Disentangling molecular and clinical stratification patterns in beta-galactosidase deficiency

Abstract

IntroductionThis study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB).MethodsClinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.ResultsThe clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1 gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group.ConclusionThis study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.

Natural history of GM1 gangliosidosis—Retrospective cohort study of 61 French patients from 1998 to 2019

“…Based on our genetic findings, we were able to compare our clinical observations with the classification used by Tebani et al, 13 and we found comparable results in association between phenotype and genotype (early‐onset <2 year corresponding to our types 1/2a patients, late‐onset >2 years to our types 2b/3 patients). Furthermore, our data suggest that the c.1733A > G variant does not appear to be associated with type 1 but repeatedly with type 2a (onset of symptoms between 6 months and 2 years).…”

“…Thirty‐seven variants have been previously published; 1 (c.457 + 96C > T, p.?) had not been described so far, probably leading to an alteration of splicing with creation of a splice site—according to Splicing Prediction Pipeline 9–13 . Twenty‐four variants have been identified in patients with type 1, 7 with type 2a, 4 with type 2b, and 6 with type 3.…”

“…had not been described so far, probably leading to an alteration of splicing with creation of a splice siteaccording to Splicing Prediction Pipeline. [9][10][11][12][13] Twenty-four variants have been identified in patients with type 1, 7 with type 2a, 4 with type 2b, and 6 with type 3. All but three variants were present in only one type of GM1 gangliosidosis (c.442C > T was found in types 1 and 2b; c.602G > A in types 2b and 3; c.716C > T in both types 1 and 3).…”

GM1 Gangliosidosis—A Mini-Review

“…Odontoid hypoplasia, as observed in all late infantile patients but not juvenile patients, requires cervical spine evaluation in late infantile patients prior to anesthesia, and anesthetic care FIGURE 2 | Genotypes in GM1 gangliosidosis. Schematic representation of 261 GLB1 variants with a reported phenotype of GM1-gangliosidosis and/or Morquio B registered in the database HGMD (2021) updated with the novel variants from Tebani et al (2021). The GLB1 gene is located on the short arm of chromosome 3 (3p21.33).…”

“…Bold text represents GM1 gangliosidosis and/or Morquio B reported phenotypes. A summary of the 261 reported variants with a phenotype of GM1 gangliosidosis and/or Morquio B disease can be found at GLB1 (HGMD, 2021; Tebani et al, 2021). The main domains of the protein are shown above the exons.…”