Best Practice & Research Clinical Endocrinology & Metabolism xxx (2014) 1e11

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The emergence of Parkinson disease among patients with Gaucher disease Deborah Elstein, PhD, Clinical Research Coordinator a, *, Roy Alcalay, MD, Assistant Professor of Neurology, Division of Movement Disorders b, Ari Zimran, MD, Director of the Gaucher Clinic a a Gaucher Clinic, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem Israel b Department of Neurology and the Taub Institute, Columbia University Medical Center, New York, NY, USA

Keywords:

a-synuclein b-glucocerebrosidase Gaucher disease Parkinson disease

In the last decade, several lines of evidence have been presented that document the clinical manifestations, genetic associations, and subcellular mechanisms of the inter-relatedness of b-glucocerebrosidase mutations and the emergence of Parkinson disease among carriers and patients with Gaucher disease. This review is an attempt to apprise the reader of the recent literature with the caveat that this is an area of intensive exploration that is constantly being updated because of the immediate clinical ramifications but also because of the impact on our understanding of Parkinson disease, and finally because of the unexpected inter-reactions between these entities on the molecular level. It has been an unexpected happenstance that it has been discovered that a rare monogenetic disease has an interface at many points with a neurological disorder of the elderly that has both familial and sporadic forms: to date there is no cure for either of these disorders. © 2014 Elsevier Ltd. All rights reserved.

Introduction Gaucher disease, arguably the most common autosomal recessive lysosomal storage disorder, is caused by mutations in the gene for b-glucocerebrosidase with consequent accumulation of * Corresponding author. Gaucher Clinic, Shaare Zedek Medical Center, 12 Bayit Street, Jerusalem 9103102, Israel. Tel.: þ972 2 655 5093; Fax: þ972 2 651 7979. E-mail addresses: [email protected] (D. Elstein), [email protected] (R. Alcalay), [email protected] (A. Zimran).

http://dx.doi.org/10.1016/j.beem.2014.08.007 1521-690X/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

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glucocerebroside in macrophages, the so-called “Gaucher” cells [1]. Although there are usually visceral and hematological signs and symptoms, including hepatosplenomegaly and varying degrees of pancytopenia, making Gaucher disease a multi-system disorder, the existence of neurological forms of the disease had heretofore been considered to be restricted to those with the specific neuronopathic forms (types 2 and 3), characterized by genotypes comprised of “severe” and/or null mutations, in contrast to the non-neuronopathic form (type 1) wherein at least one allele has a mild mutation [2]. Thus, the recent emergence of parkinsonism among patients with “mild” mutations, has altered our understanding of the basic pathophysiology [3] and genetics [4] of glucocerebrosidase deficiency. Classic Parkinson disease is a result of atrophy of the dopaminergic neurons in the substantia nigra pars compacta. Based on current hypotheses (Braak) the disease starts much earlier but only when are symptoms and signs overt is it noted clinically; unfortunately by this juncture, Parkinson-specific therapy is merely symptomatic and not disease-modifying. Early identification of patients at risk of Parkinson disease is a goal of research; however, biomarkers based on neuro-imaging and/or some non-motor symptoms (such as olfactory deficits, constipation, sleep derangement, and/or depression) that may precede the onset of the more easily-discerned motor features, is imperfect [5]. One feature of Parkinson disease that has been considered a reliable genetic and pathological marker is a-synuclein which is expressed in neuronal synapses and regulates synaptic plasticity and neural differentiation. Alpha-synuclein is the major constituent of Lewy bodies, the pathological hallmark of Parkinson disease and Lewy Body Disease dementia. There is accumulation of a-synuclein aggregates in the brains of persons with motor signs of Parkinson disease whether it is considered sporadic-like or familial-like onset. Importantly, both point mutations and multiplications of the wild-type sequence of the asynuclein (SNCA) gene have been shown to cause familial parkinsonism. Accumulation of a-synuclein directly induces misfolding and toxic aggregation of the protein which is in turn directly related to the degenerative process of Parkinson disease [6]. Concurrent Gaucher disease and Parkinson disease In 1996 we reported a small series of patients with non-neuronopathic (type 1) Gaucher disease with at least one “mild” mutation who had developed an early-onset, aggressive form of Parkinson disease that in a few patients was also refractory to L-dopa, the standard Parkinson therapy which is also part of the definitions of the disorder, and hence we considered this feature to be a form of parkinsonism [7,8]. Of note was the dichotomy between the very mild symptoms/signs of Gaucher disease and the relatively aggressive form of the Parkinson-like disease. Subsequently, new patients with Parkinson disease were identified in our Gaucher referral clinic, mostly male and mostly homozygous for the “mild” mutation common among Ashkenazi Jews, N370S, which had been considered predictive of milder Gaucher disease. These patients evinced early-onset (mean age: 46 years) Parkinson disease and some with a tendency to develop clinical dementia. In a tangential survey we noted an increased incidence of Parkinson disease among obligate carriers of one of the (six common) glucocerebrosidase mutations [9] as had others [10,11]. In the last decade, several new lines of evidence have been presented that document the clinical manifestations, the genetic associations, and the sub-cellular mechanisms of the inter-relatedness of glucocerebrosidase mutations and the emergence of Parkinson disease among patients with Gaucher disease. This review aims to apprise the reader of the recent literature with the caveat that this is an area of intensive clinical and basic research exploration that is constantly being updated because of the immediate ramifications for patients with Gaucher disease and their first-degree relatives, and also because of the impact on our understanding of Parkinson disease as a relatively common disorder of the elderly that has both genetic and epigenetic aspects, and finally, because of the unexpected interreactions between these disease entities on the molecular level. Early studies among Ashkenazi Jewish cohorts with Parkinson disease Our 1996 case series had been partially culled from a larger screening for the most common Ashkenazi Jewish mutation in the glucocerebrosidase gene, N370S, among 150 Ashkenazi Jewish patients with Parkinson disease (94 males; 62%) from five medical centers in Israel who had no personal Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

