First Report of Missense Mutation at c.1664A>G (p.Y555C) in Krabbe Disease: Genomic Analysis in the Diagnosis of Genetic Disorders

Sabitha Vadakedath¹ and Venkataramana Kandi^2,

¹Department of Biochemistry, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India

²Department of Microbiology, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India

Cite this paper

Sabitha Vadakedath and Venkataramana Kandi. First Report of Missense Mutation at c.1664A>G (p.Y555C) in Krabbe Disease: Genomic Analysis in the Diagnosis of Genetic Disorders. American Journal of Clinical Medicine Research. 2020; 8(1):1-4. doi: 10.12691/AJCMR-8-1-1

Abstract

OBJECTIVES: Genetic disorders contribute to severe morbidity and mortality among neonates and children. Most of these conditions could be attributed to the inheritance of defective gene/chromosome from the parents. Consanguinity, or coming from the same ancestral lineage is considered as a predisposing factor for the development of genetic anomalies. Krabbe disease or globoid cell leukodystrophy is an autosomal recessive disorder due to the mutation of the gene coding for galactosyl ceramidase or galactocerebrosidase (GALC gene). We present a brief report of Krabbe disease attributed to a missense mutation at C.1664A>G (p.Y555C) in exon 14, which was previously not reported in the literature as a pathogenic variant. METHODS: A combination of clinical symptoms and laboratory diagnostic methods were used to diagnose the Krabbe disease/globoid cell leukodystrophy. The deoxyribonucleic acid (DNA) sequencing for GALC gene and flanking intronic regions and an enzyme analysis was done to confirm Krabbe disease. Mutational analysis of GALC gene and flanking intronic regions was performed (Sequence analysis of 12 exons (exons-2, 3, 4, 6, 8, 9, 11, 12, 13, 14, 15, 16 & 18). RESULTS: A homozygous silent mutation at c.1350C>T (p.5450S) in exon 13, a homozygous missense mutation at c.1664C >G (p.Y555C) in exon 14, homozygous silent mutation at c. 1685T>C (p. I562I) in exon 15, homozygous silent mutation at c. 1698A>T (p. V566V) in exon 15, and a homozygous intronic variant IVS15+5C>G was observed. CONCLUSION: A homozygous missense mutation at c.1664C >G (p.Y555C) in exon 14 was observed along with undetectable enzyme activities of β-galactocerebrosidase for the first time in a patient with Krabbe disease.

Keywords

genetic disorders, India, Krabbe disease, globoid cell leukodystrophy, C.1664A>G (p.Y555C), missense mutation, neurological abnormalities

Copyright

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References

[1]	Genetic diseases in children. https://www.uptodate.com/contents/table-of- contents/pediatrics/genetic-diseases-in-children. Last accessed 11, January 2018.
[2]	Wenger DA. Krabbe Disease. 2000 Jun 19 [Updated 2011 Mar 31]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. Gene Reviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1238/.
[3]	Pavuluri P, Vadakedath S, Gundu R, Uppulety S, Kandi V. Krabbe Disease: Report of a Rare Lipid Storage and Neurodegenerative Disorder. Muacevic A, Adler JR, eds. Cureus. 2017; 9(1): e949.
[4]	Singhal BS. Leukodystrophies: Indian scenario. Indian J Pediatr. 2005 Apr; 72(4): 315-8.
[5]	Sehgal R, Sharma S, Sankhyan N, Kumar A, Gulati S. Selective corticospinal tract involvement in late-onset Krabbe disease. Neurology. 2011 Jul 19; 77(3): e20.
[6]	Kamate M, Hattiholi V. Normal neuroimaging in early-onset Krabbe disease. Pediatr Neurol. 2011 May; 44(5): 374-6.
[7]	Kamate M, Hattiholi V. Predominant corticospinal tract involvement in early-onset Krabbe disease. Pediatr Neurol. 2011 Feb; 44(2): 155-6.
[8]	Ganesan K, Desai S, Hegde A. Multiple cranial nerve enhancement: uncommon imaging finding in early infantile Krabbe's disease. J Neuroimaging. 2010 Apr; 20(2): 195-7.
[9]	Nagar VA, Ursekar MA, Krishnan P, Jankharia BG. Krabbe disease: unusual MRI findings. Pediatr Radiol. 2006 Jan; 36(1): 61-4.
[10]	Tullu MS, Muranjan MN, Kondurkar PP, Bharucha BA. Krabbe disease--clinical profile. Indian Pediatr. 2000 Sep; 37(9): 939-46.
[11]	Gulati S, Jain P, Chakrabarty B, Kumar A, Gupta N, Kabra M. The spectrum of leukodystrophies in children: Experience at a tertiary care centre from North India. Annals of Indian Academy of Neurology. 2016; 19(3): 332-338.
[12]	Zhao S, Zhan X, Wang Y, Ye J, Han L, Qiu W, Gao X, Gu X, Zhang H. Large-scale study of clinical and biochemical characteristics of Chinese patients diagnosed with Krabbe disease. Clin Genet. 2018 Feb; 93(2): 248-254.