Deficiency of Glucocerebrosidase Activity beyond Gaucher Disease: PSAP and LIMP-2 Dysfunctions.

Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the proteolytical cleavage of prosaposin (encoded by PSAP gene), which gives rise to four saposins. GCase is targeted to the lysosomes by LIMP-2, encoded by SCARB2 gene. GCase deficiency causes Gaucher Disease (GD), which is mainly due to biallelic pathogenetic variants in the GCase-encoding gene, GBA1. However, impairment of GCase activity can be rarely caused by SapC or LIMP-2 deficiencies. We report a new case of LIMP-2 deficiency and a new case of SapC deficiency (missing all four saposins, PSAP deficiency), and measured common biomarkers of GD and GCase activity. Glucosylsphingosine and chitotriosidase activity in plasma were increased in GCase deficiencies caused by PSAP and GBA1 mutations, whereas SCARB2-linked deficiency showed only Glucosylsphingosine elevation. GCase activity was reduced in fibroblasts and leukocytes: the decrease was sharper in GBA1- and SCARB2-mutant fibroblasts than PSAP-mutant ones; LIMP-2-deficient leukocytes displayed higher residual GCase activity than GBA1-mutant ones. Finally, we demonstrated that GCase mainly undergoes proteasomal degradation in LIMP-2-deficient fibroblasts and lysosomal degradation in PSAP-deficient fibroblasts. Thus, we analyzed the differential biochemical profile of GCase deficiencies due to the ultra-rare PSAP and SCARB2 biallelic pathogenic variants in comparison with the profile observed in GBA1-linked GCase deficiency.

Gaucher Disease for Hematologists

Gaucher disease (GD) is a rare hereditary lysosomal storage disease that arises due to deficiency of glucocerebrosidase. Early diagnosis is very important for starting proper treatment and preventing complications. Splenomegaly, anemia, and thrombocytopenia are the most common findings in GD and so most patients are initially referred to hematologists. The Turkish Society of Hematology established its Rare Hematological Diseases Subcommittee in 2015. One of the main topics of this subcommittee was to increase and improve awareness and education of rare diseases among hematologists in Turkey. This review presents GD with an overview of its clinical features, pathophysiology, and treatment options for hematologists.

Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson's Disease.

Parkinson's Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene (GBA). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of lysosomal storage disorder. Current therapeutic approaches fail to address neurological GD symptoms. Therefore, identifying therapeutic strategies that improve the phenotypic traits associated with GD/PD in animal models may provide an opportunity for treating neurological manifestations of GD/PD. Thiazolidinediones (TZDs, also called glitazones) are a class of compounds targeted for the treatment of type 2 diabetes, and have also shown promise for the treatment of neurodegenerative disease, including PD. Here, we tested the efficacy of glitazone administration during development in a fly GD model with deletions in the GBA homolog, dGBA1b (GBA1ΔTT/ΔTT). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 µM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1ΔTT/ΔTT mutant flies, compared to GBA1+/+ control flies. These data suggest that PGZ may represent a potential compound with which to treat GD/PD by improving function of lysosomal-autophagy pathways, a cellular process that removes misfolded or aggregated proteins.

Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α-Synuclein Mutations.

OBJECTIVE: We utilized human midbrain-like organoids (hMLOs) generated from human pluripotent stem cells carrying glucocerebrosidase gene (GBA1) and α-synuclein (α-syn; SNCA) perturbations to investigate genotype-to-phenotype relationships in Parkinson disease, with the particular aim of recapitulating α-syn- and Lewy body-related pathologies and the process of neurodegeneration in the hMLO model. METHODS: We generated and characterized hMLOs from GBA1-/- and SNCA overexpressing isogenic embryonic stem cells and also generated Lewy body-like inclusions in GBA1/SNCA dual perturbation hMLOs and conduritol-b-epoxide-treated SNCA triplication hMLOs. RESULTS: We identified for the first time that the loss of glucocerebrosidase, coupled with wild-type α-syn overexpression, results in a substantial accumulation of detergent-resistant, ß-sheet-rich α-syn aggregates and Lewy body-like inclusions in hMLOs. These Lewy body-like inclusions exhibit a spherically symmetric morphology with an eosinophilic core, containing α-syn with ubiquitin, and can also be formed in Parkinson disease patient-derived hMLOs. We also demonstrate that impaired glucocerebrosidase function promotes the formation of Lewy body-like inclusions in hMLOs derived from patients carrying the SNCA triplication. INTERPRETATION: Taken together, the data indicate that our hMLOs harboring 2 major risk factors (glucocerebrosidase deficiency and wild-type α-syn overproduction) of Parkinson disease provide a tractable model to further elucidate the underlying mechanisms for progressive Lewy body formation. ANN NEUROL 2021;90:490-505.

