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

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

J Pediatr Genet. 2021 Sep;10(3):213-221. doi: 10.1055/s-0040-1715528. Epub 2020 Sep 2.

Authors

Parag M Tamhankar^{1

2

3}, Lakshmi Vasudevan¹, Pratima Kondurkar¹, Sarfaraj Niazi⁴, Rita Christopher⁵, Dhaval Solanki⁶, Pooja Dholakia⁷, Mamta Muranjan⁸, Mahesh Kamate⁹, Umesh Kalane¹⁰, Jayesh Sheth¹¹, Vasundhara Tamhankar², Reena Gulati¹², Madhavi Vasikarla¹³, Sumita Danda¹⁴, Shaik M Naushad³, Katta M Girisha¹⁵, Shekhar Patil¹⁶

Affiliations

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.
⁴ Biomedical Informatics Center of Indian Council of Medical Research, National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India.
⁵ Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka, India.
⁶ Mantra Child and Neurology and Epilepsy Clinic, Bhavnagar, Gujarat, India.
⁷ Government Medical College, Bhavnagar, Gujarat, India.
⁸ Department of Pediatrics, Seth Gordhandas Sunderdas Medical College and King Edward Memorial hospital, Mumbai, Maharashtra, India.
⁹ Department of Pediatric Neurology, Jawaharlal Nehru Medical College, Karnataka Lingayat Education University, Belgaum, Karnataka, India.
¹⁰ Pediatric Neurology Centre, Swargate, Pune, Maharashtra, India.
¹¹ Foundation for Research in Genetics and Endocrinology Institute of Human Genetics, Foundation for Research in Genetics and Endocrinology House, Satellite, Ahmedabad, Gujarat, India.
¹² Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry, India.
¹³ Fernandez Hospital, Hyderabad, Telengana, India.
¹⁴ Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India.
¹⁵ Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India.
¹⁶ Apollo Hospital, Navi Mumbai, Maharashtra, India.

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: GCDH; glutaric aciduria; in silico; novel; variant.