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or family history of Gaucher disease. The mean age of onset of Parkinson disease among carriers of a glucocerebrosidase mutation was 57.0 years compared to 66.8 years among non-carriers of a glucocerebrosidase mutation (p ¼ 0.003). Other groups have corroborated the finding of a certain percent of patients with the co-morbidities of Gaucher disease and Parkinson disease [12e14] and still others have extended the research among patients with Parkinson disease who are carriers of a single glucocerebrosidase mutation [15e17]. In a study of 99 Ashkenazi Jewish patients with Parkinson disease from Haifa, Israel who were tested for the six most common mutations for Gaucher disease (including the N370S mutation), 31.3% were found to have at least one glucocerebrosidase mutation [17]. Evidence of increased frequency of glucocerebrosidase mutations in Parkinson disease cases has since been confirmed among Ashkenazi Jews in Tel Aviv, Israel and in NY, but with a lower frequency than reported by the Haifa team. Earlier published surveys for the prevalence of common mutations of Gaucher disease among patients with Parkinson disease had been noted to be considerably lower, approximately 11% [16], as was the case in a second survey initiated by our group by testing for six mutations common in Ashkenazi Jews (Y. Applebaum et al., unpublished). The former (Haifa) study had some ascertainment bias by virtue of including previously identified patients but was important in raising awareness of the association between the two disease entities. Virtually all other surveys, whether among Ashkenazi Jews or other ethnicities, have uncovered prevalence not as great as 31%. A large study relating to the question of incidence of glucocerebrosidase mutation(s) among patients with Parkinson disease was reported by a group from Israel: 420 patients with Parkinson disease, 333 elderly controls, and 3805 young controls were screened for eight glucocerebrosidase mutations [18]. The carrier frequency was 18% in patients with Parkinson disease, with 29% of these patients carrying “severe” mutations (those associated with more symptomatic Gaucher disease such as 84 GG and IVS2þ1) as compared to 7% carrying mutations among young healthy controls. Severe versus mild glucocerebrosidase mutations increased the risk of developing Parkinson disease by 13.6- fold versus 2.2-fold, respectively; the former were also associated with an earlier age of onset of symptoms relative to patients not having glucocerebrosidase mutations. Thus, while the actual incidence of Parkinson disease among patients and carriers of Gaucher disease was still rather low, this early study was seminal in expanding the putative association between specific glucocerebrosidase mutations and expression of Parkinson disease by implicating a correlation between severe Gaucher genotypes/mutations and the increased risk of developing severe Parkinson disease [19]. Shortly thereafter the association between glucocerebrosidase mutations and Parkinson disease was reported among many ethnicities and countries [19e24], and additionally, among patients with neuronopathic (type 3) Gaucher disease [25]. In an international meta-analysis of >5600 patients with documented Parkinson disease, the Odds Ratio for such a patient to have one glucocerebrosidase mutation was estimated to be 5.43 relative to (~5000) healthy controls and these Parkinson patients were indeed characterized by early-onset, having a family history of Parkinson disease, and exhibiting some atypical features [26]. Of note was that all of the 16 centers involved had patients with N370S and L444P mutations, but by subsequent full sequencing of approximately one-third of the cases, further mutations were identified. Examining patients with Gaucher disease for Parkinson signs and symptoms An early large study presenting the apparent bi-directionality of the association between Gaucher disease and Parkinson disease was based on 444 patients with Gaucher disease who were assessed as having a 21.4-fold life-time relative risk of developing early-onset Parkinson disease [27]. In this cohort there was evidence of more severe Gaucher disease, as demonstrated by the greater presence of osteonecrosis in affected patients [27], leading to the speculation by the authors that “prolonged bouts of systemic inflammation … might accentuate the formation of alpha synuclein aggresomes in predisposed individuals”. A French survey among Gaucher patients revealed 4% with Parkinson disease and 21% with at least one Parkinsonian/Parkinson-related sign/symptom [28]. Given the robust data from autopsy studies linking parkinsonism in Gaucher disease and carriers of glucocerebrosidase mutations, a-synuclein researchers hypothesize that the biological mechanism of Parkinson disease among Gaucher patients and carriers is similar to those with idiopathic Parkinson disease. However, it is noteworthy that there may be a unique clinical pattern beyond early-onset [8] Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

