Abstract
Glutaric acidemia I (GA I, #231670) is one of the treatable, autosomal recessively inherited metabolic disorders. Macrocephaly, acute encephalitis-like crises, dystonia and characteristic frontotemporal atrophy are the hallmarks of this disease. In this communication, we present the clinical, biochemical and molecular profile of seventeen GA I patients from 15 unrelated families from India and report seven novel mutations in GCDH gene (c.281G>A (p.Arg94Gln), c.401A>G (p.Asp134Gly), c.662T>C (p.Leu221Pro), c.881G>C (p.Arg294Pro), c.1173dupG (p.Asn392Glufs*5), c.1238A>G (p.Tyr413Cys) and c.1241A>C (p.Glu414Ala)). Out of these, c.662T>C (p.Leu221Pro) in exon 8 and c.281G>A (p.Arg94Gln) allele in exon 4 were low excretor alleles, whereas c.1241A>C (p.Glu414Ala), c.1173dupG and c.1207C>T (p.His403Tyr) in exon 11 were high excretor alleles. We conclude that c.1204C>T (p.Arg402Trp) is probably the most common mutant allele. Exons 11 and 8 are the hot spot regions of GCDH gene in Indian patients with GA I. An early diagnosis and timely intervention can improve the underlying prognosis. Molecular confirmation is helpful in providing genetic counselling and prenatal diagnosis in subsequent pregnancy.
Competing interests: None declared
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Anikster Y, Shaag A, Joseph A, Mandel H, Ben-Zeev B, Christensen E, Elpeleg ON (1996) Glutaric aciduria type I in the Arab and Jewish communities in Israel. Am J Hum Genet 59:1012–1018
Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF et al (1999) Sensitivity and specificity of free and total glutaric and 3-hydroxyglutaric acid measurements by stable- isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 22:867–881
Biery BJ, Stein DE, Morton DH, Goodman SI (1996) Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish. Am J Hum Genet 59:1006–1011
Boy N, Haege G, Heringer J et al (2013) Low lysine diet in glutaric aciduria type I- effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis 36:525–533
Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S et al (1983) CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 4:187–217
Busquets C, Merinero B, Christensen E et al (2000a) Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically and biochemically distinct. Pediatr Res 48:315–322
Christensen E, Ribes A, Busquets C et al (1997) Compound heterozygosity in the glutaryl-CoA dehydrogenase gene with R227P mutation in one allele is associated with no or very low free glutarate excretion. J Inherit Metab Dis 20:383–386
Christensen E, Ribes A, Merinero B, Zschocke J (2004) Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27:861–868
Discovery Studio 2.0 (2006) Molecular modeling program package. Accelrys Software Inc, San Diego
Dwyer TM, Rao KS, Westover JB, Kim JJ, Frerman FE (2001) The function of Arg-94 in the oxidation and decarboxylation of glutaryl-CoA by human glutaryl-CoA dehydrogenase. J Biol Chem 276:133–138
Fu Z, Wang M, Paschke R, Rao KS, Freman 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 43:9674–9684
Garbade SF, Greenberg CR, Demirkol M et al (2014) Unravelling the complex MRI pattern in glutaric aciduria type I using statistical models-a cohort study in 180patients. J Inherit Metab Dis 37:763–773
Goodman SI, Stein DE, Schlesinger S et al (1998) Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations. Hum Mutat 12:141–144
Gregersen N, Brandt NJ, Christensen E, Gron I, Rasmussen K, Brandt S (1977) Glutaric aciduria: clinical and laboratory findings in two brothers. J Pediatr 90:740–745
Harting I, Neumaier-Probst E, Seitz A et al (2009) Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain 132:1764–1782
Haworth JC, Dilling LA, Seargeant LE et al (1991) Increased prevalence of hereditary metabolic diseases among native Indians in Manitoba and northwestern Ontario. CMAJ 145:123–129
Heringer J, Boy SP, Ensenauer R et al (2010) Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol 68:743–752
Hoffmann GF, Trefz FK, Barth PG et al (1991) Glutaryl-coenzyme A dehydrogenase deficiency: a distinct encephalopathy. Pediatrics 88:1194–1203
Kamate M, Patil V, Chetal V, Darak P, Hattiholi V (2012) Glutaric aciduria type I: a treatable neurometabolic disorder. Ann Indian Acad Neurol 15:31–34
Keyser B, Muehlhausen C, Dickmanns A, Christensen E, Muschol N, Ullrich K (2008) Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). Hum Mol Genet 17:3854–3863
