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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
1   Genetic Research Center, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India
2   Centre for Medical Genetics, Mumbai, Maharashtra, India
3   Sandor Life Sciences Pvt. Ltd., Hyderabad, Andhra Pradesh, India
,
Lakshmi Vasudevan
1   Genetic Research Center, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India
,
Pratima Kondurkar
1   Genetic Research Center, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India
,
Sarfaraj Niazi 
4   Biomedical Informatics Center of Indian Council of Medical Research, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India
,
Rita Christopher
5   Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka, India
,
Dhaval Solanki
6   Mantra Child and Neurology and Epilepsy Clinic, Bhavnagar, Gujarat, India
,
Pooja Dholakia
7   Government Medical College, Bhavnagar, Gujarat, India
,
Mamta Muranjan 
8   Department of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial hospital, Mumbai, Maharashtra, India
,
Mahesh Kamate
9   Department of Pediatric Neurology, Jawaharlal Nehru Medical College, Karnataka Lingayat Education University, Belgaum, Karnataka, India
,
Umesh Kalane
10   Pediatric Neurology Centre, Swargate, Pune, Maharashtra, India
,
Jayesh Sheth 
11   Foundation for Research in Genetics and Endocrinology Institute of Human Genetics, Foundation for Research in Genetics and Endocrinology House, Satellite, Ahmedabad, Gujarat, India
,
Vasundhara Tamhankar
2   Centre for Medical Genetics, Mumbai, Maharashtra, India
,
Reena Gulati
12   Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry, India
,
Madhavi Vasikarla 
13   Fernandez Hospital, Hyderabad, Telengana, India
,
Sumita Danda 
14   Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India
,
Shaik M. Naushad
3   Sandor Life Sciences Pvt. Ltd., Hyderabad, Andhra Pradesh, India
,
Katta M. Girisha
15   Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
,
Shekhar Patil
16   Apollo Hospital, Navi Mumbai, Maharashtra, India
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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

Supplementary Material



Publication History

Received: 06 May 2020

Accepted: 27 June 2020

Article published online:
02 September 2020

© 2020. Thieme. All rights reserved.

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