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which includes a predominance of the non-motor symptoms [29] and relatively more progressive cognitive dysfunction [30]. Another interesting clinical study [31] showed that there was decreased resting regional cerebral blood flow in the lateral parietoeoccipital association cortex and precuneus bilaterally of patients with both Gaucher disease and Parkinson disease that was posited to be similar to sporadic Parkinson disease with comparable damage in midbrain neurons. Neuropathology of Parkinson disease in patients with Gaucher disease versus neurological forms of Gaucher disease Although brains of patients with the neuronopathic forms of Gaucher disease (infantile lethal type 2 and the more attenuated type 3 Gaucher disease) have been shown to evince peri-adventitial accumulation of glucocerebroside-filled “Gaucher cells” with damage and loss of neurons in many areas [1], the pattern among patients with Parkinson disease and Gaucher disease is dissimilar [3,32]. Among autopsy samples from cases of sporadic Parkinson disease or Parkinson-like symptoms, 14% and 21% respectively were reported to have glucocerebrosidase mutations or polymorphisms [3,33]. This association was evaluated on molecular and clinical/pathological levels [3,4,34] in brains from patients with Gaucher disease and signs of Parkinson disease [34]. Cerebral cortical layers 3 and 5, hippocampal regions CA2-4, and layer 4b of the calcarine cortex were shown to exhibit unique patterns, correlating with severity of Gaucher disease [34]. The presence of a-synuclein positive inclusions similar to brainstem-type Lewy bodies [35] was provocative and has led to further speculation (see below) regarding the similarities of these post-mortem findings to Lewy Body Disease [35]. Hypotheses regarding a-synuclein aggregation in Gaucher disease As mentioned previously, a-synuclein-positive Lewy bodies and inclusions were found on autopsy in the brains of patients with (type 1) Gaucher disease [3,32] with Parkinson disease. Alpha-synuclein has the propensity to aggregate as partly folded conformations [32,36] which are the insoluble fibrils at the core of Lewy bodies, but not its sole components because they also include glucocerebrosidase [37]. Immunofluorescence of brain tissue samples from patients with Parkinson disease and glucocerebrosidase mutations showed a high percentage of glucocerebrosidase in the Lewy bodies [32]. Putatively, there is a relationship between a-synuclein aggregation and defective glucocerebrosidase [37,38]. This concept has been explored on many levels and remains an area of considerable interest to basic science researchers as well as clinicians [39]. To date, a single study has shown that saposin C, a protein vital for glucocerebrosidase activity in vivo, protects the enzyme against a-synuclein inhibition by displacing a-synuclein from glucocerebrosidase in solution and from lipid vesicles [40]. This too may ultimately have therapeutic implications. Animal model evidence In general, there are no available animal models for Parkinson disease that manifest both the clinical (motor and cognitive degeneration affecting primarily dopaminergic cells) and pathological (a-synculein deposits) features of the disease in humans. In mouse models with glucocerebrosidase mutations that would induce neurological signs in humans, as evaluated by immunohistochemistry, a-synuclein and ubiquitin progressively accumulated along with neurological manifestations and brain glucocerebroside accumulation [41]. The aggregation of potentially cytotoxic proteins in Lewy bodies implies proteolytic stress but also that the consequent physiological mechanisms may be less efficient in degrading a-synuclein because of the presence of undegraded glucocerebroside; possibly, these abnormal mechanisms would now involve mitochondrial fragmentation [42]. Further investigations in mouse models show that glucocerebrosidase mutants induce a-synuclein accumulation in a dose- and time-dependent manner [43]. Thus, this has been hypothesized to be evidence of a biochemical link between glucocerebrosidase mutations and the increased risk of a synucleinopathy [43]. Evidence of a physical link between glucocerebrosidase and asynuclein has been provided by displaying selective interaction between these proteins under lysosomal (pH 5.5) conditions at the a-synuclein C-terminal residues [44]. Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

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The mechanism of ubiquitization and parkin A genetic/epigenetic hypothesis incorporating the mechanism of ubiquitization as a critical function in the development of Parkinson disease in persons with glucocerebrosidase mutations suggests that there is involvement of the E3 ubiquitin ligase, parkin (a product of the gene PARK2), in the degradation of mutant glucocerebrosidase [45]. Endoplasmic reticulum (ER)-associated degradation (ERAD) is the system whereby mis-folded proteins are detected in order to reduce ER stress and the unfolded protein response (UPR). Both Gaucher disease and Parkinson disease are considered to be mis-folded protein disorders. ERAD, according to this conceptualization, requires the functioning parkin ligase to preclude substrate accumulation and sustain intact dopaminergic neurons. This hypothesis considers the underlying defect as being due to the glucocerebrosidase mutant enzyme complexing with parkin and eventually accumulating in aggresomes [45]. Without overexpression of parkin, there is decreased sensitivity to proteasome inhibitors dependent parkin's ubiquitin-protein E3 ligase activity making it incapable of preventing the toxic effects of a-synuclein accumulation [46]. A genetic study of a-synuclein in Gaucher disease The relevance of a genetic predisposition for an early-onset familial-like Parkinson disease (as versus comparability to sporadic Parkinson disease; 31) because of glucocerebrosidase mutations has been studied in various cohorts for at least 5 years [47]. However, it also seems logical that there is an interplay of glucocerebrosidase mutations and a-synuclein aggregation because each putatively induces the same clinical picture of Parkinson disease which may be seen as a synucleinopathy. Therefore, we studied the effect of the functional polymorphism of the SNCA (a-synuclein) gene among 14 patients with both Gaucher disease and Parkinson from our clinic who were matched to other patients from our clinic who only had Gaucher disease: all were Ashkenazi Jewish; there was a predominance of male patients (79%); half were N370S homozygous with mild to moderate Gaucher disease symptoms; the mean age at diagnosis of Parkinson disease was 57.8 (range: 43e70) years; the first sign of Parkinson disease was tremor in 64%; and there was cognitive dysfunction in all patients. The Odds Ratio risk for Parkinson disease was expected to increase with number minor alleles of the SNCA polymorphism but in this cohort there was no significant difference between the two groups [48]. An important by-product of this study was verification that the actual percent of those with Gaucher disease and Parkinson disease in the context of an adult population of ~500 Ashkenazi Jewish (only) adult patients (male and female) with various genotypes was ~2.8%. The above investigation into a genetic risk factor for synucleinopathies was a foray into a potential genetic susceptibility specifically of patients with Gaucher disease for a synucleinopathy, and as such this study seemed to highlight equal risk based on this SNCA polymorphic variance for Parkinson disease in the Gaucher patients who did not evince Parkinson disease as in those who did. Moreover, this molecular study is in line with the contention that both mutated and wild type glucocerebrosidase can induce Parkinson-like synucleinopathy [49]. In a functional knockdown model of Gaucher disease, there was evidence that over-expression of mutated glucocerebrosidase significantly increased a-synuclein levels while at the same time decreasing evoked dopamine release [50]. The issues that are indirectly raised by these data relate to recognition that the mere presence of mutated glucocerebrosidase is inimical to neurological integrity but also that there is putatively accelerated evolution of neurological co-morbidities because of induction of biochemical changes and neuroinflammation. These findings dovetail with clinical findings in patients and the theory of the suspicion of chronic, albeit low-grade, inflammation in Gaucher disease as a result of glucocerebroside accumulation [51]. Genetic/polymorphic studies in Parkinson disease that may have relevance to those with glucocerebrosidase mutations Approaching from another perspective, it may be surmised that some of the genetic/polymorphic susceptibility factors that have been identified in Parkinson disease may be present in persons with Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

