Dual genetic findings in a child with focal epilepsy; severe hexosaminidase A deficiency and NPRL3 gene: A case report
TL;DR
This case emphasises the importance of incidental findings identified through broad genetic testing, and the need for careful genotype–phenotype correlation with multiple variant detection, in children born to consanguineous parents with mild speech delay and seizures.
Abstract
Tay-Sachs disease (TSD) is a rare autosomal recessive lysosomal storage disorder caused by hexosaminidase A ( HEXA) mutations. HEXA-related disorders demonstrate considerable phenotypic variability, and reduced enzyme activity may be detected before overt clinical manifestations. We report a 3-year 6-month-old male born to consanguineous parents with mild speech delay and seizures. Neuroimaging and electroencephalography were abnormal. Whole exome sequencing identified a heterozygous pathogenic copy number variant and an incidental pathogenic HEXA variant. Enzyme assay was positive, yet the child was asymptomatic for TSD. This case highlights the need for careful genotype–phenotype correlation with multiple variant detection. While NPRL3 haploinsufficiency explains seizure, the HEXA deficiency represents a presymptomatic metabolic condition, highlighting the importance of genomic testing and the spectrum of GM2 gangliosidosis. Early detection of β-HEXA deficiency before the onset allows better counselling and prognosis. This case emphasises the importance of incidental findings identified through broad genetic testing.