Kolker S, Garbade S, Greenberg CR et al (2006) Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59:840–847
Kolker S, Garbade SF, Boy N et al (2007) Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by newborn screening in Germany. Pediatr Res 62:357–363
Kolker S, Christensen E, Leonard JV, Greenberg CR et al (2011) Diagnosis and management of glutaric aciduria type I–revised recommendations. J Inherit Metab Dis 34:677–694
Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 26:283–291
Lee CS, Chien YH, Peng SF et al (2013) Promising outcomes in glutaric aciduria type I patients detected by newborn screening. Metab Brain Dis 28:61–67
Lindner M, Kölker S, Schulze A, Christensen E, Greenberg CR, Hoffmann GF (2004) Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27:851–859
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Momany FA, Rone R (1992) Validation of the general purpose QUANTA ®3.2/CHARMm® force field. J Comput Chem 13:888–900
Morton DH, Bennett MJ, Seargeant LE, Nichter CA, Kelley RI (1991) Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genet 41:89–95
Mushimoto Y, Fukuda S, Hasegawa Y et al (2011) Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab 102:343–348
Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815
Schmiesing J, Schluter H, Ullrich K, Braulke T, Muhlhausen C (2014) Interaction of glutaric aciduria type 1-related glutaryl-CoA dehydrogenase with mitochondrial matrix proteins. PLoS One 9(2):e87715
Schwartz M, Christensen E, Superti-Furga A, Brandt NJ (1998) The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I. Hum Genet 102:452–458
Sen A, Pillay RS (2011) Striatal necrosis in type 1 glutaric aciduria: different stages in two siblings. J Pediatr Neurosci 6:146–148
Spassov VZ, Yan L, Flook PK (2007) The dominant role of side-chain backbone interactions in structural realization of amino acid-code. ChiRotor: a side-chain prediction algorithm based on side-chain backbone interactions. Protein Sci 16:494–506
Strauss KA, Puffenberger EG, Robinson DL et al (2003) Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet 121C:38–52
Viau K, Ernst SL, Vanzo RJ et al (2012) Glutaric acidemia type 1: outcomes before and after expanded newborn screening. Mol Genet Metab 106:430–438
Wang Q, Li X, Ding Y et al (2013) Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. Brain Dev pii: S0387-7604(13)00309-4
Zschocke J, Quak E, Guldberg P, Hoffmann GF (2000) Mutation analysis in glutaric aciduria type I. J Med Genet 37:177–181
Acknowledgement
Indian Council of Medical Research for funding
Dr Rita Christopher, NIMHANS Bangalore, Sandor proteomics, Hyderabad
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Georg Hoffmann
Electronic Supplementary Material
Appendices
Take-Home Message
Exons 11 and 8 of the GCDH gene seem to be the mutational hot spot regions in Indian patients with GA I.
Compliance with Ethics Guidelines
Conflict of Interest
Neerja Gupta, Pawan Kumar Singh, Manoj Kumar, Shivaram Shastri, Sheffali Gulati, Atin Kumar, Anuja Agarwala, Seema Kapoor, Mohandas Nair, Savita Sapra, Sudhisha Dubey, Ankur Singh, Punit Kaur and Madhulika Kabra declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
Details of the Contributions of Individual Authors
-
Planning: Neerja Gupta, Pawan Kumar Singh, Sudhisha Dubey, Madhulika Kabra
-
Conducting: Neerja Gupta, Pawan Kumar Singh, Shivaram Shastri, Sheffali, Gulati, Atin Kumar, Anuja Agarwala, Seema Kapoor, Ankur Singh, Mohandas Nair, Savita Sapra, Sudhisha Dubey, Manoj Kumar, Punit Kaur and Madhulika Kabra
-
Reporting: Neerja Gupta, Pawan Kumar Singh, Shivaram Shastri, Sheffali Gulati, Seema Kapoor, Manoj Kumar and Madhulika Kabra
-
Neerja Gupta and Pawan Kumar Singh participated equally and should share “first authorship”.
Rights and permissions
Copyright information
© 2014 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Gupta, N. et al. (2014). Glutaric Acidemia Type 1-Clinico-Molecular Profile and Novel Mutations in GCDH Gene in Indian Patients. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 21. JIMD Reports, vol 21. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_377
Download citation
DOI: https://doi.org/10.1007/8904_2014_377
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-47171-5
Online ISBN: 978-3-662-47172-2
eBook Packages: MedicineMedicine (R0)