Prevalence of Type 1 Gaucher Disease in Patients with Multiple Myeloma: Updated Interim Analysis of a Prospective, Multicentre, Observational Study
Massimo OffidaniCarmela ZizzoSerena RupoliIrene FedericiSonia MorèAlessandra BossiValentina Maria ManieriMaria Teresa PetrucciTommaso Caravita di TorittoMarino BrunoriAlessandro GozzettiAttilio TordiFrancesca FazioChiara LisiAssunta MelaccioLucia CiuffredaAntonietta FalconeFrancesca FioritoniSilvia GentiliAgostina SiniscalchiFabio TrastulliLaura CorvattaErika MorsiaAttilio OlivieriGiovanni Duro
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Mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are among the most common known genetic risk factors for the development of Parkinson disease and related synucleinopathies. A great deal is known about GBA1, as mutations in GBA1 are causal for the rare autosomal storage disorder Gaucher disease. Over the past decades, significant progress has been made in understanding the genetics and cell biology of glucocerebrosidase. A least 495 different mutations, found throughout the 11 exons of the gene are reported, including both common and rare variants. Mutations in GBA1 may lead to degradation of the protein, disruptions in lysosomal targeting and diminished performance of the enzyme in the lysosome. Gaucher disease is phenotypically diverse and has both neuronopathic and non-neuronopathic forms. Both patients with Gaucher disease and heterozygous carriers are at increased risk of developing Parkinson disease and Dementia with Lewy Bodies, although our understanding of the mechanism for this association remains incomplete. There appears to be an inverse relationship between glucocerebrosidase and α-synuclein levels, and even patients with sporadic Parkinson disease have decreased glucocerebrosidase. Glucocerebrosidase may interact with α-synuclein to maintain basic cellular functions, or impaired glucocerebrosidase could contribute to Parkinson pathogenesis by disrupting lysosomal homeostasis, enhancing endoplasmic reticulum stress or contributing to mitochondrial impairment. However, the majority of patients with GBA1 mutations never develop parkinsonism, so clearly other risk factors play a role. Treatments for Gaucher disease have been developed that increase visceral glucocerebrosidase levels and decrease lipid storage, although they have yet to properly address the neurological defects associated with impaired glucocerebrosidase. Mouse and induced pluripotent stem cell derived models have improved our understanding of glucocerebrosidase function and the consequences of its deficiency. These models have been used to test novel therapies including chaperone proteins, histone deacetylase inhibitors, and gene therapy approaches that enhance glucocerebrosidase levels and could prove efficacious in the treatment of forms of parkinsonism. Consequently, this rare monogenic disorder, Gaucher disease, provides unique insights directly applicable to our understanding and treatment of Parkinson disease, a common and complex neurodegenerative disorder.
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Alcalay, RN, Levy, OA, Waters, CC, Fahn, S, et al. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain. 2015; DOI: http://dx.doi.org/10.1093/brain/awv179 Gaucher disease is caused by mutations in both alleles of the glucocerebrosidase (GBA) gene. A strong association also exists between GBA mutations and Parkinson's disease (PD).1, 2 However, the precise mechanisms underlying this association are not clear. For example, whether the increased susceptibility to PD in GBA mutation carriers is secondary to reduced activity of the glucocerebrosidase enzyme is not known. In an attempt to address this question, Alcalay and colleagues used mass spectroscopy to measure glucocerebrosidase enzymatic activity in dried blood spots in patients with PD (n = 517) and healthy controls (n = 252).3 Patients had complete sequencing for GBA mutations as well as the LRRK2 G2019S mutation. As expected, they found that PD patients were more likely to carry GBA mutations or variants (17% vs 6.7%, P < 0.001) and were also more likely to carry the LRRK2 G2019S mutation (7.5% vs 0.8%, P < 0.001). They found that glucocerebrosidase activity correlated with the number of mutated GBA alleles, with GBA homozygotes/compound heterozygotes having lower enzymatic activity than GBA heterozygotes, and GBA heterozygotes having lower enzymatic activity than non-GBA, non-LRRK2 carriers. When analyses were repeated with the exclusion of GBA and LRRK2 G2019S mutation carriers and those with a positive family history or early-onset PD, PD patients had lower glucocerebrosidase enzymatic activity compared with controls. The results are consistent with the notion that lower glucocerebrosidase enzymatic activity contributes to the pathogenesis of PD in GBA mutation carriers. Furthermore, patients with “idiopathic” PD also may have lower enzymatic activity. Clearly, a reduction in glucocerebrosidase enzymatic activity cannot cause PD in its own right, because not all patients with Gaucher disease develop PD. Further studies are needed to explore the mechanisms of this association as the glucocerebrosidase enzyme emerges as a potential therapeutic target in PD. Kishore Raj Kumar, MBBS, PhD, FRACP1,2 1Department of Neurology and Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and The University of Sydney 2Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research 1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique. K.R.K.: 1A, 1B, 1C, 3A, 3B
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ABSTRACT Introduction: Glucocerebrosidase 1 mutations, the most common genetic contributor to Parkinson's disease (PD), have been associated with decreased glucocerebrosidase enzymatic activity in PD patients with glucocerebrosidase 1 mutations (glucocerebrosidase 1–PD). However, it is unknown whether this decrease in enzymatic activity leads to lysosphingolipid accumulations. Methods: The levels of hexosylsphingosines, globotriaosylsphingosine, sphingomyelin, and sphingomyelin‐509 were measured in dried blood spots from glucocerebrosidase 1–PD patients (n = 23), sporadic PD patients (n = 105), Gaucher disease patients (n = 32), and controls (n = 88) by liquid chromatography‐tandem mass spectrometry. Results: Glucocerebrosidase 1–PD patients had increased hexosylsphingosine levels when compared with sporadic PD patients ( P < .001) and controls ( P < .0001). Hexosylsphingosine levels were increased in glucocerebrosidase 1 mutation carriers of glucocerebrosidase 1 (L444P; N370S; n = 11, P = .001) and glucocerebrosidase 1 polymorphic variants (E326K, T369M) associated with PD (n = 12, P = .04) when compared with controls. Conclusions: Lysosphingolipid accumulations in PD patients who bear glucocerebrosidase 1 mutations suggest that substrate reduction therapy might be viewed as a possible strategy for glucocerebrosidase 1–PD treatment. © 2018 International Parkinson and Movement Disorder Society
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