Elevated holo-transcobalamin in Gaucher disease type II: A case report.

Gaucher disease (GD), one of the most common lysosomal disorders, is caused by deficiency of ß-glucocerebrosidase. Based on the presence and severity of neurological complications, GD is classified into types I, II (the most severe form), and III. Abnormalities in systemic markers of vitamin B12 (B12 ) metabolism have been reported in GD type I patients, suggesting a higher prevalence of B12 deficiency in these patients. A 2-month-old male with GD type II was admitted to the hospital presenting jaundice, hepatosplenomegaly, and ichthyosis. At admission, cholestasis and ascites, abnormal liver function enzymes, prolonged prothrombin time, and high levels of B12 were confirmed. Analysis of biomarkers of B12 status revealed elevated B12 and holo-transcobalamin (holo-TC) levels. The B12 profile found in our patient is the opposite to what is described for GD type I patients. Holo-TC may increase in inflammatory states or due to liver diseases. In GD, the accumulation of glucocerebroside may be a trigger that initiates a systemic inflammatory reaction, characterized by macrophage activation. We suggest higher levels of holo-TC could be associated with a more severe (neuronopathic) GD, and be a biomarker of GD type II.

Early initiation of ambroxol treatment diminishes neurological manifestations of type 3 Gaucher disease: A long-term outcome of two siblings.

Gaucher disease type 3 (GD3) is a severely debilitating disorder characterized by multisystemic manifestations and neurodegeneration. Enzyme replacement therapy alleviates visceral signs and symptoms but has no effect on neurological features. Ambroxol has been suggested as an enzyme enhancement agent. Some studies have confirmed its effectiveness in preventing the progression of neurological manifestations of neuronopathic Gaucher disease. In this study, we report two GD3 siblings in whom ambroxol combined with enzyme replacement therapy was initiated at different stages of the disease. We demonstrate the enzyme enhancement effect of ambroxol on L444P/H225Q;D409H glucocerebrosidase activity through results of fibroblast studies and long-term clinical outcomes of the two patients. The sibling diagnosed at the age of four-and-a-half years with significant neurological involvement manifested relatively rapid improvement on ambroxol treatment, followed by stabilization of further course. The younger sibling, in whom the treatment was started at seven weeks, displayed attention deficit and low average cognitive functioning at the age of seven years, but did not manifest other neurological symptoms. The difference in neurological outcomes indicates that ambroxol delayed or even halted the evolution of neurological manifestations in the younger sibling. This observation suggests that early initiation of ambroxol treatment may arrest neurological involvement in some GD3 patients.

Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles.

Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson's disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations in glucosidase, beta acid 1 (GBA), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster disease progression. To explore how GBA mutations influence pathogenesis, we previously created a Drosophila model of GBA deficiency (Gba1b) that manifests neurodegeneration and accelerated protein aggregation. Proteomic analysis of Gba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from Gba1b mutants. Accordingly, we hypothesized that GBA may influence pathogenic protein aggregate spread via EVs. We found that accumulation of ubiquitinated proteins and Ref(2)P, Drosophila homologue of mammalian p62, were reduced in muscle and brain tissue of Gba1b flies by ectopic expression of wildtype GCase in muscle. Neuronal GCase expression also rescued protein aggregation both cell-autonomously in brain and non-cell-autonomously in muscle. Muscle-specific GBA expression reduced the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from Gba1b flies. Perturbing EV biogenesis through neutral sphingomyelinase (nSMase), an enzyme important for EV release and ceramide metabolism, enhanced protein aggregation when knocked down in muscle, but did not modify Gba1b mutant protein aggregation when knocked down in neurons. Lipidomic analysis of nSMase knockdown on ceramide and glucosylceramide levels suggested that Gba1b mutant protein aggregation may depend on relative depletion of specific ceramide species often enriched in EVs. Finally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency promotes accelerated protein aggregate spread between cells and tissues via dysregulated EVs, and EV-mediated trafficking of GCase may partially account for the reduction in aggregate spread.

Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Fibroblasts from idiopathic Parkinson's disease exhibit deficiency of lysosomal glucocerebrosidase activity associated with reduced levels of the trafficking receptor LIMP2.

Lysosomal dysfunction is a central pathway associated with Parkinson's disease (PD) pathogenesis. Haploinsufficiency of the lysosomal hydrolase GBA (encoding glucocerebrosidase (GCase)) is one of the largest genetic risk factors for developing PD. Deficiencies in the activity of the GCase enzyme have been observed in human tissues from both genetic (harboring mutations in the GBA gene) and idiopathic forms of the disease. To understand the mechanisms behind the deficits of lysosomal GCase enzyme activity in idiopathic PD, this study utilized a large cohort of fibroblast cells from control subjects and PD patients with and without mutations in the GBA gene (N370S mutation) (control, n = 15; idiopathic PD, n = 31; PD with GBA N370S mutation, n = 6). The current data demonstrates that idiopathic PD fibroblasts devoid of any mutations in the GBA gene also exhibit reduction in lysosomal GCase activity, similar to those with the GBA N370S mutation. This reduced GCase enzyme activity in idiopathic PD cells was accompanied by decreased expression of the GBA trafficking receptor, LIMP2, and increased ER retention of the GBA protein in these cells. Importantly, in idiopathic PD fibroblasts LIMP2 protein levels correlated significantly with GCase activity, which was not the case in control subjects or in genetic PD GBA N370S cells. In conclusion, idiopathic PD fibroblasts have decreased GCase activity primarily driven by altered LIMP2-mediated transport of GBA to lysosome and the reduced GCase activity exhibited by  the genetic GBA N370S derived PD fibroblasts occurs through a different mechanism.

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review.

The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with GD. Literature searches were conducted using MEDLINE, Embase, PubMed, ScienceOpen, Science.gov, Biological Abstracts, and Sci-Hub to identify original research articles relevant to lyso-Gb1 and GD published before March 2019. Seventy-four articles met the inclusion criteria, encompassing 56 related to pathology and 21 related to clinical biomarkers. Evidence for lyso-Gb1 as a pathogenic mediator of GD was unequivocal, although its precise role requires further elucidation. Lyso-Gb1 was deemed a statistically reliable diagnostic and pharmacodynamic biomarker in GD. Evidence supports lyso-Gb1 as a disease-monitoring biomarker for GD, and some evidence supports lyso-Gb1 as a prognostic biomarker, but further study is required. Lyso-Gb1 meets the criteria for a biomarker as it is easily accessible and reliably quantifiable in plasma and dried blood spots, enables the elucidation of GD molecular pathogenesis, is diagnostically valuable, and reflects therapeutic responses. Evidentiary standards appropriate for verifying inter-laboratory lyso-Gb1 concentrations in plasma and in other anatomical sites are needed.

Gaucher disease-associated alterations in mesenchymal stem cells reduce osteogenesis and favour adipogenesis processes with concomitant increased osteoclastogenesis.

