Abstract
Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.
Highlights
Tay Sachs disease (TSD) (MIM# 272800) is an autosomal recessive neurodegenerative disorder due to b-hexosaminidase A deficiency caused by mutation in the HEXA gene (MIM* 606869) encoding the a subunit of hexosaminidase A, a lysosomal enzyme composed of a and b polypeptides [1]
Fifteen families were included in the study
Neuroimaging in form of computed tomography (CT scan) or magnetic resonance imaging (MRI) of the brain of the proband was available in 10/13 patients and showed characteristic findings of putaminal hyperintensity and thalamic hypointensity in CT scan or T2 weighted images of MRI of the brain
Summary
Tay Sachs disease (TSD) (MIM# 272800) is an autosomal recessive neurodegenerative disorder due to b-hexosaminidase A deficiency caused by mutation in the HEXA gene (MIM* 606869) encoding the a subunit of hexosaminidase A, a lysosomal enzyme composed of a and b polypeptides [1]. 130 mutations have been reported so far in the HEXA gene to cause TSD and its variants, including single base substitutions, small deletion, duplications and insertions splicing alterations, complex gene rearrangement and partial large duplications (http://www.hgmd.cf.ac.uk/). Most of these mutations are private mutations and have been present in a single or few families. G.A(p.G269S) mutations are commonly found in non-Ashkenazi Jewish populations, along with an intron 9 splice site mutation (c.1073+1 G.A) and the 7.6 kb French Canadian deletion. About 35% of non-Jewish individuals carry one of the two pseudodeficiency alleles; c.739C.T (p.R247W) and c.745C.T (p.R249W), which are not associated with neurological manifestations, since
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