Rees PG et al (1997) Heart transplantation for Barth syndrome. Pediatr Cardiol 18(2):143–145PubMedCrossRef

Anikster Y, Kleta R, Shaag A et al (2001) Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet 69(6):1218–1224PubMedCrossRef

Barth PG, Van't Veer-Korthof ET, Van Delden L et al (1981) An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leukocytes. In: Busch HFM, Jennekens FGI, Schotte HR (eds) Mitochondria and Muscular Diseases. Beetsterzwaag: 161–164

Barth PG, Scholte JA, Berden JA, Van der Klei-Van Moorsel JM et al (1983) An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes. J Neurol Sci 62:327–355PubMedCrossRef

Barth PG, Valianpour F, Bowen VM et al (2004) X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. Am J Med Genet A 126A(4):349–354PubMedCrossRef

Besley GT, Lendon M, Broadhead DM et al (1995) Mitochondrial complex deficiencies in a male with cardiomyopathy and 3-methylglutaconic aciduria. J Inherit Metab Dis 18(2):221–223PubMedCrossRef

Bione S, D'Adamo P, Maestrini E et al (1996) A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet 12(4):385–389PubMedCrossRef

Brennan LE, Nakagawa J, Egger D et al (1999) Characterisation and mitochondrial localisation of AUH, an AU-specific RNA-binding enoyl-CoA hydratase. Gene 228:85–91PubMedCrossRef

Cantlay A, Shokrollahi K, Allen J et al (1999) Genetic analysis of the G4.5 gene in families with suspected Barth syndrome. J Pediatr 135:311–315PubMedCrossRef

Chitayat D, Chemke J, Gibson KM et al (1992) 3-Methylglutaconic aciduria: a marker for as yet unspecified disorders and the relevance of prenatal diagnosis in a ‘new’ type (‘type 4’). J Inherit Metab Dis 15:204–212PubMedCrossRef

Christodoulou J, McInnes R, Jay V et al (1994) Barth syndrome: clinical observations and genetic lnkage studies. Am J Med Genet 50(3):255–264PubMedCrossRef

Cízková A, Stránecký V, Mayr JA et al (2008) TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet 40(11):1288–1290PubMedCrossRef

Costeff H, Gadoth N, Apter N et al (1989) A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia. Neurology 39(4):595–597PubMed

Dale DC, Bolyard AA, Schwinzer BG et al (2006) The severe chronic neutropenia international registry: 10-year follow-up report. Support Cancer Ther 3(4):220–231PubMedCrossRef

Davey KM, Parboosingh JS, McLeod DR et al (2006) Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. J Med Genet 43(5):385–393PubMedCrossRef

De Koning T, Duran M, Dorland L et al (1996) Maternal 3-methylglutaconic aciduria associated with abnormalities in offspring. Lancet 348(9031):887–888PubMedCrossRef

De Kremer RD, Paschini-Capra A, Bacman S et al (2001) Barth’s syndrome-like disorder: a new phenotype with a maternally inherited A3243G substitution of mitochondrial DNA (MELAS mutation). Am J Med Genet 99(2):83–93PubMedCrossRef

De Meirleir L, Seneca S, Lissens W et al (2004) Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet 41(2):120–4PubMedCrossRef

De Vries MC, Rodenburg RJ, Morava E et al (2007) Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. Eur J Pediatr 166(3):229–234PubMedCrossRef

Di Rosa G, Deodato F, Loupatty FJ et al (2006) Hypertrophic cardiomyopathy, cataract, developmental delay, lactic acidosis: a novel subtype of 3-methylglutaconic aciduria. J Inherit Metab Dis 29(4):546–550PubMedCrossRef

Duran M, Beemer FA, Tibosch AS et al (1982). Inherited 3-methylglutaconic aciduria in two brothers--another defect of leucine metabolism. J Pediatr 101(4):551–4PubMedCrossRef

Duran M, Baumgartner ER, Suormala TM et al (1993) Cerebrospinal fluid organic acids in Biotinidase deficiency. J Inherit Metab Dis 16:513–516PubMedCrossRef

Edmond J, Popjak G (1974) Transfer of carbon atoms from mevalonate to n-fatty acids. J Biol Chem 249(1):66–71PubMed

Elpeleg ON, Costeff H, Joseph A et al (1994) 3-Methylglutaconic aciduria in the Iraqi-Jewish ‘optic atrophy plus’ (Costeff) syndrome. Dev Med Child Neurol 36(2):167–172PubMedCrossRef

Engelke U, Kremer B, Kluijtmans L et al (2006) NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism. NMR Biomed 19(2):271–278PubMedCrossRef

Ensenauer R, Muller CB, Schwab KO et al (2000) 3-Methylglutaconyl-CoA hydratase deficiency: a new patient with speech retardation as the leading sign. J Inherit Metab Dis 23:341–344PubMedCrossRef

Eriguchi M, Mizuta H, Kurohara K et al (2006) 3-methylglutaconic aciduria type I causes leukoencephalopathy of adult onset. Neurology 67:1895–1896PubMedCrossRef