Gaucher disease (GD) is caused by pathogenic mutations in GBA1, the gene that encodes the lysosomal enzyme ß-glucocerebrosidase. Until now, treatments for GD cannot completely reverse bone problems. The aim of this work was to evaluate the potential of MSCs from GD patients (GD MSCs) to differentiate towards the osteoblast (GD Ob) and adipocyte (GD Ad) lineages, and their role in osteoclastogenesis. We observed that GD Ob exhibited reduced mineralization, collagen deposition and alkaline phosphatase activity (ALP), as well as decreased gene expression of RUNX2, COLA1 and ALP. We also evaluated the process of osteoclastogenesis and observed that conditioned media from GD MSCs supernatants induced an increase in the number of osteoclasts. In this model, osteoclastogenesis was induced by RANKL and IL-1ß. Furthermore, results showed that in GD MSCs there was a promotion in NLRP3 and PPAR-γ gene expression. Adipogenic differentiation revealed that GD Ad had an increase in PPAR-γ and a reduced RUNX2 gene expression, promoting adipocyte differentiation. In conclusion, our results show that GD MSCs exhibited deficient GD Ob differentiation and increased adipogenesis. In addition, we show that GD MSCs promoted increased osteoclastogenesis through RANKL and IL-1ß. These changes in GD MSCs are likely to contribute to skeletal imbalance observed in GD patients.

Systemic enzyme delivery by blood-brain barrier-penetrating SapC-DOPS nanovesicles for treatment of neuronopathic Gaucher disease.

BACKGROUND: Enzyme replacement therapy (ERT) can positively affect the visceral manifestations of lysosomal storage diseases (LSDs). However, the exclusion of the intravenous ERT agents from the central nervous system (CNS) prevents direct therapeutic effects. METHODS: Using a neuronopathic Gaucher disease (nGD) mouse model, CNS-ERT was created using a systemic, non-invasive, and CNS-selective delivery system based on nanovesicles of saposin C (SapC) and dioleoylphosphatidylserine (DOPS) to deliver to CNS cells and tissues the corrective, functional acid ß-glucosidase (GCase). FINDINGS: Compared to free GCase, human GCase formulated with SapC-DOPS nanovesicles (SapC-DOPS-GCase) was more stable in serum, taken up into cells, mostly by a mannose receptor-independent pathway, and resulted in higher activity in GCase-deficient cells. In contrast to free GCase, SapC-DOPS-GCase nanovesicles penetrated through the blood-brain barrier into the CNS. The CNS targeting was mediated by surface phosphatidylserine (PS) of blood vessel and brain cells. Increased GCase activity and reduced GCase substrate levels were found in the CNS of SapC-DOPS-GCase-treated nGD mice, which showed profound improvement in brain inflammation and neurological phenotypes. INTERPRETATION: This first-in-class CNS-ERT approach provides considerable promise of therapeutic benefits for neurodegenerative diseases. FUNDING: This study was supported by the National Institutes of Health grants R21NS 095047 to XQ and YS, R01NS 086134 and UH2NS092981 in part to YS; Cincinnati Children's Hospital Medical Center Research Innovation/Pilot award to YS and XQ; Gardner Neuroscience Institute/Neurobiology Research Center Pilot award to XQ and YS, Hematology-Oncology Programmatic Support from University of Cincinnati and New Drug State Key Project grant 009ZX09102-205 to XQ.

The definition of neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.

Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.

Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson's disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1-/-) mice. We now show that stimulation with physiological glutamate concentrations causes pathological [Ca2+]c responses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca2+ uptake was reduced in gba1-/- cells as was expression of the mitochondrial calcium uniporter. The rate of free radical generation was increased in gba1-/- neurons. Behavior of gba1+/- neurons was similar to gba1-/- in terms of all variables, consistent with a contribution of these mechanisms to the pathogenesis of PD. These data signpost reduced bioenergetic capacity and [Ca2+]c dysregulation as mechanisms driving neurodegeneration.

Role of ß-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish.

