Radiographic Cortical Thickness Index Predicts Fragility Fracture in Gaucher Disease.

Background Patients with Gaucher disease (GD) have a high risk of fragility fractures. Routine evaluation of bone involvement in these patients includes radiography and repeated dual-energy x-ray absorptiometry (DXA). However, osteonecrosis and bone fracture may affect the accuracy of DXA. Purpose To assess the utility of DXA and radiographic femoral cortical thickness measurements as predictors of fragility fracture in patients with GD with long-term follow-up (up to 30 years). Materials and Methods Patients with GD age 16 years and older with a detailed medical history, at least one bone image (DXA and/or radiographs), and minimum 2 years follow-up were retrospectively identified using three merged UK-based registries (Gaucherite study, enrollment 2015-2017; Clinical Bone Registry, enrollment 2003-2006; and Mortality Registry, enrollment 1993-2019). Cortical thickness index (CTI) and canal-to-calcar ratio (CCR) were measured by two independent observers, and inter- and intraobserver reliability was calculated. The fracture-predictive value of DXA, CTI, CCR, and cutoff values were calculated using receiver operating characteristic curves. Statistical differences were assessed using univariable and multivariable analysis. Results Bone imaging in 247 patients (123 men, 124 women; baseline median age, 39 years; IQR, 27-50 years) was reviewed. The median follow-up period was 11 years (IQR, 7-19 years; range, 2-30 years). Thirty-five patients had fractures before or at first bone imaging, 23 patients had fractures after first bone imaging, and 189 patients remained fracture-free. Inter- and intraobserver reproducibility for CTI/CCR measurements was substantial (range, 0.96-0.98). In the 212 patients with no baseline fracture, CTI (cutoff, ≤0.50) predicted future fractures with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI: 0.84, 0.99; sensitivity, 92%; specificity, 96%) than DXA T-score at total hip (AUC, 0.78; 95% CI: 0.51, 0.91; sensitivity, 64%; specificity, 93%), femoral neck (AUC, 0.73; 95% CI: 0.50, 0.86; sensitivity, 64%; specificity, 73%), lumbar spine (AUC, 0.69; 95% CI: 0.49, 0.82; sensitivity, 57%; specificity, 63%), and forearm (AUC, 0.78; 95% CI: 0.59, 0.89; sensitivity, 70%; specificity, 70%). Conclusion Radiographic cortical thickness index of 0.50 or less was a reliable independent predictor of fracture risk in Gaucher disease. Clinical trial registration no. NCT03240653 © RSNA, 2022 Supplemental material is available for this article.

Evaluation of the Nutritional Status of Gaucher Disease Type I Patients under Enzyme Replacement Treatment.

(1) Background: Gaucher disease (GD) is a rare lysosomal storage disease. The few studies analyzing Resting Energy Expenditure (REE) in GD involved mainly untreated patients and supported a hypermetabolic condition possibly due to the associated inflammatory state. Definitive conclusions could not be drawn also because of the heterogeneity and the small size of the samples investigated. In order to expand current knowledge concerning, in particular the condition of patients under Enzyme Replacement Therapy (ERT), we evaluated the nutritional status of a relatively large sample of GD patients followed at Federico II University Hospital in Naples, Italy. (2) Methods: The study, having a cross-sectional design and involving 26 patients on ERT, included routine biochemical analyses, bioelectrical impedance analysis, indirect calorimetry, and administration of food frequency and physical activity questionnaires. The results in GD patients were compared with those from an appropriate control group. (3) Results: GD patients had normal biochemical parameters in 80% of cases, except for HDL-cholesterol, consumed a hyper-lipidic diet, and had a 60% prevalence of overweight/obesity. Body composition did not differ between patients and controls; however, measured REE was significantly lower than predicted and was reduced in comparison with the healthy controls. (4) Conclusions: This study provided novel elements to the present knowledge about REE and the nutritional status of GD patients under ERT. Its results warrant confirmation in even larger GD population samples and a more in-depth investigation of the long-term effects of treatment superimposed on the basic pathophysiological disease condition.

Gaucher Disease Diagnosis Using Lyso-Gb1 on Dry Blood Spot Samples: Time to Change the Paradigm?