Faull K, Bolton P, Halpern B et al (1976) Patient with defect in leucine metabolism. New Eng J Med 294:1013PubMed

Figarella-Branger D, Pellissier JF, Scheiner C et al (1992) Defects of the mitochondrial respiratory chain complexes in three pediatric cases with hypotonia and cardiac involvement. J Neurol Sci 108(1):105–113PubMedCrossRef

Gibson KM, Bennett MJ, Mize CE et al (1992) 3-methylglutaconic aciduria associated with Pearson syndrome and respiratory chain defects. J Pediatr 121:940–942PubMedCrossRef

Gibson KM, Wappner RS, Jooste S et al (1998) Variable clinical presentation in three patients with 3-methylglutaconyl-coenzyme A hydratase deficiency. J Inherit Metab Dis 21(6):631–638PubMedCrossRef

Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430PubMedCrossRef

Gunay-Aygun M (2005) 3-methylglutaconic aciduria: a common biochemical marker in various syndromes with diverse clinical features. Mol Genet Metab 84:1–3PubMedCrossRef

Hastings R, Steward C, Tsai-Goodman B et al (2009) Dysmorphology of Barth syndrome. Clin Dysmorphol 18(4):185–187PubMedCrossRef

Ho G, Walter J, Christodoulou J (2008) Costeff optic atrophy syndrome: New clinical case and novel molecular findings. J Inherit Metab Dis. Short Report #134

Holme E, Greter J, Jacobsen CE et al (1992) Mitochondrial ATP-synthase deficiency in a child with 3-methylglutaconic aciduria. Pediatr Res 32(6):731–735PubMedCrossRef

Honzík T, Tesarová M, Mayr JA et al (2010) Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation. Arch Dis Child 95(4):296–301PubMedCrossRef

Houtkooper RH, Vaz FM (2008) Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci 65(16):2493–2506PubMedCrossRef

Houtkooper RH, Turkenburg M, Poll-The BT et al (2009) The enigmatic role of tafazzin in cardiolipin metabolism. Biochim Biophys Acta 1788(10):2003–2014PubMedCrossRef

Hughes-Fulford M, Feingold KR, Searle GL et al (1986) Role of the kidneys in the metabolism of circulating mevalonate in humans. J Clin Endocrinol Metab 62(6):1227–1231PubMedCrossRef

Huizing M, Dorward H, Ly L et al (2010) OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. Mol Genet Metab 100(2):149–154PubMedCrossRef

Ibel H, Endres W, Hadorn HB et al (1993) Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria. Eur J Pediatr 152(8):665–670PubMedCrossRef

IJlst L, Loupatty FJ, Ruiter JP et al (2002) 3-Methylglutaconic aciduria type I is caused by mutations in AUH. Am J Hum Genet 71(6):1463–1466PubMedCrossRef

Illsinger S, Lucke T, Zschocke J et al (2004) 3-Methylglutaconic aciduria type I in a boy with fever-associated seizures. Pediatr Neurol 30:213–215PubMedCrossRef

Jakobs C, Danse P, Veerman A (1991) Organic aciduria in Pearson syndrome. Eur J Pediatr 150(9):684PubMedCrossRef

Kelley R, Kratz L (1995) 3-methylglutaconic Acidemia in Smith-Lemli-Opitz syndrome. Pediatr Res 37(5):671–674PubMedCrossRef

Kelley R, Cheatham J, Clark B et al (1991) X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria. J Pediatr 119:738–747PubMedCrossRef

Kleta R, Skovby F, Christensen E et al (2002) 3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings. Mol Genet Metab 76(3):201–206PubMedCrossRef

Law LK, Tang NL, Hui J et al (2003) 3-methyglutaconic aciduria in a Chinese patient with glycogen storage disease Ib. J Inherit Metab Dis 26(7):705–709PubMedCrossRef

Leipnitz G, Seminotti B, Amaral AU et al (2008) Induction of oxidative stress by the metabolites accumulating in 3-methylglutaconic aciduria in cerebral cortex of young rats. Life Sci 82:652–662PubMedCrossRef

Liang WC, Ohkuma A, Hayashi YK et al (2009) ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromuscul Disord 19(3):212–216PubMedCrossRef

Lichter-Konecki U, Trefz F, Rötig A et al (1993) 3-methylglutaconic aciduria in a patient with Pearson syndrome. Eur J Pediatr 152(4):378–379PubMedCrossRef

Ly TB, Peters V, Gibson KM et al (2003) Mutations in the AUH gene cause 3-methylglutaconic aciduria type I. Hum Mutat 21(4):401–407PubMedCrossRef

Lynen F, Knappe J, Lorch E et al (1961) On the biochemical function of biotin. II. Putification and mode of action of beta-methyl-crotonyl-carboxylase. Biochem Z 335:123–167PubMed

Mangat J, Lunnon-Wood T, Rees P et al (2007) Successful cardiac transplantation in Barth syndrome–single-centre experience of four patients. Pediatr Transplant 11(3):327–331PubMedCrossRef