ß-glucosidases [GBA1 (glucocerebrosidase) and GBA2] are ubiquitous essential enzymes. Lysosomal GBA1 and cytosol-facing GBA2 degrade glucosylceramide (GlcCer); GBA1 deficiency causes Gaucher disease, a lysosomal storage disorder characterized by lysosomal accumulation of GlcCer, which is partly converted to glucosylsphingosine (GlcSph). GBA1 and GBA2 also may transfer glucose from GlcCer to cholesterol, yielding glucosylated cholesterol (GlcChol). Here, we aimed to clarify the role of zebrafish Gba2 in glycosphingolipid metabolism during Gba1 deficiency in zebrafish (Danio rerio), which are able to survive total Gba1 deficiency. We developed Gba1 (gba1-/-), Gba2 (gba2-/-), and double (gba1-/-:gba2-/-) zebrafish knockouts using CRISPR/Cas9 and explored the effects of both genetic and pharmacological interventions on GlcCer metabolism in individual larvae. Activity-based probes and quantification of relevant glycolipid metabolites confirmed enzyme deficiency. GlcSph increased in gba1-/- larvae (0.09 pmol/fish) but did not increase more in gba1-/-:gba2-/- larvae. GlcCer was comparable in gba1-/- and WT larvae but increased in gba2-/- and gba1-/-:gba2-/- larvae. Independent of Gba1 status, GlcChol was low in all gba2-/- larvae (0.05 vs. 0.18 pmol/fish in WT). Pharmacologic inactivation of zebrafish Gba1 comparably increased GlcSph. Inhibition of GlcCer synthase (GCS) in Gba1-deficient larvae reduced GlcCer and GlcSph, and concomitant inhibition of GCS and Gba2 with iminosugars also reduced excessive GlcChol. Finally, overexpression of human GBA1 and injection of recombinant GBA1 both decreased GlcSph. We determined that zebrafish larvae offer an attractive model to study glucosidase actions in glycosphingolipid metabolism in vivo, and we identified distinguishing characteristics of zebrafish Gba2 deficiency.

Age-related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia.

Heterozygous mutations in GBA1, the gene which encodes the lysosomal enzyme glucocerebrosidase (GCase), are a strong genetic risk factor for the development of Lewy body dementia (LBD). Until this point however, recapitulation of the symptoms and pathology of LBD has been limited to a homozygous GBA1 mouse model which genetically and enzymatically reflects the lysosomal storage disorder Gaucher's disease. This study reports for the first time cognitive impairment by two independent behavioural tests in heterozygous GBA1 mutant mice (D409V/WT) which demonstrate significant cognitive impairment by the age of 12 months. Furthermore, reductions in GBA1 GCase enzyme activity within the brain reflects levels seen in sporadic and GBA1 mutant LBD patients. While there is no overt deposition of Lewy bodies within the hippocampus, alterations to cholinergic machinery and glial proliferation are evident, both pathological features of LBD. Interestingly, we also describe the novel finding of significantly reduced GBA2 GCase enzyme activity specifically within the hippocampus. This suggests that reduced GBA1 GCase enzyme activity dis-equilibrates the finely balanced glycosphingolipid metabolism pathway and that reductions in GBA2 GCase enzyme could contribute to the pathological and behavioural effects seen. Overall, this study presents evidence to suggest that pathological hallmarks associated with LBD specifically affecting brain regions intrinsically linked with cognition are present in the D409V/WT mice. In the absence of Lewy body deposition, the D409V/WT mice could be considered an early pre-clinical model of LBD with potential for drug discovery. Since few robust pre-clinical models of LBD currently exist, with further characterization, the mouse model described here may contribute significantly to developments in the LBD field.

Gene expression profile in patients with Gaucher disease indicates activation of inflammatory processes.

Gaucher disease (GD) is a rare inherited metabolic disease caused by pathogenic variants in the GBA1 gene. So far, the pathomechanism of GD was investigated mainly in animal models. In order to delineate the molecular changes in GD cells we analysed gene expression profile in cultured skin fibroblasts from GD patients, control individuals and, additionally, patients with Niemann-Pick type C disease (NPC). We used expression microarrays with subsequent validation by qRT-PCR method. In the comparison GD patients vs. controls, the most pronounced relative fold change (rFC) in expression was observed for genes IL13RA2 and IFI6 (up-regulated) and ATOH8 and CRISPLD2 (down-regulated). Products of up-regulated and down-regulated genes were both enriched in genes associated with immune response. In addition, products of down-regulated genes were associated with cell-to-cell and cell-to-matrix interactions, matrix remodelling, PI3K-Akt signalling pathway and a neuronal survival pathway. Up-regulation of PLAU, IFIT1, TMEM158 and down-regulation of ATOH8 and ISLR distinguished GD patients from both NPC patients and healthy controls. Our results emphasize the inflammatory character of changes occurring in human GD cells indicating that further studies on novel therapeutics for GD should consider anti-inflammatory agents.

Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: Final results from the Phase 2 trial.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) and poor, intermediate or extensive CYP2D6-metabolizer phenotypes (>90% of patients). We report the final results of a Phase 2 trial and extension (NCT00358150) in previously untreated adult GD1 patients who had splenomegaly with thrombocytopenia and/or anemia and received 50 or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg eliglustat) twice daily for 8 years. In total, 19 of 26 patients completed the trial. After 8 years of eliglustat, mean spleen and liver volumes decreased by 69% and 34%, respectively. Mean hemoglobin concentration and platelet count increased by 2.2 g/dL and 113%, respectively. All patients met at least 3 of 4 therapeutic goals established for patients on long-term enzyme replacement therapy. Mean final values for patients with severe splenomegaly (n = 6), moderate-to-severe anemia (n = 6), or severe thrombocytopenia (n = 8) were similar to patients with milder disease at baseline and within long-term therapeutic goal thresholds. Biomarker median percent changes from baseline were -91% for chitotriosidase, -87% for CCL18, -92% for glucosylsphingosine, and -80% for plasma glucosylceramide. Mean lumbar spine T-score increased by 0.96, moving from the osteopenic to the normal range. Mean quality-of-life scores, mostly below normal at baseline, moved into ranges seen in healthy adults. Eliglustat was well-tolerated; 98% of adverse events were mild or moderate and 94% were considered unrelated to treatment. Clinically meaningful improvements in all parameters continued or were maintained over 8 years, with the largest margins of improvement seen in the most severely affected patients.

Pharmacological treatment of pediatric Gaucher disease.

INTRODUCTION: Gaucher disease (GD) is an autosomal recessive disorder resulting from the deficiency of the lysosomal enzyme glucocerebrosidase (b-glucosidase), associated with varying degrees of visceral, bone and central nervous system pathology, leading to wide phenotypic diversity. Response to therapy and clinical outcomes are very different between the three clinical subtypes - non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms; hence a definitive clinical diagnosis is essential. The availability of two therapeutic options, i.e. enzyme replacement and substrate reduction, has transformed the natural course of the disease. As pre-treatment disease severity clearly impacts results of therapy, early diagnosis and initiation of treatment especially in the pediatric population are keys to achieving an optimal outcome. Areas covered: We reviewed the literature concerning the treatment of GD focusing on pediatric presentations, various pharmacological treatment options and recommendations for management goals. A PubMed literature search was performed for relevant publications between 1991 and September 2018. Expert commentary: The approval of enzyme replacement therapy (ERT) for GD in the pediatric age group has significantly altered the course of the disease, especially for non-neuronopathic and chronic neuronopathic forms, as ERT does not cross the blood-brain barrier. Early diagnosis, regular follow-up and early initiation of treatment can thus prevent some irreversible complications and improve patient quality of life.

Reduced glucocerebrosidase activity in monocytes from patients with Parkinson's disease.

Missense mutations in glucocerebrosidase (GBA1) that impair the activity of the encoded lysosomal lipid metabolism enzyme (GCase) are linked to an increased risk of Parkinson's disease. However, reduced GCase activity is also found in brain tissue from Parkinson's disease patients without GBA1 mutations, implicating GCase dysfunction in the more common idiopathic form of Parkinson's disease. GCase is very highly expressed in monocytes, and thus we measured GCase activity in blood samples from recently diagnosed Parkinson's disease patients. Flow cytometry and immunoblotting assays were used to measure levels of GCase activity and protein in monocytes and lymphocytes from patients with Parkinson's disease (n = 48) and matched controls (n = 44). Gene sequencing was performed to screen participants for GBA1 missense mutations. In the Parkinson's disease patients, GCase activity was significantly reduced in monocytes, but not lymphocytes, compared to controls, even when GBA1 mutation carriers were excluded. Monocyte GCase activity correlated with plasma ceramide levels in the Parkinson's disease patients. Our results add to evidence for GCase dysfunction in idiopathic Parkinson's disease and warrant further work to determine if monocyte GCase activity associates with Parkinson's disease progression.