Dystonia and parkinsonism in GM1 type 3 gangliosidosis

Roze, Emmanuel; Paschke, Eduard; Lopez, Nathalie; Eck, T. F.; Yoshida, Katsumi; Maurel-Ollivier, Annie; Doummar, Diane; Caillaud, Catherine; Galanaud, Damien; Villemeur, Thierry Billette de; Vidailhet, Marie; Roubergue, Anne

doi:10.1002/mds.20593

Cited by 91 publications

(66 citation statements)

References 8 publications

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“…Patient 20 was homozygous for the c.1313G>A (p.G438E) mutation, previously described at a homozygous level both in Morquio B and in GM1 gangliosidosis type III patients [25, 26]. Our patient shows some features of skeletal dysplasia typical of Morquio syndrome i.e, thoracic deformity and short stature but no ligamentous laxity.…”

Section: Discussionmentioning

confidence: 53%

“…The p.K578R mutation, identified in Patient 15, was previously associated with the infantile phenotype [24]. In Patient 20, the p.G438E mutation, previously described in Morquio B patients and type III GM1 gangliosidosis, both at a homozygous level [25, 26], was found. In Patient 1, the new complex allele pR68W/p.R109W, in combination with the known c.442C>T (p.R148C) [27] was found (see Table 3).…”

Section: Resultsmentioning

confidence: 78%

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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

124

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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Section: Discussionmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 78%

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

124

144

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“…An extensive body of literature can be found on the potential involvement of GM1 gangliosides in the pathogenesis of PD [43], through either accelerated αS aggregation in mice having decreased GM1 levels [44], [45] or a decrease in PD-type symptoms upon administration of GM1 [46], [47]. There is also evidence for a connection between Parkinson’s disease and disorders with defective glucocerebroside metabolism like Gaucher’s disease that indirectly affect GM1 levels [48].…”

Section: Discussionmentioning

confidence: 99%

N-Alpha-Acetylation of α-Synuclein Increases Its Helical Folding Propensity, GM1 Binding Specificity and Resistance to Aggregation

et al. 2014

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A switch in the conformational properties of α-synuclein (αS) is hypothesized to be a key step in the pathogenic mechanism of Parkinson’s disease (PD). Whereas the beta-sheet-rich state of αS has long been associated with its pathological aggregation in PD, a partially alpha-helical state was found to be related to physiological lipid binding; this suggests a potential role of the alpha-helical state in controlling synaptic vesicle cycling and resistance to β-sheet rich aggregation. N-terminal acetylation is the predominant post-translational modification of mammalian αS. Using circular dichroism, isothermal titration calorimetry, and fluorescence spectroscopy, we have analyzed the effects of N-terminal acetylation on the propensity of recombinant human αS to form the two conformational states in interaction with lipid membranes. Small unilamellar vesicles of negatively charged lipids served as model membranes. Consistent with previous NMR studies using phosphatidylserine, we found that membrane-induced α-helical folding was enhanced by N-terminal acetylation and that greater exothermic heat could be measured upon vesicle binding of the modified protein. Interestingly, the folding and lipid binding enhancements with phosphatidylserine in vitro were weak when compared to that of αS with GM1, a lipid enriched in presynaptic membranes. The resultant increase in helical folding propensity of N-acetylated αS enhanced its resistance to aggregation. Our findings demonstrate the significance of the extreme N-terminus for folding nucleation, for relative GM1 specificity of αS-membrane interaction, and for a protective function of N-terminal-acetylation against αS aggregation mediated by GM1.

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“…Dystonia of the extremities growing worse during the course of the day with normal intellect and a dramatic response to treatment with L -dopa is characteristic of Segawa syndrome,[15] Lysosomal storage disorders that can present with dystonia include Niemann-Pick disease type C,[1617] Gaucher disease type 3, GM2 gangliosidosis[1819] and GM1 gangliosidosis. [2021]…”

Section: Ataxia and Extrapyramidal Movement Disordersmentioning

confidence: 99%

An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist

Christopher

Sankaran

2008

Ann Indian Acad Neurol

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Neurological dysfunction is an important manifestation of inherited metabolic disorders. Although these are more common in childhood, adult onset forms with a different clinical presentation are often encountered. Recent advances in the diagnosis and treatment of these conditions have substantially improved the outcome in many of these conditions. This makes it essential that the practicing physician be familiar with the clinical presentation and diagnosis of these disorders. For the evaluation of a patient with a possible inborn error of metabolism, simple screening tests may aid in the diagnosis and provide direction for more comprehensive laboratory analysis. In this review, we present a practical approach to diagnosis of neurometabolic disorders. Establishing a specific diagnosis in these disorders will enable the clinician in offering a definitive long-term treatment, prognosis and genetic counselling.

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Dystonia and parkinsonism in GM1 type 3 gangliosidosis

Cited by 91 publications

References 8 publications

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

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

N-Alpha-Acetylation of α-Synuclein Increases Its Helical Folding Propensity, GM1 Binding Specificity and Resistance to Aggregation

An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist

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