Matsumori M, Shoji Y, Takahashi T et al (2005) A molecular lesion in a Japanese patient with severe phenotype of 3-methylglutaconic aciduria type I. Pediatr Int 47:684–686PubMedCrossRef

Mayr JA, Havlícková V, Zimmermann F et al (2010) Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 {varepsilon} subunit. Hum Mol Genet 19(17):3430–3439PubMedCrossRef

Mazzocco MM, Henry AE, Kelly RI (2007) Barth syndrome is associated with a cognitive phenotype. J Dev Behav Pediatr 28(1):22–30PubMedCrossRef

Morava E, Sengers R, ter Laak H et al (2004) Congenital hypertrophic cardiomyopathy, cataract, mitochondrial myopathy and defective oxidative phosphorylation in two siblings with Sengers-like syndrome. Eur J Pediatr 163(8):467–471PubMedCrossRef

Narisawa K, Gibson KM, Sweetman L et al (1986) Deficiency of 3-methylglutaconyl-coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria. J Clin Invest 77:1148–1152PubMedCrossRef

Neas K, Bennetts B, Carpenter K et al (2005) OPA3 mutation screening in patients with unexplained 3-methylglutaconic aciduria. J Inherit Metab Dis 28(4):525–532PubMedCrossRef

Pei W, Kratz LE, Bernardini I et al (2010) A model of Costeff syndrome reveals metabolic and protective functions of mitochondrial OPA3. Development 137(15):2587–2596PubMedCrossRef

Reynier P, Amati-Bonneau P, Verny C et al (2004) OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet 41(9):e110PubMedCrossRef

Roesch K, Curran SP, Tranebjaerg L et al (2002) Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum Mol Genet 11(5):477–486PubMedCrossRef

Ruesch S, Krakenbuhl S, Kleinle S et al (1996) Combined 3-methylglutaconic and 3-hydroxy-3-methylglutaric aciduria with endocardial fibroelastosis and dilatative cardiomyopathy in male and female siblings with partial deficiency of complex II/III in fibroblasts. Enzyme Protein 49(5–6):321–329PubMed

Ryu SW, Jeong HJ, Choi M, et al (2010) Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation. Cell Mol Life Sci 67(16):2839–50PubMedCrossRef

Scaglia F, Sutton VR, Bodamer OA et al (2001) Mitochondrial DNA depletion associated with partial complex II and IV deficiencies and 3-methylglutaconic aciduria. J Child Neurol 16(2):136–138PubMed

Schmidt MR, Birkebaek N, Gonzalez I, Sunde L (2004) Barth syndrome without 3-methylglutaconic aciduria. Acta Paediatr 93(3):419–421PubMedCrossRef

Schroepfer GJ Jr (1981) Sterol biosynthesis. Annu Rev Biochem 50:585–621PubMedCrossRef

Sperl W, Jesina P, Zeman J et al (2006) Deficiency of mitochondrial ATP synthase of nuclear genetic origin. Neuromuscul Disord 12:821–829CrossRef

Valianpour F, Wanders RJA, Overmars H et al (2002) Cardiolipin deficiency in X-linked cardioskeletal myopathy and neutropenia (Barth syndrome, MIM 302060): a study in cultured skin fibroblasts. J Pediat 141:729–733PubMedCrossRef

Verny C, Amati-Bonneau P, Dubas F et al (2005) An OPA3 gene mutation is responsible for the disease associating optic atrophy and cataract with extrapyramidal signs. Rev Neurol (Paris) 161:451–454CrossRef

Walsh R, Conway H, Roche G et al (1997) 3-Methylglutaconic aciduria in pregnancy. Lancet 349(9054):776PubMedCrossRef

Walsh R, Conway H, Roche G, Mayne PD (1999) What is the origin of 3-methylglutaconic acid? J Inherit Metab Dis 22(3):251–255PubMedCrossRef

Weinstock SB, Kopito RR, Endemann G et al (1984) The shunt pathway of mevalonate metabolism in the isolated perfused rat liver. J Biol Chem 259(14):8939–8944PubMed

Wortmann S, Rodenburg RJ, Huizing M et al (2006) Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation. Mol Genet Metab 88(1):47–52PubMedCrossRef

Wortmann SB, Rodenburg RJT, Jonckheere A et al (2009) Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy. Brain 132(Pt 1):136–146PubMed

Wortmann SB, Kremer BH, Graham A et al (2010) 3-Methylglutaconic aciduria type I redefined; a syndrome with late onset leukoencephalopathy. Neurology [in press]

Yen TY, Hwu WL, Chien YH et al (2008) Acute metabolic decompensation and sudden death in Barth syndrome: report of a family and a literature review. Eur J Pediatr 167(8):941–944PubMedCrossRef

Title: The 3-methylglutaconic acidurias: what’s new?
Authors: Saskia B. Wortmann
Leo A. Kluijtmans
Udo F. H. Engelke
Ron A. Wevers
Eva Morava
Publication date: 01-01-2012
Publisher: Springer Netherlands
Published in: Journal of Inherited Metabolic Disease / Issue 1/2012
Print ISSN: 0141-8955
Electronic ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-010-9210-7

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