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glucocerebrosidase mutations (in a manner reminiscent of the study of a-synuclein variants: see above). Osteopontin, a multi-functional immuno-modulatory protein which is expressed in the substantia nigra and regulates inflammatory processes and which has recently been shown to be neuroprotective in Parkinson disease rat model [52], has long been recognized as regulatory in human Parkinson disease neuro-degeneration [53]. Because the specific single-nucleotide polymorphism-66 polymorphic genotype TT was associated with the occurrence of Lewy body disease [54], we tested the incidence of this variant in patients with Gaucher disease with at least one N370S mutated allele including patients who also had Parkinson disease. We discovered that all the patients, both those with and without Parkinson disease, had a high incidence of this variant, possibly implying that this osteopontin genotype is an additional epigenetic susceptibility factor in patients with Gaucher disease [55]. Thus, it is actually surprising that well-documented risk factors for Parkinson disease are pervasive among patients with Gaucher disease and not specifically in those who develop Parkinson disease. It may prove to be the case that the genetic interactions between these disease entities are multi-genetic and may partly explain the aggressive nature of Parkinson disease in patients with glucocerebrosidase mutation(s). Age of onset of Parkinson disease and cognitive concerns A very recent study in Chinese patients with Parkinson disease with the leucine-rich repeat kinase 2 (LRRK2) genetic variant including some with one “severe” glucocerebrosidase mutation (L444P) showed that relative to those with only Parkinson disease, those with the glucocerebrosidase mutation were significantly younger at Parkinson disease onset and had a more progressive course, especially worse postural instability and gait disorders, motor complications, cognitive decline, hallucination, sexual dysfunction, and constipation [56]. In general, this study, albeit in a non-Ashkenazi Jewish cohort, confirms early-onset and aggressive Parkinson disease in those with a severe glucocerebrosidase mutation. But not only “severe” mutations induce an aggressive course: in another study from the UK, among Parkinson disease patients undergoing deep brain stimulation (based on severity criteria), most of the 16 patients who also had a glucocerebrosidase mutation were genotyped with E326K which many have considered a polymorphic variant [57], yet these patients achieved the criteria for deep brain stimulation earlier and developed earlier cognitive impairment than those who did not have the mutation [58]. Increasingly too, glucocerebrosidase mutations have been identified as a risk factor for dementia in the phenotype of Lewy Body Disease with a higher Odds Ratio than in those not carrying a glucocerebrosidase mutation; moreover, as in Parkinson disease with one glucocerebrosidase mutation, those with Lewy Body Disease and one glucocerebrosidase mutation evince an earlier onset and higher disease severity scores [59,60]. Both sets of findings, of early-onset and cognitive dysfunction, are further supported by studies based on magnetic resonance imaging metrics of the differential impact of carrying one glucocerebrosidase mutation relative to no mutation on early-onset destruction of brain white matter in patients with Parkinson disease [61]. Unlike persons with Parkinson disease or Lewy Body Disease with only one mutated allele for glucocerebrosidase, Israeli patients with both Gaucher disease (two mutated alleles) have been reported to be predominantly male, with less severe Gaucher signs/symptoms and a significant progression in cognitive decline as among the earliest characteristics of Parkinson disease [62]. Agespecific estimates of Parkinson disease penetrance in patients with Gaucher disease and those carrying only one mutation have been reported by a group from New York: 5.4% of patients >60 years were identified as having both Gaucher disease and Parkinson disease and 4.9% of obligate carriers had Parkinson disease; among the obligatory carriers, risk of Parkinson disease by ages 65 and 85 years respectively was estimated as 2.2% and 10.9%, respectively [11]. Arguments supporting and decrying use of Gaucher-specific therapies for Parkinson disease in the presence of glucocerebrosidase mutations and possibly in their absence There is no evidence that any of the currently used Gaucher treatments help reduce the risk for Parkinson disease or advent of Parkinson disease symptoms. There is also no evidence that any Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

