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Metabolic Brain Disease

, Volume 32, Issue 5, pp 1417–1426 | Cite as

Genotype-phenotype correlation in 18 Egyptian patients with glutaric acidemia type I

  • Ahmed Mosaeilhy
  • Magdy M. Mohamed
  • George Priya Doss C
  • Heba S. A. El Abd
  • Radwa Gamal
  • Osama K. ZakiEmail author
  • Hatem ZayedEmail author
Original Article

Abstract

Glutaric acidemia I (GAI) is an autosomal recessive metabolic disease caused by a deficiency of glutaryl-CoA dehydrogenase enzyme (GCDH). Patients with GAI are characterized by macrocephaly, acute encephalitis-like crises, dystonia and frontotemporal atrophy. In this study, we investigated 18 Egyptian patients that were diagnosed with GAI based on their clinical, neuroradiological, and biochemical profiles. Of the 18 patients, 16 had developmental delay and/or regression, dystonia was prominent in 75% of the cases, and three patients died. Molecular genetics analysis identified 14 different mutations in the GCDH gene in the 18 patients, of the 14 mutations, nine were missense, three were in the 3′-Untranslated Region (3′-UTR), one was nonsense, and one was a silent mutation. Four novel mutations were identified (c.148 T > A; p.Trp50Arg, c.158C > A; p.Pro53Gln, c.1284C > G; p.Ile428Met, and c.1189G > T; p.Glu397*) that were all absent in 300 normal chromosomes. The 3′-UTR mutation (c.*165A > G; rs8012), was the most frequent mutation observed (0.5; 18/36), followed by the most common mutation among Caucasian patients (p.Arg402Trp; rs121434369) with allele frequency of 0.36 (13/36), and the 3′-UTR mutation (c.*288G > T; rs9384, 0.22; 8/16). The p.Arg257Gln mutation was found with allele frequency of ~0.17 (6/36). The marked homozygosity observed in our patients is probably due to the high level of consanguinity that is observed in 100% of the cases. We used nine in silico prediction tools to predict the pathogenicity (SIFT, PhD-SNP, SNAP, Meta-SNP, PolyPhen2, and Align GVGD) and protein stability (I-Mutant2.0, Mupro, and istable) of the nine missense mutants. The mutant p.Arg402Trp was predicted to be most deleterious by all the six pathogenicity prediction tools and destabilizing by all the three-stability prediction tools, and highly conserved by the ConSurf server. Using the clinical, biochemical, family history of the 18 patients, and the in silico analysis of the missense mutations, our study showed a mix of conclusive and inconclusive genotype-phenotype correlations among our patient’s cohort and suggests the usefulness of using various sophisticated computational analysis to be utilized for future variant classifications in the genetic clinics.

Keywords

Glutaric acidemia type I Glutaryl-CoA dehydrogenase Variant assessment Genotype-phenotype correlation Computational analysis Organic acidemia Egypt 

Notes

Compliance with ethical standards

Conflict of interest

All author declare that they have no conflict of interest.

