Genotypic and phenotypic characterization of Brazilian patients with GM1 gangliosidosis

Abstract

GM1 gangliosidosis is a lysosomal disorder caused by β-galactosidase deficiency due to mutations in the GLB1 gene. It is a rare neurodegenerative disorder with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we review GLB1 mutations and clinical features from 65 Brazilian GM1 gangliosidosis patients. Molecular analysis showed 17 different mutations and c.1622-1627insG was the most frequent, accounting for 50% of the alleles. Cognitive impairment was the main clinical sign, observed in 82% of patients, followed by hepatosplenomegaly observed in 56% of patients. It was possible to establish a significant correlation between age at onset of symptoms preceding the first year of life and the presence of the mutation c.1622-1627insG (p=0.03). Overall our findings differ from literature and represent the exclusive genotypic profile found in Brazilian GM1 gangliosidosis patients.

Clinical Findings and Natural History in Ten Unrelated Families with Juvenile and Adult GM1 Gangliosidosis

“…Finally, the frequency of GM1 gangliosidosis in our clinic is similar to another Brazilian case series from Rio Grande do Sul, where the juvenile phenotype was the most common (Sperb et al 2013). However, there might be a bias in our records because the infantile form is probably underdiagnosed in our population.…”

“…A total of 102 mutations in GLB1 gene have been also revised showing extensive molecular heterogeneity and hindering a clear genotype-phenotype correlation. In the Brazilian population, Sperb et al (2013) revised 32 patients with all types of GM1 gangliosidosis from different regions from Brazil who were diagnosed at their reference laboratory, including clinical and molecular analysis. The series included five subjects with the infantile, 15 with the juvenile, and nine with the adult form.…”

“…As in many other metabolic disorders, they represent a clinical continuum rather than separate entities. Many patients also present as Morquio B disease (OMIM#253010) which is allelic to the various forms of GM1 gangliosidosis (Giugliani et al 1987;Paschke et al 2001;Sperb et al 2013).…”

Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice

“…In support of this, eight weekly ICV doses of rhBeta-Gal in GLB1 KO mice coincides with near-tocomplete normalization of Beta-Gal activity levels and Beta-Gal protein levels in the liver ( Fig 5A) and bone marrow ( Fig 5B) of the majority of animals. While substrate levels in liver and bone marrow of these mice were not measured, the degree of Beta-Gal augmentation in liver and bone marrow is well above the critical threshold of ~15% of normal residual lysosomal enzyme activity that is needed to mediate substrate turnover and prevent lysosomal storage disease progression in GM1 gangliosidosis patients (8,9). It is therefore possible that an ICV route of rhBeta-Gal administration may also result in exposure of enzyme to systemic sites of disease progression in sufficient amounts to mediate substrate clearance.…”

Candidate Molecules for Chemical Chaperone Therapy of G M1 -Gangliosidosis

“…The accumulation of these gangliosides is most prominent in the brain. Oligosaccharides derived from keratan sulfate or other glyco proteins also accumulate in visceral organs and are excreted in urine of patients with G M1 -gangliosidosis as well as Morquio B disease, another rare systemic bone [22][23][24][25][26][27].…”