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Parkinson treatments should be tailored differently for patients with Gaucher disease. Having said that, enzyme enhancing treatments that penetrate the brain may be able to modify disease risk and progression as reported in some animal studies. The concept that Gaucher severity is reactive to chronic low-grade stimulation by storage material and consequent inflammation is not new [51]; but whereas this may be a mere observation regarding physiological mechanisms, there are implications for therapeutic interventions that target storage material. Both Gaucher disease-specific enzyme replacement therapy [63] and substrate reduction therapy [64] result in decreased lipid storage and, by extension, decreased inflammatory adjuvants. Hypothetically, these concepts may have therapeutic applicability. Increasing enzymatic activity in the central nervous system of a transgenic mouse model with a Gaucher-inducing genotype and neuronopathic phenotype has been shown to reduce a-synuclein aggregation and its concomitant functional deficits [65]. Early preclinical data from studies using a Gaucher-specific pharmacological chaperone in a Parkinson mouse model have also reported decreased a-synuclein accumulation in the brain [66]. Thus, the therapeutic arena of Gaucher-specific treatments, which currently includes three approved and marketed infusible enzymes as well as one infusible enzyme and one oral enzyme each in clinical trials, plus one oral substrate reduction option and another in the latter stages of FDA and EMA processing, as well as considerable investments in chaperones and gene therapies, may one day have applicability not only to carriers of two and possibly one glucocerebrosidase mutation(s), but potentially also to those with Parkinson disease (and/or Lewy Body disease-like disorders of asynuclein accumulation). Interestingly, patients with Gaucher disease and Parkinson disease are not necessarily aware of the significant risk that carrying glucocerebrosidase mutation(s) has for developing Parkinson disease [67], yet this may be an extraordinarily important factor in future therapeutic options for their disease because increasing glucocerebrosidase activity may modulate a-synuclein processing in the central nervous system [63,66]. One means of increasing mis-folded glucocerebrosidase via crossing the bloodebrain barrier would be the use of pharmacological chaperones such as ambroxol [68] which has already been tested in a clinical pilot study of (non-neuronopathic) patients with Gaucher disease [69]. In a paradigm of fibroblast lines from skin biopsies from patients with Gaucher disease and persons with single glucocerebrosidase mutations with and without Parkinson disease, treatment with ambroxol improved multiple biochemical abnormalities including increasing glucocerebrosidase activity and decreasing oxidative stress in all sample cohorts including healthy persons [70]. A plausible molecular underpinning of this phenomenon has been suggested as related to ERAD as shown in earlier studies of skin fibroblasts from patients with both neuronopathic and non-neuronopathic Gaucher disease [71]. Studies such as these may indeed accelerate the path to effective treatment not just for those with Gaucher disease and Parkinson disease but for those with the synucleinopathy of Parkinson disease (and/or Lewy Body Disease) as well. However, introduction of supra-normal amounts of exogenous glucocerebrosidase (such as standard enzyme replacement therapy) may not be a benign process. There are those who have posited that glucocerebroside has an evolutionary advantage [72]: i.e., glucocerebroside has a beneficial immunomodulatory function in promoting of dendritic cells, natural killer T cells, and regulatory T lymphocytes by altering lipid rafts and the intercellular cross-talk in the bowel, liver, and spleen [73] and as shown in several experimental animal models of various immune-induced pathologies [74,75]. Relevant to the story of Gaucher disease is that there is also impact on development of (type 2) diabetes mellitus and/or the metabolic syndrome [76] which often is reported in Gaucher patients receiving enzyme replacement therapy. Therefore, it may not be the case that Gaucher-specific enzyme replacement therapy would be benign because of its class effects whereas for Parkinson disease (as well as in those with Gaucher disease), pharmacological chaperones may be the more physiologically correct and hence beneficial option. Conclusion The most recent review of the association of Parkinson disease and synucleinopathies with glucocerebrosidase mutations and Gaucher disease by Ellen Sidransky, a leader in this field, is entitled Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