References

  1. Adzhubei, I., D. M. Jordan and S. R. Sunyaev (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7: Unit7.20.Google Scholar
  2. Ali SK, Sneha P, Priyadharshini Christy J, Zayed H, George Priya Doss C (2016) Molecular dynamics-based analyses of the structural instability and secondary structure of the fibrinogen gamma chain protein with the D356V mutation. J Biomol Struct Dyn:1–11Google Scholar
  3. Baric I, Wagner L, Feyh P, Liesert M, Buckel W et al (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 22:867–881CrossRefPubMedGoogle Scholar
  4. 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 59:1006–1011PubMedPubMedCentralGoogle Scholar
  5. Bijarnia S, Wiley V, Carpenter K, Christodoulou J, Ellaway CJ et al (2008) Glutaric aciduria type I: outcome following detection by newborn screening. J Inherit Metab Dis 31:503–507CrossRefPubMedGoogle Scholar
  6. Boneh A, Beauchamp M, Humphrey M, Watkins J, Peters H et al (2008) Newborn screening for glutaric aciduria type I in Victoria: treatment and outcome. Mol Genet Metab 94:287–291CrossRefPubMedGoogle Scholar
  7. Bromberg Y, Rost B (2007) SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res 35:3823–3835CrossRefPubMedPubMedCentralGoogle Scholar
  8. Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C et al (1985) Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 35:73–77CrossRefPubMedGoogle Scholar
  9. Busquets C, Merinero B, Christensen E, Gelpi JL, Campistol J et al (2000) Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct. Pediatr Res 48:315–322CrossRefPubMedGoogle Scholar
  10. Capriotti E, Fariselli P, Casadio R (2005) I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 33:W306–W310CrossRefPubMedPubMedCentralGoogle Scholar
  11. Capriotti E, Calabrese R, Casadio R (2006) Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics 22:2729–2734CrossRefPubMedGoogle Scholar
  12. Capriotti E, Altman RB, Bromberg Y (2013) Collective judgment predicts disease-associated single nucleotide variants. BMC Genomics 14(Suppl 3):S2CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chace DH, Kalas TA, Naylor EW (2003) Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem 49:1797–1817CrossRefPubMedGoogle Scholar
  14. Chen CW, Lin J, Chu YW (2013) iStable: off-the-shelf predictor integration for predicting protein stability changes. BMC Bioinformatics 14(Suppl 2):S5CrossRefGoogle Scholar
  15. Cheng J, Randall A, Baldi P (2006) Prediction of protein stability changes for single-site mutations using support vector machines. Proteins 62:1125–1132CrossRefPubMedGoogle Scholar
  16. Christensen E, Ribes A, Merinero B, Zschocke J (2004) Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27:861–868CrossRefPubMedGoogle Scholar
  17. Doss CG, Alasmar DR, Bux RI, Sneha P, Bakhsh FD et al (2016) Genetic epidemiology of glucose-6-dehydrogenase deficiency in the Arab world. Sci Rep 6:37284CrossRefPubMedPubMedCentralGoogle Scholar
  18. Georgiou T, Nicolaidou P, Hadjichristou A, Ioannou R, Dionysiou M et al (2014) Molecular analysis of Cypriot patients with Glutaric aciduria type I: identification of two novel mutations. Clin Biochem 47:1300–1305CrossRefPubMedGoogle Scholar
  19. Glaser F, Pupko T, Paz I, Bell RE, Bechor-Shental D et al (2003) ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics 19:163–164CrossRefPubMedGoogle Scholar
  20. Goodman SI, Stein DE, Schlesinger S, Christensen E, Schwartz M et al (1998) Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations. Hum Mutat 12:141–144CrossRefPubMedGoogle Scholar
  21. Greenberg CR, Prasad AN, Dilling LA, Thompson JR, Haworth JC et al (2002) Outcome of the first 3-years of a DNA-based neonatal screening program for glutaric acidemia type 1 in Manitoba and northwestern Ontario, Canada. Mol Genet Metab 75:70–78CrossRefPubMedGoogle Scholar
  22. Gupta N, Singh PK, Kumar M, Shastri S, Gulati S et al (2015) Glutaric Acidemia type 1-Clinico-molecular profile and novel mutations in GCDH Gene in Indian patients. JIMD Rep 21:45–55CrossRefPubMedPubMedCentralGoogle Scholar
