Diagnosis and Molecular Characterization of Nonclassic Forms of Tay-Sachs Disease in Brazil

Abstract

Molecular analysis of five Brazilian families, including eight patients presenting with nonclassic Tay-Sachs disease, was performed to identify frequent causative mutations and their correlation with clinical course. Three patients were affected by the B1 subacute variant and were shown to carry the R178H mutation (the DN allele), which is also common among Portuguese patients. Two of them were compound heterozygotes, whereas the third presented with the mutation in both alleles. Since Brazil was a Portuguese colony for over two centuries, common ancestry might be the probable explanation. The fourth patient presented with a juvenile phenotype and carries the R499H mutation, which has been reported only once worldwide and is associated with residual enzyme activity, responsible for a slower clinical course. The fifth family, of an Ashkenazi Jewish background, showed an extensive intrafamilial clinical variability among three affected sibs presenting with muscle atrophy, ataxia, and psychiatric symptoms. They were first diagnosed as having atypical spinal muscular atrophy and, subsequently, spinocerebellar ataxia, but, recently, the diagnosis of late-onset Tay-Sachs disease was confirmed based on reduced plasma hexosaminidase A activity and the G269S/InsTATC1278 genotype. It is therefore highly recommended to test patients with a similar clinical history for Tay-Sachs disease. In the same family, one first cousin committed suicide at the age of 24 years, presenting with a clinical phenotype that suggested an undiagnosed case and highlighting the effect of the intrafamilial clinical variability in delaying a prompt diagnosis. It is now recognized that his parents are, in fact, a carrier couple. Additionally, another relative had been previously identified as a heterozygote in a Tay-Sachs disease screening program, but the information was not shared among the family. Since this information might anticipate diagnosis and genetic counseling, it is advisable that heterozygote screening programs encourage families to share genetic information.

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

“…The p.R499H mutation has been already described in patients affected with the juvenile form of TSD (Paw et al, 1990;Rozenberg et al, 2006;Tanaka et al, 2003), and it has been shown that this mutation would lead to a small structural change of the HexA subunit. In light of these data, it is not surprising that this patient presented a milder form of the disease.…”

“…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).…”

Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene

“…Macular cherry red spots were absent in this patient. Cherry red spots are characteristic of infantile Tay-Sachs and Sandhoff diseases, but are rarely present in juvenile or subacute cases [16], [17], [18], [19], [20], [21], [22], [23]. The lack of cherry red spots may also apply to later-onset cases of G M2 gangliosidosis AB.…”

A thematic review of scientific and family interests in Canavan Disease: where are the developmentalists?

“…2011) falls into the category of clinical therapeutic approaches. Of the remaining articles, five fell into the category of diagnosis and genetic counselling (Rozenberg et al . 2006; Weinstein 2007; Batzer & Ravitzky 2009; Coughlin 2009; Shapiro & Natowitcz 2009) while four articles fell into the category of the biochemistry of Tay‐Sachs disease (Yoshino et al .…”