For years, the gold standard for diagnosing Gaucher disease (GD) has been detecting reduced ß-glucocerebrosidase (GCase) activity in peripheral blood cells combined with GBA1 mutation analysis. The use of dried blood spot (DBS) specimens offers many advantages, including easy collection, the need for a small amount of blood, and simpler transportation. However, DBS has limitations for measuring GCase activity. In this paper, we recount our cross-sectional study and publish seven years of experience using DBS samples and levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1), for GD diagnosis. Of 444 screened subjects, 99 (22.3%) were diagnosed with GD at a median (range) age of 21 (1-78) years. Lyso-Gb levels for genetically confirmed GD patients vs. subjects negative to GD diagnosis were 252 (9-1340) ng/mL and 5.4 (1.5-16) ng/mL, respectively. Patients diagnosed with GD1 and mild GBA1 variants had lower median (range) lyso-Gb1, 194 (9-1050), compared to GD1 and severe GBA1 variants, 447 (38-1340) ng/mL, and neuronopathic GD, 325 (116-1270) ng/mL (p = 0.001). Subjects with heterozygous GBA1 variants (carrier) had higher lyso-Gb1 levels, 5.8 (2.5-15.3) ng/mL, compared to wild-type GBA1, 4.9 (1.5-16), ng/mL (p = 0.001). Lyso-Gb1 levels, median (range), were 5 (2.7-10.7) in heterozygous GBA1 carriers with Parkinson's disease (PD), similar to lyso-Gb1 levels in subjects without PD. We call for a paradigm change for the diagnosis of GD based on lyso-Gb1 measurements and confirmatory GBA1 mutation analyses in DBS. Lyso-Gb1 levels could not be used to differentiate between heterozygous GBA1 carriers and wild type.

A scientific pharmacognosy on Gaucher's disease: an in silico analysis.

From ancient times, studies on herbal medicine and pharmacognosy have increased gradually worldwide, due to the increased side effects, adverse drug reactions, and charge lines of modern medicines. Plants are well known for their medicinal effects and nutritional values. They contain bioactive compounds which display a wide spectrum of therapeutic effects. Gaucher's disease (GD) is a rare autosomal recessively inherited metabolic disorder caused due to the defect in Glucosylceramidase beta gene coding for the enzyme acid-ß-glucosidase in humans. We revealed the profound binding efficiency of five selected bioactive compounds from different plants against the main enzyme acid-ß-glucosidase responsible for GD through molecular docking. An in silico approach along with the ADMET profiles of phytocompounds was done using the Schrodinger software. The preventive measure of GD leads to side effects, inaccessible and unaffordable which put forth the emergence of phytocompounds which have fewer toxic effects, and one such compound is ß-D-Glucopyranose with the best docking score (-10.28 kcal/mol) and an excellent binding affinity than other ligands, which could be further analyzed for stability using molecular dynamics study and in vitro. Being a dietary supplement, these compounds could be prepared in any form of formulation as a drug.

Assessment of cellular cobalamin metabolism in Gaucher disease.

BACKGROUND: Gaucher disease (GD) is a lysosomal disorder caused by biallelic pathogenic mutations in the GBA1 gene that encodes beta-glucosidase (GCase), and more rarely, by a deficiency in the GCase activator, saposin C. Clinically, GD manifests with heterogeneous multiorgan involvement mainly affecting hematological, hepatic and neurological axes. This disorder is divided into three types, based on the absence (type I) or presence and severity (types II and III) of involvement of the central nervous system. At the cellular level, deficiency of GBA1 disturbs lysosomal storage with buildup of glucocerebroside. The consequences of disturbed lysosomal metabolism on biochemical pathways that require lysosomal processing are unknown. Abnormal systemic markers of cobalamin (Cbl, B12) metabolism have been reported in patients with GD, suggesting impairments in lysosomal handling of Cbl or in its downstream utilization events. METHODS: Cultured skin fibroblasts from control humans (n = 3), from patients with GD types I (n = 1), II (n = 1) and III (n = 1) and an asymptomatic carrier of GD were examined for their GCase enzymatic activity and lysosomal compartment intactness. Control human and GD fibroblasts were cultured in growth medium with and without 500 nM hydroxocobalamin supplementation. Cellular cobalamin status was examined via determination of metabolomic markers in cell lysate (intracellular) and conditioned culture medium (extracellular). The presence of transcobalamin (TC) in whole cell lysates was examined by Western blot. RESULTS: Cultured skin fibroblasts from GD patients exhibited reduced GCase activity compared to healthy individuals and an asymptomatic carrier of GD, demonstrating a preserved disease phenotype in this cell type. The concentrations of total homocysteine (tHcy), methylmalonic acid (MMA), cysteine (Cys) and methionine (Met) in GD cells were comparable to control levels, except in one patient with GD III. The response of these metabolomic markers to supplementation with hydroxocobalamin (HOCbl) yielded variable results. The content of transcobalamin in whole cell lysates was comparable in control human and GD patients. CONCLUSIONS: Our results indicate that cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts. Extending these studies to hepatocytes, macrophages and plasma will shed light on cell- and compartment-specific vitamin B12 metabolism in Gaucher disease.

Oxidative Stress Parameters, Trace Elements, and Lipid Profile in Iranian Patients with Gaucher Disease.