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“Glucocerebrosidase is shaking up the synucleinopathies” [77]. This title is not merely tongue-incheek. It is absolutely obvious that the rapid change in our perception of the mechanisms at play in Parkinson disease and the synucleinopathies has been propelled by the new directions embarked upon in glucocerebrosidase research, although there is still a long way ahead. The title of the Sidransky review is also reminiscent of the title of a book by one of our patients, Ms. Elaine Benton, who has both Gaucher disease and Parkinson disease, which is entitled “Parkinson's, Shaken Not Stirred” [78]. Admittedly, Sidransky, as others, has galvanized researchers and clinicians alike in pursuit of the correlations and clinical implications that these associations have for those who suffer from a rare lysosomal disorder and a common neurological disorder [79]. However, in order not to lose sight of the human element it behooves researchers and clinicians alike to appreciate the toll that the actual co-existence of these diseases has on the individual and his/her first-degree relatives. The impact ranges from help with activities of daily living to the genetic counseling of children, and to the potential desire for the sophistication of pre-natal planning. As Ms. Benton is wise and optimistic and above all gracious, she couches her deteriorating life-style in wry poetry. Yet, like the legendary James Bond who ordered his vodka martinis as “shaken not stirred” probably because of his supra-human consumption of alcohol (tongue-in-cheek) induced a tremor (not unlike Ms. Benton's) and hence needed someone else to shake rather than stir his drinks, patients with Parkinson disease suffer from clinically overt signs and symptoms that seem overwhelming relative to the burden of Gaucher disease. Thus, there is an urgency to unraveling the many strands of experimental data that speak for and against the use of Gaucher-specific enzyme replacement therapy and/or glucocerebrosidase-targeted pharmacological chaperones. In the current atmosphere of receding grant monies for rare disorders, the complexity of glucocerebrosidase mutations with the common synucleinopathies may shake thing up after all. Summary In reviewing the rapidly evolving current literature on the emergence of the importance of bglucocerebrosidase deficiency for Parkinson disease and potentially for other a-synucleinopathies, one is struck by the relevance of both basic and clinical research in this field which is actually a dovetailing of two entities that heretofore had had no known commonality. While much has been discovered in the past two decades in terms of the biochemistry and biology, the molecular and the sub-molecular, and also in terms of the clinical associations between and within the two diseases and those who suffer from either one or both, much more awaits elucidation. The amazing technological leaps available to the next generation of researchers may afford an even more accelerated pace in unraveling this genetic conundrum.

Practice points ▪ Because of the increased risk of early-onset Parkinson disease in patients with Gaucher disease, treating physicians should include a series of appropriate questions at baseline examination to elicit a personal or family history of Parkinson disease, and additionally, to routinely inquire about emergence of neurological symptoms and/or signs among adult patients with Gaucher disease. In cases of neurological complaints, clinicians should have a low threshold to refer patients for a neurologic consultation, preferably with movement disorders specialists. ▪ Because risk factors for Parkinson disease have been found for mutations of other lysosomal disorders [80], it would be prudent to heighten awareness of this possibility among physicians and among adults patients with a lysosomal disorders, but possibly also among obligate carriers of (the autosomal recessive) lysosomal disorders.

Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

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Research agenda ▪ The link between Gaucher disease and Parkinson disease highlights the importance of developing enzyme enhancement therapies that cross the blood brain barrier. These therapies may be helpful for Gaucher patients with neurological manifestations (type 3 and possibly type 2) and hopefully would reduce the risk of Parkinson disease in patients with type 1 Gaucher disease. ▪ Because of the potential of small molecule chaperones to impact neurological features of mis-folded protein disorders such as Gaucher disease and potentially Parkinson disease, this modality should be given priority at the molecular level and in human clinical trials. ▪ Because ambroxol has a decades-long safety record in neonates, children, and adults, and has proven to be beneficial in alleviating many of the visceral features of Gaucher disease, this compound should be a priority for clinical research in patients with Gaucher disease and Parkinson disease, and theoretically in patients who only suffer from Parkinson disease.

Disclosure The authors report no conflicts of interests regarding the contents of this review. Funding No special funding was received for this review. References *[1] Zimran A, Elstein D. Lipid storage diseases. In: Lichtman MA, Kipps T, Seligsohn U, et al., editors. Williams hematology. 8th ed. New York: McGraw-Hill; 2010. p. 1065e71. [2] Beutler E, Gelbart T, Scott CR. Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis 2005;35(3): 355e64. [3] Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 2004;82:192e207. [4] Tayebi N, Callahan M, Madike V, et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 2001;73:313e21. [5] Berg D, Postuma RB, Bloem B, et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease. Mov Disord 2014 Apr;29(4):454e62. [6] Saracchi E, Fermi S, Brighina L. Emerging candidate biomarkers for Parkinson's disease: a review. Aging Dis 2013;5(1): 27e34. [7] Neudorfer O. Occurrence of parkinsonianism among patients and carriers of type I Gaucher disease. MD Thesis. Hebrew University-Hadassah Medical School; 1994. *[8] Neudorfer O, Giladi N, Elstein D, et al. Occurrence of Parkinson's syndrome in type I Gaucher disease. Q J Med 1996;89: 691e4. [9] Halperin A, Elstein D, Zimran A. Increased incidence of Parkinson disease among relatives of patients with Gaucher disease. Blood Cells Mol Dis 2006;36:426e8. *[10] Goker-Alpan O, Schiffmann R, LaMarca ME, et al. Parkinsonism among Gaucher disease carriers. J Med Genet 2004;41: 937e40. [11] Rana HQ, Balwani M, Bier L, et al. Age-specific Parkinson disease risk in GBA mutation carriers: information for genetic counseling. Genet Med 2013;15(2):146e9. [12] Machaczka M, Rucinska M, Skotnicki AB, et al. Parkinson's syndrome preceding clinical manifestation of Gaucher's disease. Am J Hematol 1999;61:216e7. [13] Varkonyi J, Simon Z, Soos K, et al. Gaucher disease type I complicated with Parkinson's syndrome. Haematologia (Budapest) 2002;32:271e5. [14] Bembi B, Zambito Marsala S, Sidransky E, et al. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology 2003;61:99e101. [15] Lwin A, Orvisky E, Goker-Alpan O, et al. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 2004;81:70e3. [16] Clark LN, Nicolai A, Afridi S, et al. Pilot association study of the beta-glucocerebrosidase N370S allele and Parkinson's disease in subjects of Jewish ethnicity. Mov Disord 2005;20:100e3. [17] Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 2004;351:1972e7.

