Clinical Characteristics, Molecular Profile, and Outcomes in Indian Patients with Glutaric Aciduria Type 1

Parag M. Tamhankar; Lakshmi Vasudevan; Pratima Kondurkar; Sarfaraj Niazi; Rita Christopher; Dhaval Solanki; Pooja Dholakia; Mamta Muranjan; Mahesh Kamate; Umesh Kalane; Jayesh Sheth; Vasundhara Tamhankar; Reena Gulati; Madhavi Vasikarla; Sumita Danda; Shaik M. Naushad; Katta M. Girisha; Shekhar Patil

doi:10.1055/s-0040-1715528

Journal of Pediatric Genetics, Inhaltsverzeichnis

J Pediatr Genet 2021; 10(03): 213-221
DOI: 10.1055/s-0040-1715528

Original Article

Clinical Characteristics, Molecular Profile, and Outcomes in Indian Patients with Glutaric Aciduria Type 1

Parag M. Tamhankar

¹Genetic Research Center, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India

²Centre for Medical Genetics, Mumbai, Maharashtra, India

³Sandor Life Sciences Pvt. Ltd., Hyderabad, Andhra Pradesh, India

,

Lakshmi Vasudevan

¹Genetic Research Center, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India

,

Pratima Kondurkar

¹Genetic Research Center, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India

,

Sarfaraj Niazi

⁴Biomedical Informatics Center of Indian Council of Medical Research, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India

,

Rita Christopher

⁵Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka, India

,

Dhaval Solanki

⁶Mantra Child and Neurology and Epilepsy Clinic, Bhavnagar, Gujarat, India

,

Pooja Dholakia

⁷Government Medical College, Bhavnagar, Gujarat, India

,

Mamta Muranjan

⁸Department of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial hospital, Mumbai, Maharashtra, India

,

Mahesh Kamate

⁹Department of Pediatric Neurology, Jawaharlal Nehru Medical College, Karnataka Lingayat Education University, Belgaum, Karnataka, India

,

Umesh Kalane

¹⁰Pediatric Neurology Centre, Swargate, Pune, Maharashtra, India

,

Jayesh Sheth

¹¹Foundation for Research in Genetics and Endocrinology Institute of Human Genetics, Foundation for Research in Genetics and Endocrinology House, Satellite, Ahmedabad, Gujarat, India

,

Vasundhara Tamhankar

²Centre for Medical Genetics, Mumbai, Maharashtra, India

,

Reena Gulati

¹²Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry, India

,

Madhavi Vasikarla

¹³Fernandez Hospital, Hyderabad, Telengana, India

,

Sumita Danda

¹⁴Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India

,

Shaik M. Naushad

³Sandor Life Sciences Pvt. Ltd., Hyderabad, Andhra Pradesh, India

,

Katta M. Girisha

¹⁵Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India

,

Shekhar Patil

¹⁶Apollo Hospital, Navi Mumbai, Maharashtra, India

› Institutsangaben

Abstract

Glutaric acidemia type 1 (GA-1, OMIM 231670) is an autosomal recessive inborn error of metabolism caused by the deficiency of glutaryl-coenzyme A (CoA) dehydrogenase with most children presenting in infancy with encephalopathy, dystonia, and macrocephaly. In this article, we presented the clinical characteristics, molecular profile, and outcomes in 29 unrelated families with affected children (30 cases total). The mean age at onset of illness was 10 months (±14.58), whereas the mean age at referral for molecular diagnosis was 29.44 months (±28.11). Patients were residents of nine different states of India. Clinical presentation varied from acute encephalitis followed by neuroregression and chronic/insidious developmental delay. Neurological sequelae varied from asymptomatic (no sequelae, 2 patients) to moderate (5 patients) and severe (23 patients) sequelae. All patients underwent blood tandem mass spectrometry (TMS on dried blood spots) and/or urine gas chromatography mass spectrometry (GCMS). Neuroimaging demonstrated batwing appearance in 95% cases. Sanger's sequencing of GCDH, covering all exons and exon–intron boundaries, was performed for all patients. Variants identified include 15 novel coding variants: p.Met100Thr, p.Gly107Ser, p.Leu179Val, p.Pro217Ser, p. Phe236Leufs*107, p.Ser255Pro, p.Met266Leufs*2, p.Gln330Ter, p.Thr344Ile, p.Leu345Pro, p.Lys377Arg, p.Leu424Pro, p.Asn373Lys, p.Lys377Arg, p.Asn392Metfs*9, and nine known genetic variants such as p.Arg128Gln, p.Leu179Arg, p.Trp225Ter, p.Met339Val, p.Gly354Ser, p.Arg402Gln, p.Arg402Trp, p.His403Tyr, and p.Ala433Val (Ensembl transcript ID: ENST00000222214). Using in silico analysis, genetic variants were shown to be affecting the residues responsible for homotetramer formation of the glutaryl-CoA dehydrogenase protein. Treatment included oral carnitine, riboflavin, protein-restricted diet, lysine-deficient special formulae, and management of acute crises with intravenous glucose and hydration. However, the mortality (9/30, 27.58%) and morbidity was high in our cohort with only two patients affording the diet. Our study is the largest multicentric, genetic variant–proven series of glutaric aciduria type 1 from India till date.