Gaucher disease (GD) is most frequent disorder of glycolipid storage. The glucosylceramide accumulation might lead to oxidative stress and changes in lipid profile. Regarding the main role of trace elements in hematopoiesis and oxidative stress, this study was aimed to evaluate the zinc and copper levels, three oxidative stress parameters, and lipid profile in GD. Thirty-three patients with GD along with 64 age- and sex-matched healthy controls participated in the study. The levels of zinc and copper were determined using atomic absorption/flame emission spectrophotometer. Malondialdehyde level was measured using HPLC. Total antioxidant capacity (TAC), catalase activity, and lipid profile were assessed using colorimetric methods. Data were analyzed using SPSS software version 16.0. Significant decrease in the serum levels of Zn (p < 0.001) and Cu (p < 0.001) was observed in patients with GD compared to controls. Subjects in control group showed significantly higher levels of TAC than patients with GD (p < 0.001). In contrast, plasma concentration of malondialdehyde was insignificantly higher in patients with GD than controls (p = 0.06). There was a direct correlation between TAC and hemoglobin concentration (p = 0.035; r = 0.369) in patients with GD. Furthermore, the calculated area under receiver operating characteristic curve for HDL cholesterol was equal to 0.938. The results showed that both zinc and copper levels decreased in patients with GD. Patients with GD showed decreased serum content of TAC. It was found that improving the deficiency of zinc and copper by supplementing them could be useful in management of patients with GD.

Liquid chromatography-tandem mass spectrometric method for the quantification of eliglustat in rat plasma and the application in a pre-clinical study.

Eliglustat is an oral substrate reduction therapy drug and has been approved as a first-line treatment for adults with Gaucher disease type 1 (GD 1). In the present study, we aimed to develop and establish an accurate and simple ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the measurement of eliglustat concentration in rat plasma. The goal of chromatographic separation of eliglustat and the internal standard (bosutinib) was finished on an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 µm) column. Acetonitrile and 0.1% formic acid in water were employed as the mobile phase in a mode of gradient elution with the 0.40 mL/min flow rate. The detection was carried out on a XEVO TQ-S triple quadrupole tandem mass spectrometer coupled with electrospray ionization (ESI) interface in the positive-ion mode. Multiple reaction monitoring (MRM) was used to monitor the precursor-to-product ion transitions of m/z 405.4 → 84.1 for eliglustat and m/z 530.2 → 141.2 for bosutinib (IS), respectively. It was found that the linearity of the method in the range of 1-500 ng/mL was good for eliglustat. The values of intra- and inter-day accuracy and precision were all within the acceptance limits, and no matrix effect was found in this method. The current developed method was further performed to support in vivo pharmacokinetic study of eliglustat after oral treatment with 10 mg/kg eliglustat to rats.

Bone manifestations in neuronopathic Gaucher disease while receiving high-dose enzyme replacement therapy.

Avascular necrosis (AVN), one type of bone infarction, is a major irreversible complication of Gaucher disease (GD). In this report, two pediatric patients with GD type 3, homozygous for the L483P pathogenic variant (formerly L444P), developed AVN despite treatment on long-term, high-dose enzyme replacement therapy (ERT). ERT was initiated in both patients, who had intact spleens, shortly after diagnosis with an initial dramatic response. However, both patients exhibited AVN after 5.5 and 11 years on high-dose ERT, respectively, despite good compliance and normalized hematological findings and visceral symptoms. This report demonstrates the importance of careful, regular surveillance of the musculoskeletal system in addition to monitoring the neurological symptoms associated with neuronopathic GD. Additionally, it highlights the limitations of ERT in terms of targeting certain sanctuary sites such as bone marrow and suggests the need for new treatment modalities other than ERT monotherapy to address these limitations.

Neuronopathic Gaucher disease presenting with microcytic hypochromic anemia.

Gaucher disease (GD) is caused by a hereditary deficiency of glucocerebrosidase, resulting in accumulation of glucosylceramide and potentially manifesting as hepatosplenomegaly. We report the case of a 15-month-old boy with chronic neuronopathic GD. The patient had prolonged anemia despite continued iron supplementation for 3 months. White blood count (WBC), hemoglobin (Hb), platelet count, and corrected reticulocyte count were 3,300 /µL, 8.7 g/dL, 90,000 /µL, and 0.55, respectively. The patient had microcytic hypochromic anemia with mildly elevated ferritin. Physical examination revealed hepatosplenomegaly. Bone-marrow aspiration showed sheets of Gaucher cells. Glucocerebrosidase activity in monocytes was significantly lower than normal. Genetic analysis revealed a homozygous L444P mutation of GBA, and he was diagnosed with type 1 GD. Enzyme replacement treatment (ERT) consisting of imiglucerase was initiated and was effective; WBC, Hb, and platelet count gradually normalized and the hepatosplenomegaly improved. However, when the patient entered elementary school, he showed mild impaired cognitive function, and supranuclear gaze palsy occurred the same year. He was ultimately diagnosed with type 3 GD and continued ERT. Pediatric hemato-oncologists should be aware of GD, especially when patients exhibit anemia refractory to iron therapy, radiologic bone deformity, neurologic signs or symptoms, and growth retardation.

