Molecular analysis of theHEXAgene in Italian patients with infantile and late Onset Tay-Sachs disease: detection of fourteen novel alleles

Abstract

Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the hexosaminidase A deficiency. We report the molecular characterization performed on 31 Italian patients, 22 with the infantile, acute form of TSD and nine patients with the subacute juvenile form, biochemically classified as B1 Variant. Of the 29 different alleles identified, fourteen were due to 15 novel mutations, two being in-cis on a new complex allele. The new alleles caused four frameshifts, three premature stop codons, three amino acid changes, two amino acid deletions and two splicing alterations. As previously reported, the c.533G>A (p.R178H) mutation was present either in homozygosity or as compound heterozygote, in all the patients with the late onset TSD form (B1 Variant); the allele frequency in this group is discussed by comparison with that found in infantile TSD.

GM2 gangliosidoses in Spain: Analysis of the HEXA and HEXB genes in 34 Tay–Sachs and 14 Sandhoff patients

“…Some of them have been reported as frequent in some populations, for example the 4-bp duplication c.1274_1277dupTATC in exon 11 was found in 80-98% of the Ashkenazi Jewish carriers (Myerowitz and Costigan, 1988;Triggs-Raine et al, 1990, the 7.6 Kb deletion including exon 1 was found to be the major mutation causing TSD in the French Canadian population (Myerowitz and Hogikyan, 1986), 50% of the Moroccan Jewish carriers presented the p.F305del mutation (Navon and Proia, 1991); and the abnormal splicing mutation c.1073 + 1G> A (IVS9 + 1G> A) has been reported to represent 15% of the alleles of non-Jewish TaySachs carriers (Akerman et al, 1992). The p.R178H B1 variant associated mutation has been also reported to be highly frequent, reaching 95% and 75% of the alleles in the Portuguese and Italian patients with this variant, respectively (Dos Santos et al, 1991;Montalvo et al, 2005).…”

Molecular analysis of HEXA gene in Argentinean patients affected with Tay–Sachs disease: Possible common origin of the prevalent c.459+5A>G mutation

“…In light of these data, it is not surprising that this patient presented a milder form of the disease. Both patients 22 and 23 carried the c.533G>A (p.R178H) mutation, which is associated with the B1 phenotype and the late onset form of TSD (dos Santos et al, 1991;Gravel et al, 2001;Montalvo et al, 2005). The second mutation found in patient 23 was the 4 bp duplication c.1274_1277dupTATC that accounts for 81% of Askenazi Jewish alleles.…”

“…Some mutations in the HEXA gene cause the B1 Variant, associated with the late onset form of TSD, characterized by the presence of a HexA isoenzyme inactive against the physiological substrate, GM2 ganglioside, but active towards the commonly used synthetic substrate (Bayleran et al, 1984;Tutor, 2004). Among the HEXA mutations associated with the B1 Variant, the most common is the c.533G>A (p.R178H) (Akli et al, 1993;dos Santos et al, 1991;Gravel et al, 2001;Montalvo et al, 2005;Rozenberg et al, 2006).…”

An update on inherited ataxias

“…Differential diagnosis of AR ataxias should, according to recent fi ndings, also consider oligosymptomatic late-onset forms of metabolic diseases. For example, in Tay-Sachs disease, compound heterozygous mutations in the HEXA gene [ 47 ] Molecular Pathways and Prospects of Treatment FRDA, with a prevalence of 1 in 30,000 to 50,000 people, is the most prevalent hereditary ataxia. It is clinically well described as a juvenile-onset ataxia with progressive gait and limb ataxia, loss of deep tendon refl exes, cerebellar dysarthria, impaired vibration sense, and spasticity.…”