Keywords

glutaric aciduria - GCDH - novel - variant - in silico

Volltext

Referenzen

References
1 Fu Z, Wang M, Paschke R, Rao KS, Frerman FE, Kim JJ. Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions. Biochemistry 2004; 43 (30) 9674-9684
2 Boy N, Mühlhausen C, Maier EM. et al; Additional individual contributors. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis 2017; 40 (01) 75-101
3 Altschul SF, Madden TL, Schäffer AA. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 1997; 25 (17) 3389-3402
4 Kleinberger J, Maloney KA, Pollin TI, Jeng LJ. An openly available online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of sequence variants. Genet Med 2016; 18 (11) 1165
5 Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012; 40 (Web Server issue): W452-7
6 Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013; 7: Unit7.20 . Doi: 10.1002/0471142905.hg0720s76
7 Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010; 7 (08) 575-576
8 Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 2011; 39 (17) e118
9 Yue P, Melamud E, Moult J. SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinformatics 2006; 7: 166
10 Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 2010; 11: 548
11 Discovery Studio Modeling Environment, Release 4.5. 2015. BIOVIA, Dassault Systèmes, San Diego
12 Tina KG, Bhadra R, Srinivasan N. PIC: protein interactions calculator. Nucleic Acids Res 2007;35(Web Server issue): W473-6. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436848/
13 DeLano WL. The PyMOL Molecular Graphics System, San Carlos. Accessed July 19, 2020 at: https://www.scirp.org/(S(vtj3fa45qm1ean45vvffcz55))/reference/ReferencesPapers.aspx?ReferenceID=1958992
14 Nair MKC, George B, Philip E, Lekshmi MA, Haran JC, Sathy N. Trivandrum developmental screening chart. Indian Pediatr 1991; 28 (08) 869-872
15 Kamat VV. Measuring Intelligence of Indian Children. 4th ed. London, United Kingdom: Oxford University Press; 1968
16 Kurkina MV, Mihaylova SV, Baydakova GV. et al. Molecular and biochemical study of glutaric aciduria type 1 in 49 Russian families: nine novel mutations in the GCDH gene. Metab Brain Dis 2020; 35 (06) 1009-1016
17 Westover JB, Goodman SI, Frerman FE. Pathogenic mutations in the carboxyl-terminal domain of glutaryl-CoA dehydrogenase: effects on catalytic activity and the stability of the tetramer. Mol Genet Metab 2003; 79 (04) 245-256
18 Rao KS, Albro M, Zirrolli JA, Vander Velde D, Jones DN, Frerman FE. Protonation of crotonyl-CoA dienolate by human glutaryl-CoA dehydrogenase occurs by solvent-derived protons. Biochemistry 2005; 44 (42) 13932-13940
19 Mushimoto Y, Fukuda S, Hasegawa Y. et al. Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab 2011; 102 (03) 343-348
20 Zayed H, El Khayat H, Tomoum H. et al. Clinical, biochemical, neuroradiological and molecular characterization of Egyptian patients with glutaric acidemia type 1. Metab Brain Dis 2019; 34 (04) 1231-1241
21 Gupta N, Singh PK, Kumar M. et al. Glutaric acidemia type 1-clinico-molecular profile and novel mutations in GCDH gene in indian patients. JIMD Rep 2015; 21: 45-55
22 Radha Rama Devi A, Ramesh VA, Nagarajaram HA, Satish SP, Jayanthi U, Lingappa L. Spectrum of mutations in glutaryl-CoA dehydrogenase gene in glutaric aciduria type I--study from South India. Brain Dev 2016; 38 (01) 54-60
23 Tp KV, Muntaj S, Devaraju KS, Kamate M, Vedamurthy AB. Genetic screening of selected disease-causing mutations in glutaryl-CoA dehydrogenase gene among Indian patients with glutaric aciduria type I. J Pediatr Genet 2017; 6 (03) 142-148
24 Guerreiro G, Faverzani J, Jacques CED. et al. Oxidative damage in glutaric aciduria type I patients and the protective effects of l-carnitine treatment. J Cell Biochem 2018; 119 (12) 10021-10032
25 Bishop FS, Liu JK, McCall TD, Brockmeyer DL. Glutaric aciduria type 1 presenting as bilateral subdural hematomas mimicking nonaccidental trauma. Case report and review of the literature. J Neurosurg 2007; 106 (3, suppl) 222-226
26 Demailly D, Vianey-Saban C, Acquaviva C. et al. Atypical glutaric aciduria type I with hemidystonia and asymmetric radiological findings misdiagnosed as an Ischemic Stroke. Mov Disord Clin Pract (Hoboken) 2018; 5 (04) 436-438
27 Kamate M, Patil V, Chetal V, Darak P, Hattiholi V. Glutaric aciduria type I: a treatable neurometabolic disorder. Ann Indian Acad Neurol 2012; 15 (01) 31-34
28 Vasikarla M, Pandita A, Sharma D, Pratap OT, Murki S. Diagnosis and genetic analysis of glutaric acidaemia type I: very rarely seen inborn error of metabolism. Sultan Qaboos Univ Med J 2015; 15 (04) e572-e573
29 Goodman SI, Gallegos DA, Pullin CJ. et al. Antenatal diagnosis of glutaric acidemia. Am J Hum Genet 1980; 32 (05) 695-699
30 Peng HH, Shaw SW, Huang KG. Prenatal diagnosis of fetal glutaric aciduria type 1 with rare compound heterozygous mutations in GCDH gene. Taiwan J Obstet Gynecol 2018; 57 (01) 137-140
31 Shaik M, TP KV, Kamate M, AB V. Is Expanded Newborn Screening Adequate to Detect Indian Biochemical Low Excretor Phenotype Patients of Glutaric Aciduria Type I?. Indian J Pediatr 2019; 86 (11) 995-1001

Zusatzmaterial