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D. Elstein et al. / Best Practice & Research Clinical Endocrinology & Metabolism xxx (2014) 1e11

*[18] Gan-Or Z, Giladi N, Rozovski U, et al. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 2008;70:2277e83. [19] Eblan MJ, Nguyen J, Ziegler SG, et al. Glucocerebrosidase mutations are also found in subjects with early-onset parkinsonism from Venezuela. Mov Disord 2006;21(2):282e3. [20] Ziegler SG, Eblan MJ, Gutti U, et al. Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Mol Genet Metab 2007;91(2):195e200. [21] Hughes DA, Ginsberg L, Baker R, et al. Effective treatment of an elderly patient with Gaucher's disease and Parkinsonism: a case report of 24 months' oral substrate reduction therapy with miglustat. Parkisonism Relat Disord 2007;13: 365e8. [22] Wu YR, Chen CM, Chao CY, et al. Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese. J Neurol Neurosurg Psychiatry 2007;78:977e9. [23] Spitz M, Rozenberg R, Pereira Lda V, et al. Association between Parkinson's disease and glucocerebrosidase mutations in Brazil. Parkinsonism Relat Disord 2008;14:58e62. [24] De Marco EV, Annesi G, Tarantino P, et al. Glucocerebrosidase gene mutations are associated with Parkinson's disease in southern Italy. Mov Disord 2008;23:460e3. [25] Kono S, Shirakawa K, Ouchi Y, et al. Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier. J Neurol Sci 2007;252(2):181e4. *[26] Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009;361(17):1651e61. [27] Bultron G, Kacena K, Pearson D, et al. The risk of Parkinson's disease in type 1 Gaucher disease. J Inherit Metab Dis 2010; 33(2):167e73. rin P, Rose C, de Roux-Serratrice C, et al. The neurological manifestations of Gaucher disease type 1: the French [28] Che Observatoire on Gaucher disease (FROG). Mov Disord 2010;33(4):331e8. [29] Brockmann K, Srulijes K, Hauser AK, et al. GBA-associated PD presents with nonmotor characteristics. Neurology 2011; 77(3):276e80. [30] Alcalay RN, Caccappolo E, Mejia-Santana H, et al. Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology 2012;78(18):1434e40. *[31] Goker-Alpan O, Masdeu JC, Kohn PD, et al. The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow. Brain 2012;135(Pt 8):2440e8. [32] Choi JH, Stubblefield B, Cookson MR, et al. Aggregation of a-synuclein in brain samples from subjects with glucocerebrosidase mutations. Mol Genet Metab 2011;104(1e2):185e8. [33] Sidransky E. Gaucher disease: complexity in a “simple” disorder. Mol Genet Metab 2004;83:6e15. [34] Tayebi N, Walker J, Stubblefield B, et al. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 2003;79:104e9. [35] Bras J, Paisan-Ruiz C, Guerreiro R, et al. Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol 2008;65:379e82. [36] Uversky VN, Cooper EM, Bower KS, et al. Accelerated a-synuclein fibrillation in crowded milieu. Federation of European Biochemical Societies. Letters 2002;515(1e3):99e103. [37] Schlossmacher MG, Cullen V, Muthing J. The glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 2005;352(7):728e31. [38] Goker-Alpan O, Stubblefield BK, Giasson BI, et al. Glucocerebrosidase is present in a-synuclein inclusions in Lewy body disorders. Acta Neuropathol 2010;120(5):641e9. [39] Hruska KS, Goker-Alpan O, Sidransky E. Gaucher disease and the synucleinopathies. J Biomed Biotechnol 2006;2006(3): 78549. [40] Yap TL, Gruschus JM, Velayati A, et al. Saposin C protects glucocerebrosidase against a-synuclein inhibition. Biochemistry 2013;52(41):7161e3. *[41] Xu YH, Sun Y, Ran H, et al. Accumulation and distribution of a-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. Mol Genet Metab 2011;102(4):436e47. [42] Osellame LD, Duchen MR. Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. Autophagy 2013;9(10). [43] Cullen V, Sardi SP, Ng J, et al. Acid b-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter a-synuclein processing. Ann Neurol 2011;69(6):940e53. *[44] Yap TL, Gruschus JM, Velayati A, et al. Alpha-synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem 2011;286(32):28080e8. [45] Ron I, Rapaport D, Horowitz M. Interaction between Parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease. Hum Mol Genet 2010;19(19):3771e81. [46] Petrucelli L, O'Farrell C, Lockhart PJ, et al. Parkin protects against the toxicity associated with mutant a-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 2002;36(6):1007e19. *[47] Nichols WC, Pankratz N, Marek DK, et al. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology 2009;72(4):310e6. [48] Altarescu G, Ioscovich D, Alcalay RN, et al. a-Synuclein rs356219 polymorphisms in patients with gaucher disease and Parkinson disease. Neurosci Lett 2014 Aug 8;580C:104e7. [49] Kong B, Yang T, Gu JW, et al. The association between lysosomal protein glucocerebrosidase and Parkinson's disease. Eur Rev Med Pharmacol Sci 2013;17(2):143e51. [50] Ginns EI, Mak SK, Ko N, et al. Neuroinflammation and a-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction. Mol Genet Metab 2014;111(2):152e62. [51] Shoenfeld Y, Beresovski A, Zharhary D, et al. Natural autoantibodies in sera of patients with Gaucher's disease. J Clin Immunol 1995;15(6):363e72. [52] Ailane S, Long P, Jenner P, et al. Expression of integrin and CD44 receptors recognising osteopontin in the normal and LPSlesioned rat substantia nigra. Eur J Neurosci 2013;38(3):2468e76.

