Neurological effects of glucocerebrosidase gene mutations

Mullin, Stephen; Hughes, D.A.; Mehta, Atul; Schapira, Anthony H.V.

doi:10.1111/ene.13837

Cited by 32 publications

(30 citation statements)

References 114 publications

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“…The 186-day exposure period comprised 28 days of dose escalation, with each dose administered 3 times per day as follows: 60 mg (days 1-7), 120 mg (days 8-14), 180 mg (days [15][16][17][18][19][20][21], and 300 mg (days [22][23][24][25][26][27][28]. This exposure period was followed by 158 days of administration of ambroxol at 1.26 g per day (420 mg 3 times per day).…”

Section: Key Pointsmentioning

confidence: 99%

Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations

et al. 2020

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IMPORTANCEMutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD.OBJECTIVE To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations.INTERVENTIONS An escalating dose of oral ambroxol to 1.26 g per day.

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Section: Key Pointsmentioning

confidence: 99%

Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations

et al. 2020

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“…The inflammatory effect of GlcCer accumulation was recently proposed to be the consequence of complement C5a activation [45]. However, more recent reports identified patients with type 1 GD developing peripheral polyneuropathy at an older age [33]. Moreover, a subset of patients was recently reported to present mild but distinctive intellectual impairment, suggesting an involvement of the central nervous system [46,47].…”

Section: Gba Variants Gd Pd and How They Interplaymentioning

confidence: 99%

“…Rapid progression of the disease with death in early childhood is characteristic of type 2 disease, while in type 3 the progression is slower. Type 2 and 3 diseases are also suggested to be the more evident forms of a spectrum disease [33]. About 300 different mutations have been reported to affect the GBA gene.…”

Section: Gba Variants Gd Pd and How They Interplaymentioning

confidence: 99%

“…GD is the most relevant example of the former. The clinical presentation ranges from a mild visceral impairment detectable in adulthood to a severe neurologic impairment that is lethal by early childhood, without a clear relationship with the underlying mutation or the amounts of residual enzyme activity [27,32,33]. On the other hand, B4GALNT1-CDG is one of about 70 known genetic defects determining an inherited spastic paraplegia [34], and ST3GAL3-CDG is reported as one of the many conditions causing West syndrome, potentially evolving to Lennox–Gestaut syndrome [35].…”

Section: Introductionmentioning

confidence: 99%

“…Many such disorders are typically transmitted in an autosomal recessive manner (see Table 1, Table 2 and Table 3). However, emerging data show that heterozygous carriers of glucocerebrosidase GBA [33], sphingomyelinase SMPD1 [36], galactocerebrosidase (GALC) [37], and α-galactosidase (GLA) [38] variants are as much at risk for neurodegenerative diseases such as synucleopathies and multiple sclerosis as those with recessive homozygotes.…”

Section: Introductionmentioning

confidence: 99%

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The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

Indellicato

Trinchera

2019

IJMS

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Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann–Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson’s disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson’s disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies.

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A Multi‐Step Model of Parkinson's Disease Pathogenesis

et al. 2021

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Background:Parkinson's disease (PD) may result from the combined effect of multiple etiological factors. The relationship between disease incidence and age, as demonstrated in the cancer literature, can be used to model a multistep pathogenic process, potentially affording unique insights into disease development. Objectives: We tested whether the observed incidence of PD is consistent with a multistep process, estimated the number of steps required and whether this varies with age, and examined drivers of sex differences in PD incidence. Methods: Our validated probabilistic modeling process, based on medication prescribing, generated nationwide age-and sex-adjusted PD incidence data spanning 2006-2017. Models of log(incidence) versus log(age) were compared using Bayes factors, to estimate (1) if a linear relationship was present (indicative of a multistep process); (2) the relationship's slope (one less than number of steps); (3) whether slope was lower at younger ages; and (4) whether slope or y-intercept varied with sex. Results: Across >15,000 incident cases of PD, there was a clear linear relationship between log(age) and log(incidence). Evidence was strongest for a model with an initial slope of 5.2 [3.8, 6.4], an inflexion point at age 45, and beyond this a slope of 6.8 [6.4, 7.2]. There was evidence for the intercept varying by sex, but no evidence for slope being sex-dependent. Conclusions: The age-specific incidence of PD is consistent with a process that develops in multiple, discrete stepson average six before age 45 and eight after. The model supports theories emphasizing the primacy of environmental factors in driving sex differences in PD incidence.

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Neurological effects of glucocerebrosidase gene mutations

Cited by 32 publications

References 114 publications

Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations

Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations

The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

A Multi‐Step Model of Parkinson's Disease Pathogenesis

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