  23. Heringer J, Boy SP, Ensenauer R, Assmann B, Zschocke J et al (2010) Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol 68:743–752CrossRefPubMedGoogle Scholar
  24. Hoffmann GF, Trefz FK, Barth PG, Bohles HJ, Biggemann B et al (1991) Glutaryl-coenzyme a dehydrogenase deficiency: a distinct encephalopathy. Pediatrics 88:1194–1203PubMedGoogle Scholar
  25. Kim HS, Yu HJ, Lee J, Park HD, Kim JH et al (2014) A Korean patient with glutaric aciduria type 1 with a novel mutation in the glutaryl CoA dehydrogenase gene. Ann Clin Lab Sci 44:213–216PubMedGoogle Scholar
  26. Kolker S, Garbade SF, Greenberg CR, Leonard JV, Saudubray JM et al (2006) Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59:840–847CrossRefPubMedGoogle Scholar
  27. Kolker S, Christensen E, Leonard JV, Greenberg CR, Burlina AB et al (2007) Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis 30:5–22CrossRefPubMedGoogle Scholar
  28. Korman SH, Jakobs C, Darmin PS, Gutman A, van der Knaap MS et al (2007) Glutaric aciduria type 1: clinical, biochemical and molecular findings in patients from Israel. Eur J Paediatr Neurol 11:81–89CrossRefPubMedGoogle Scholar
  29. Lindner M, Kolker S, Schulze A, Christensen E, Greenberg CR et al (2004) Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27:851–859CrossRefPubMedGoogle Scholar
  30. Mohammad SA, Abdelkhalek HS, Ahmed KA, Zaki OK (2015) Glutaric aciduria type 1: neuroimaging features with clinical correlation. Pediatr Radiol 45:1696–1705CrossRefPubMedGoogle Scholar
  31. Moseilhy A, Hassan MM, El Abd HS, Mohammad SA, El Bekay R et al (2016) Severe neurological manifestations in an Egyptian patient with a novel frameshift mutation in the Glutaryl-CoA dehydrogenase gene. Metab Brain DisGoogle Scholar
  32. Mushimoto Y, Fukuda S, Hasegawa Y, Kobayashi H, Purevsuren J et al (2011) Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab 102:343–348CrossRefPubMedGoogle Scholar
  33. Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814CrossRefPubMedPubMedCentralGoogle Scholar
  34. Sneha P, Kumar D, Tanwar H, Siva R, Doss GP et al (2017) Structural analysis of G1691S variant in the human filamin b gene responsible for Larsen syndrome: a comparative computational approach. J Cell BiochemGoogle Scholar
  35. Strauss KA, Puffenberger EG, Robinson DL, Morton DH (2003) Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C Semin Med Genet 121c:38–52CrossRefPubMedGoogle Scholar
  36. Tang NL, Hui J, Law LK, Lam YY, Chan KY et al (2000) Recurrent and novel mutations of GCDH gene in Chinese glutaric acidemia type I families. Hum Mutat 16:446CrossRefPubMedGoogle Scholar
  37. Tavtigian SV, Deffenbaugh AM, Yin L, Judkins T, Scholl T et al (2006) Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43:295–305CrossRefPubMedGoogle Scholar
  38. Thong MK, Yunus ZM (2008) Spectrum of inherited metabolic disorders in Malaysia. Ann Acad Med Singap 37:66–65PubMedGoogle Scholar
  39. Wang Q, Li X, Ding Y, Liu Y, Song J et al (2014) Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. Brain and Development 36:813–822CrossRefPubMedGoogle Scholar
  40. Zaki OK, El Abd HS, Mohamed SA, Zayed H (2016) Novel mutation in an Egyptian patient with infantile Canavan disease. Metab Brain Dis 31:573–577CrossRefPubMedGoogle Scholar
  41. Zaki OK, Krishnamoorthy N, El Abd HS, Harche SA, Mattar RA et al (2017) Two patients with Canavan disease and structural modeling of a novel mutation. Metab Brain Dis 32:171–177CrossRefPubMedGoogle Scholar
  42. Zschocke J, Quak E, Guldberg P, Hoffmann GF (2000) Mutation analysis in glutaric aciduria type I. J Med Genet 37:177–181CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Medical Genetics Unit, Pediatric Department, Faculty of MedicineAin-Shams UniversityCairoEgypt
  2. 2.Department of Biochemistry, Faculty of MedicineAin Shams UniversityCairoEgypt
  3. 3.Department of Integrative Biology, School of BioSciences and TechnologyVIT- UniversityVelloreIndia
  4. 4.Genetics UnitAin Shams Pediatrics HospitalCairoEgypt
  5. 5.Department of Biomedical Sciences, College of Health and SciencesQatar UniversityDohaQatar

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