Open AccessJournal Article
Gaucher disease: insights from a rare Mendelian disorder.
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TL;DR: Unraveling the factors contributing to heterogeneity in a single gene disorder may have a direct impact on studies of the pathophysiology and therapeutic options available for these more common and complex neurologic diseases.
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Abstract: It is becoming quite evident that studies of Mendelian disorders can provide important insights into common neurologic disorders These rare inherited disorders often offer a unique window into seemingly unrelated diseases The number of studies focusing on genetic contributions to neurologic disorders is growing exponentially When undertaking the challenges associated with identifying the genes underlying complex neurological disorders, it is valuable to consider lessons gleaned from decades of studies of rare Mendelian disorders
This review will focus on lessons learned and challenges encountered in the study of one such monogenic disorder, Gaucher disease, focusing both on purely clinical observations, as well as the impact of such insights on understanding more common complex diseases
Studies of patients with Gaucher disease have led to unanticipated research directions impacting several distinct medical disciplines Some notable examples include the link between mutations in the glucocerebrosidase gene and the development of Parkinson disease and related Lewy body disorders, elucidation of the role of glucocerebrosidase in skin barrier function and neonatal viability, and the connection between lysosomal transport and myoclonic epilepsy
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Citations
A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments
Jérôme Stirnemann,Nadia Belmatoug,Fabrice Camou,Christine Serratrice,Roseline Froissart,Catherine Caillaud,Thierry Levade,Leonardo Astudillo,Jacques Serratrice,Anaïs Brassier,Christian Rose,Thierry Billette de Villemeur,Marc G. Berger +12 more
TL;DR: Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3.
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Sphingolipid lysosomal storage disorders
TL;DR: Emerging mechanistic links with more common diseases suggest the authors need to rethink the current concept of disease boundaries.
315
Characterization of LAMP1-labeled nondegradative lysosomal and endocytic compartments in neurons.
TL;DR: This study uses immunoelectron microscopy and confocal imaging to provide quantitative analysis of LAMP1 distribution in various autophagic and endolysosomal organelles in neurons and suggests that labeling a set of lysosomal hydrolases combined with various endolySosomal markers would be more accurate than simply relying on LAMP 1/2 staining to assess neuronal lysOSome distribution, trafficking, and functionality under physiological and pathological conditions.
Dysregulated Lipid Metabolism and Its Role in α-Synucleinopathy in Parkinson's Disease.
TL;DR: Three facets of metabolic lipid dysregulation as they relate to PD pathology and potential pathomechanisms involved in disease progression are described, while highlighting incongruous findings and gaps in knowledge that necessitate further research.
The relationship between glucocerebrosidase mutations and Parkinson disease
TL;DR: It is likely that, as in idiopathic PD, alpha‐synuclein accumulation, mitochondrial dysfunction, autophagic impairment, oxidative and endoplasmic reticulum stress may contribute to the development and progression of PD‐GBA1.
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References
Replacement Therapy for Inherited Enzyme Deficiency — Macrophage-Targeted Glucocerebrosidase for Gaucher's Disease
Norman W. Barton,Roscoe O. Brady,James M. Dambrosia,A. M. Di Bisceglie,Samuel H. Doppelt,Suvimol Hill,Henry J. Mankin,Gary J. Murray,Robert I. Parker,Charles E. Argoff +9 more
TL;DR: Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease.
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Gaucher Disease Glucocerebrosidase and α-Synuclein Form a Bidirectional Pathogenic Loop in Synucleinopathies
Joseph R. Mazzulli,You Hai Xu,You Hai Xu,Ying Sun,Ying Sun,Adam L. Knight,Pamela J. McLean,Guy A. Caldwell,Guy A. Caldwell,Ellen Sidransky,Gregory A. Grabowski,Gregory A. Grabowski,Dimitri Krainc +12 more
TL;DR: It is shown that functional loss of GD-linked glucocerebrosidase in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies.
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Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease
Juliane Neumann,Jose Bras,Jose Bras,Emma Deas,Sean S. O'Sullivan,Laura Parkkinen,Robin H. Lachmann,Abi Li,Janice L. Holton,Rita Guerreiro,Rita Guerreiro,Reema Paudel,Badmavady Segarane,Andrew B. Singleton,Andrew J. Lees,John Hardy,Henry Houlden,Tamas Revesz,Nicholas W. Wood +18 more
TL;DR: It is demonstrated that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene and suggested that to date, this is the most common genetic factor identified for the disease.
Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA).
TL;DR: The spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase are discussed.
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