New GLB1 mutation in siblings with Morquio type B disease presenting with mental regression

Mayer, Fabiana Quoos; Pereira, Fernanda dos Santos; Fensom, Anthony H.; Slade, Christina; Matte, Úrsula; Giugliani, Roberto

doi:10.1016/j.ymgme.2008.11.159

Cited by 15 publications

(18 citation statements)

References 5 publications

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“…The catalytic (Glu268, Glu188) and galactose binding (Tyr83, Asn187, Tyr333, Glu129, Ala128) residues of b-gal have been identified, but additional residues and/or domains may in addition be involved in the degradation of keratan sulfate (McCarter et al 1997;Ohto et al 2011). A mutation affecting the Tyr333 residue of the b-gal catalytic site (Y333H) has previously been observed in siblings with intermediate GM1 and MBD features together with keratan sulfaturia and GM1-specific oligosacchariduria (Giugliani et al 1987;Mayer et al 2009). Since our patient shows intermediate phenotype and both oligosaccharide and keratan storage, G311R could affect the ligand binding and/or catalytic activity of b-gal, and thus its specificity for both keratan sulfate and ganglioside GM1.…”

Section: Discussionmentioning

confidence: 97%

“…In contrast, patients with MBD retain neurological functions, but develop generalized skeletal dysplasia, keratan sulfaturia and corneal clouding (Suzuki et al 2001). However, the clinical demarcation between GM1 and MBD can be obscured as in some patients displaying mental regression and the skeletal abnormalities of MBD (Giugliani et al 1987;Mayer et al 2009). …”

Section: Gm1-gangliosidosis (Gm1) Andmentioning

confidence: 99%

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β-Galactosidosis in Patient with Intermediate GM1 and MBD Phenotype

et al. 2012

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A 5-year-old girl with clinical and biochemical phenotypes encompassing both GM1-gangliosidosis (GM1) and Morquio B disease (MBD) is described. Mild generalized skeletal dysplasia and keratan sulfaturia were consistent with a diagnosis of MBD, while developmental delay and GM1-specific oligosacchariduria were consistent with GM1 gangliosidosis. No observable b-galactosidase activity was detected in leukocytes, and two mutations, p.R201H (c.602G>A) and p.G311R (c.931G>A), were identified by gene sequencing. The R201H substitution has been previously reported in patients with both GM1 and MBD, and G311R is a novel mutation. Our patient represents a further example of the clinical heterogeneity that can result from mutations at the b-galactosidase locus.

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Section: Discussionmentioning

confidence: 97%

Section: Gm1-gangliosidosis (Gm1) Andmentioning

confidence: 99%

β-Galactosidosis in Patient with Intermediate GM1 and MBD Phenotype

et al. 2012

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“…However, a clear-cut phenotype classification between GM1 types I, II, III and Morquio B can be difficult. The considerations raised from the clinical and genetic assessment of our patients’ cohort together with the description of a neurological Morquio type B form [6], and with previous evaluations on the convergence between the different forms of GM1 gangliosidosis and between GM1 gangliosidosis and Morquio B [7,22,25,34,36], warn physicians about the complications of defining disease severity in each case, and therefore of recommending any treatment that may be available. Polymorphisms could also play interesting roles on resulting enzyme activities and/or phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…An intermediate phenotype between GM1 gangliosidosis and Morquio B disease was also recently proposed in a patient homozygous for the p.R333H mutation [6]. Likewise, a patient with an intermediate phenotype between infantile and juvenile GM1 gangliosidosis has been reported and associated with a complex allele carrying the common p.R201H amino acid substitution in cis with the p.L436F polymorphism [7].…”

Section: Introductionmentioning

confidence: 98%

GM1 gangliosidosis and Morquio B disease: An update on genetic alterations and clinical findings

Caciotti

Garman

Rivera-Colón

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

122

144

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GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000– 1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes, showed that all the amino acids replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease.

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“…Hypotheses have been raised proposing that more than 100 different mutations could be responsible for the Morquio or GM1 gangliosidosis phenotypes (Callahan, 1999; Brunetti-Pierri and Scaglia, 2008). However, patients with intermediate phenotypes have also been described (Giugliani et al , 1987; Mayer et al , 2009). …”

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confidence: 99%

Population analysis of the GLB1 gene in South Brazil

et al. 2011

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Infantile GM1 gangliosidosis is caused by the absence or reduction of lysosomal beta-galactosidase activity. Studies conducted in Brazil have indicated that it is one of the most frequent lysosomal storage disorders in the southern part of the country. To assess the incidence of this disorder, 390 blood donors were tested for the presence of two common mutations (1622–1627insG and R59H) in the GLB1 gene. Another group, consisting of 26 GM1 patients, and the blood donors were tested for the presence of two polymorphisms (R521C and S532G), in an attempt to elucidate whether there is a founder effect. The frequencies of the R59H and 1622–1627insG mutations among the GM1 patients studied were 19.2% and 38.5%, respectively. The frequency of polymorphism S532G was 16.7%, whereas R521C was not found in the patients. The overall frequency of either R59H or 1622–1627insG was 57.7% of the disease-causing alleles. This epidemiological study suggested a carrier frequency of 1:58. Seven different haplotypes were found. The 1622–1627insG mutation was not found to be linked to any polymorphism, whereas linkage disequilibrium was found for haplotype 2 (R59H, S532G) (p < 0.001). These data confirm the high incidence of GM1 gangliosidosis and the high frequency of two common mutations in southern Brazil.

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New GLB1 mutation in siblings with Morquio type B disease presenting with mental regression

Cited by 15 publications

References 5 publications

β-Galactosidosis in Patient with Intermediate GM1 and MBD Phenotype

β-Galactosidosis in Patient with Intermediate GM1 and MBD Phenotype

GM1 gangliosidosis and Morquio B disease: An update on genetic alterations and clinical findings

Population analysis of the GLB1 gene in South Brazil

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