Please cite this article in press as: Elstein D, et al., The emergence of Parkinson disease among patients with Gaucher disease, Best Practice & Research Clinical Endocrinology & Metabolism (2014), http:// dx.doi.org/10.1016/j.beem.2014.08.007

D. Elstein et al. / Best Practice & Research Clinical Endocrinology & Metabolism xxx (2014) 1e11

11

[53] Maetzler W, Berg D, Schalamberidze N, et al. Osteopontin is elevated in Parkinson's disease and its absence leads to reduced neurodegeneration in the MPTP model. Neurobiol Dis 2007;25(3):473e82. [54] Maetzler W, Michelis J, Tomiuk J, et al. A single-nucleotide polymorphism of the osteopontin gene may contribute to a susceptibility to Lewy body disease. J Neural Transm 2009;116(5):599e605. [55] Ribner A, Altarescu G, Zimran A, et al. Osteopontin polymorphic susceptibility factor for Parkinson's disease among patients with Gaucher disease. Mov Disord 2011;26(7):1341e3. [56] Wang C, Cai Y, Gu Z, et al. Clinical profiles of Parkinson's disease associated with common leucine-rich repeat kinase 2 and glucocerebrosidase genetic variants in Chinese individuals. Neurobiol Aging 2014;35(3). 725.e1e6. [57] Duran R, Mencacci NE, Angeli AV, et al. The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease. Mov Disord 2013;28(2):232e6. [58] Angeli A, Mencacci NE, Duran R, et al. Genotype and phenotype in Parkinson's disease: lessons in heterogeneity from deep brain stimulation. Mov Disord 2013;28(10):1370e5. [59] Nalls MA, Duran R, Lopez G, et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. J Am Med Assoc Neurol 2013;70(6):727e35. [60] Li Y, Sekine T, Funayama M, et al. Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease. Neurobiol Aging 2014;35(4):935.e3e8. [61] Agosta F, Kostic VS, Davidovic K, et al. White matter abnormalities in Parkinson's disease patients with glucocerebrosidase gene mutations. Mov Disord 2013;28(6):772e8. [62] Chetrit EB, Alcalay RN, Steiner-Birmanns B, et al. Phenotype in patients with Gaucher disease and Parkinson disease. Blood Cells Mol Dis 2013;50(3):218e21. [63] Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme deficiencyemacrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991;324:1464e70. [64] Butters TD, Dwek RA, Platt FM. Therapeutic applications of imino sugars in lysosomal storage disorders. Curr Top Med Chem 2003;3(5):561e74. [65] Sardi SP, Clarke J, Viel C, et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci U S A 2013;110(9):3537e42. [66] www.amicusrx.com/preclinical.aspx. [67] Sakanaka K, Waters CH, Levy OA, et al. Knowledge of and interest in genetic results among Parkinson disease patients and caregivers. J Genet Couns 2014;23(1):114e20. [68] Maegawa GH, Tropak MB, Buttner JD, et al. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem 2009;284(35):23502e16. *[69] Zimran A, Altarescu G, Elstein D. Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol Dis 2013;50(2):134e7. [70] McNeill A, Magalhaes J, Shen C, et al. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain 2014 May;137(Pt 5):1481e95. [71] Bendikov-Bar I, Maor G, Filocamo M, et al. Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase. Blood Cells Mol Dis 2013;50(2):141e5. [72] Ilan Y, Elstein D, Zimran A. Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent. Immunol Cell Biol 2009;87(7):514e24. [73] Margalit M, Abu Gazala S, Alper R, et al. Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes. Am J Physiol Gastrointest Liver Physiol 2005;289(5):G917e25. [74] Zigmond E, Preston S, Pappo O, et al. Beta-glucosylceramide: a novel method for enhancement of natural killer T lymphoycte plasticity in murine models of immune-mediated disorders. Gut 2007;56(1):82e9. [75] Zigmond E, Zangen SW, Pappo O, et al. Beta-glycosphingolipids improve glucose intolerance and hepatic steatosis of the Cohen diabetic rat. Am J Physiol Endocrinol Metab 2009;296(1):E72e8. [76] Langeveld M, de Fost M, Aerts JM, et al. Overweight, insulin resistance and type II diabetes in type I Gaucher disease patients in relation to enzyme replacement therapy. Blood Cells Mol Dis 2008;40(3):428e32. [77] Siebert M, Sidransky E, Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain 2014 May;137(Pt 5): 1304e22. [78] www.elainebenton.net (an eKindle book). [79] Sidransky E. Gaucher disease: insights from a rare Mendelian disorder. Discov Med 2012;14(77):273e81. [80] Gan-Or Z, Ozelius LJ, Bar-Shira A, et al. The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology 2013;80(17):1606e10.

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