Abstract
Glutaric aciduria type I (GA1; OMIM #231670) is an autosomal recessively inherited and treatable disorder characterized by the accumulation and irregular excretion of glutaric acid due to a defect in the glutaryl-CoA dehydrogenase enzyme involved in the catabolic pathways of l-lysine, l-hydroxylysine, and l-tryptophan. Glutaryl-CoA dehydrogenase is encoded by the GCDH gene (OMIM #608801), and several mutations in this gene are known to result in GA1. GA1 usually presents in the first 18–36 months of life with mild or severe acute encephalopathy, movement disorders, and striatal degeneration. Few cases of adult-onset GA1 have been described so far in the literature, often with non-specific and sometimes longstanding neurological symptoms. Since a preventive metabolic treatment is available, neurologists must be aware of this rare but likely underdiagnosed presentation, especially when typical neuroimaging features are identified. Here, we describe 35-year-old presenting with headache and subjective memory problems. There was no history of dystonic movement disorders. Neurological examination and neurocognitive tests were normal. Brain MRI scan revealed white matter abnormalities associated with subependymal nodules and mild frontotemporal hypoplasia suggestive of glutaric aciduria type 1 (GA1). Genetic testing confirmed the presence of homozygous c.1204C > T (p.R402W) variant in the GCDH gene, inherited from heterozygous parents.
Similar content being viewed by others
References
Lindner M, Kölker S, Schulze A, Christensen E, Greenberg CR, Hoffmann GF (2004) Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27(6):851–859
Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB, Burlina AP, Dixon M, Duran M, García Cazorla A, Goodman SI, Koeller DM, Kyllerman M, Mühlhausen C, Müller E, Okun JG, Wilcken B, Hoffmann GF, Burgard P (2011) Diagnosis and management of glutaric aciduria type I – revised recommendations. J Inherit Metab Dis 34(3):677–694
Zschocke J, Quak E, Guldberg P, Hoffmann GF (2000) Mutation analysis in glutaric aciduria type I. J Med Genet 37(3):177–181
Sauer SW, Okun JG, Fricker G, Mahringer A, Müller I, Crnic LR, Mühlhausen C, Hoffmann GF, Hörster F, Goodman SI, Harding CO, Koeller DM, Kölker S (2006) Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem 97(3):899–910
Funk CB, Prasad AN, Frosk P, Sauer S, Kölker S, Greenberg CR, del Bigio M (2005) Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain 128(Pt 4):711–722
Baric I et al (1998) Diagnosis and management of glutaric aciduria type I. J Inherit Metab Dis 21(4):326–340
Tuncel AT et al (2018) Organic acidurias in adults: late complications and management. J Inherit Metab Dis 41(5):765–776.a
Heringer J, Boy SP, Ensenauer R, Assmann B, Zschocke J, Harting I, Lücke T, Maier EM, Mühlhausen C, Haege G, Hoffmann GF, Burgard P, Kölker S (2010) Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol 68(5):743–752
Fu Z, Wang M, Paschke R, Rao KS, Frerman FE, Kim JJ (2004) Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions. Biochemistry 43(30):9674–9684
Berman HM et al (2000) The Protein Data Bank. Nucleic Acids Res 28(1):235–242
Krieger E et al (2009) Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: four approaches that performed well in CASP8. Proteins 77(Suppl 9):114–122
Tina KG, Bhadra R, Srinivasan N (2007) PIC: Protein Interactions Calculator. Nucleic Acids Res 35(Web Server issue):W473–W476
Choi Y, Chan AP (2015) PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31(16):2745–2747
Sim NL et al (2012) SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 40(Web Server issue):W452–W457
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249
Goodman SI and Frerman F.. (2001) Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. McGraw-Hill Inc.: New York, USA. p. 2195–2204
Kulkens S et al (2005) Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 64(12):2142–2144
Bahr O et al (2002) Adult onset glutaric aciduria type I presenting with a leukoencephalopathy. Neurology 59(11):1802–1804
Fraidakis MJ, Liadinioti C, Stefanis L, Dinopoulos A, Pons R, Papathanassiou M, Garcia-Villoria J, Ribes A (2015) Rare late-onset presentation of glutaric aciduria type I in a 16-year-old woman with a novel GCDH mutation. JIMD Rep 18:85–92
Badve MS, Bhuta S, McGill J (2015) Rare presentation of a treatable disorder: glutaric aciduria type 1. N Z Med J 128(1409):61–64
Boy N, Mengler K, Thimm E, Schiergens KA, Marquardt T, Weinhold N, Marquardt I, Das AM, Freisinger P, Grünert SC, Vossbeck J, Steinfeld R, Baumgartner MR, Beblo S, Dieckmann A, Näke A, Lindner M, Heringer J, Hoffmann GF, Mühlhausen C, Maier EM, Ensenauer R, Garbade SF, Kölker S (2018) Newborn screening: a disease-changing intervention for glutaric aciduria type 1. Ann Neurol 83(5):970–979
Wang Q, Li X, Ding Y, Liu Y, Song J, Yang Y (2014) Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. Brain Dev 36(9):813–822
Boy N et al (2017) Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity. Orphanet J Rare Dis 12
Herskovitz M, Goldsher D, Sela BA, Mandel H (2013) Subependymal mass lesions and peripheral polyneuropathy in adult-onset glutaric aciduria type I. Neurology 81(9):849–850
Kolker S et al (2015) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis 38(6):1059–1074
Korman SH, Jakobs C, Darmin PS, Gutman A, van der Knaap M, Ben-Neriah Z, Dweikat I, Wexler ID, Salomons GS (2007) Glutaric aciduria type 1: clinical, biochemical and molecular findings in patients from Israel. Eur J Paediatr Neurol 11(2):81–89
Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF (1999) Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 22(8):867–881
Christensen E, Ribes A, Merinero B, Zschocke J (2004) Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27(6):861–868
Kolker S et al (2006) Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59(6):840–847
Hedlund, G.L., N. Longo, and M. Pasquali, Glutaric acidemia type 1. Am J Med Genet C Semin Med Genet, 2006. 142c(2): p. 86–94
Heringer J et al (2015) Newborn screening for glutaric aciduria type I: benefits and limitations. Int J Neonatal Screen 1(2):57–68
Westover JB, Goodman SI, Frerman FE (2003) Pathogenic mutations in the carboxyl-terminal domain of glutaryl-CoA dehydrogenase: effects on catalytic activity and the stability of the tetramer. Mol Genet Metab 79(4):245–256
Keyser B, Mühlhausen C, Dickmanns A, Christensen E, Muschol N, Ullrich K, Braulke T (2008) Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). Hum Mol Genet 17(24):3854–3863
Kolker S et al (2007) Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis 30(1):5–22
Bijarnia S, Wiley V, Carpenter K, Christodoulou J, Ellaway CJ, Wilcken B (2008) Glutaric aciduria type I: outcome following detection by newborn screening. J Inherit Metab Dis 31(4):503–507
Boneh A, Beauchamp M, Humphrey M, Watkins J, Peters H, Yaplito-Lee J (2008) Newborn screening for glutaric aciduria type I in Victoria: treatment and outcome. Mol Genet Metab 94(3):287–291
Kolker S et al (2015) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 38(6):1041–1057
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gelener, P., Severino, M., Diker, S. et al. Adult-onset glutaric aciduria type I: rare presentation of a treatable disorder. Neurogenetics 21, 179–186 (2020). https://doi.org/10.1007/s10048-020-00610-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-020-00610-9