Thalamic and dentate nucleus abnormalities in the brain of children with Gaucher disease.

Gaucher disease (GD) represents the most common lysosomal storage defect. It is classified into three phenotypes: type 1 non-neuronopathic, type 2 acute neuronopathic, and type 3 subacute/chronic neuronopathic. Although children affected by GD may present with a broad spectrum of neurological signs, brain magnetic resonance imaging (MRI) findings are usually normal or non-specific. We report three cases of GD with previously undescribed brain MRI changes mainly affecting the thalami and/or the dentate nuclei. We discuss the possible etiopathogenesis of these abnormalities. Correlation between brain MRI abnormalities, neurological symptoms, and treatment efficacy is still unclear.

Probing the Inhibitor versus Chaperone Properties of sp²-Iminosugars towards Human ß-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease.

A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 ß-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N'-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.

Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports.

BACKGROUND: Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods. CASE PRESENTATION: We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms. The first patient was diagnosed at age 17 and developed Gaucher disease-related bone manifestations that worsened despite starting imiglucerase enzyme replacement therapy. After switching to miglustat substrate reduction therapy, her bone symptoms improved, but she developed tremors and eventually switched back to enzyme replacement therapy. Miglustat was later recommenced in combination with ongoing enzyme replacement therapy due to continued bone pain, and her bone symptoms improved along with maintained visceral manifestations. Enzyme replacement therapy was subsequently tapered off and the patient has since been successfully maintained on miglustat. The second patient was diagnosed aged 3, and commenced imiglucerase enzyme replacement therapy aged 15. After 9 years on enzyme replacement therapy she switched to miglustat substrate reduction therapy and her core symptoms were maintained/stable for 3 years. Imiglucerase enzyme replacement therapy was later added as a boost to therapy and her symptoms were subsequently maintained over a 2.3-year period. However, miglustat was discontinued due to her relocation, necessitating an increase in enzyme replacement therapy dose. Overall, both patients benefited from combination therapy. CONCLUSION: While the majority of Gaucher disease type 1 patients will not need treatment with both substrate reduction therapy and enzyme replacement therapy, the current case reports demonstrate that judicious use of combination therapy may be of benefit in some cases.

Twelve years of experience with miglustat in the treatment of type 1 Gaucher disease: The Spanish ZAGAL project.

We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p<0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate naïve and ERT stabilized patients. No unexpected safety signals were identified during 12-years follow-up.

A new framework for evaluating the health impacts of treatment for Gaucher disease type 1.

BACKGROUND: The Disease Severity Scoring System (DS3) is a validated measure for evaluating Gaucher disease type 1 (GD1) severity. We developed a new framework, consisting of health states, transition probabilities between those states, and preferences for those states (utilities) based on the DS3 to predict long-term outcomes of patients starting treatment. We defined nine mutually exclusive (alive) health states based on three DS3 categories: mild (0 ≤ DS3 ≤ 3.5) without symptoms of bone disease; mild with bone pain, mild with severe skeletal complications (SSC) defined as lytic lesions, avascular necrosis, or fracture; moderate (3.5 < DS3 ≤ 6.5) without SSC; moderate with SSC; marked (6.5 < DS3 ≤ 9.5) without SSC; marked with SSC; severe (9.5 < DS3 ≤ 19) without SSC; and severe with SSC. Health-state transition probabilities and utilities were estimated from a longitudinal sample of patients with GD1 who started enzyme replacement therapy (the DS3 Score Study). Age dependent GD1-specific mortality was derived from published data. We used a Markov state-transition model to illustrate how to estimate time spent in each health state. RESULTS: The average predicted utilities for each health state ranged from 0.76 for mild disease with no clinical symptoms of bone disease to 0.52 with severe disease with SSC. Transition probabilities depended on disease severity (DS3 score) at treatment initiation and whether patients had undergone a total splenectomy or had an intact spleen/partial splenectomy prior to starting treatment. Patients who started treatment with intact or residual spleens spent more time in better health states than those who started treatment with total splenectomy. CONCLUSIONS: This new framework, which is based on the DS3, can be used to project the long-term outcomes of GD1 patients starting treatment. The framework could also be used to compare the long-term outcomes of different GD1 treatment options. TRIAL REGISTRATION: NCT01136304 . Registered: May 31, 2010 (retrospectively registered).

Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease.

BACKGROUND: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal ß-glucocerebrosidase (GCase). In GD, partial or complete loss of GCase activity causes the accumulation of the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine in the lysosomes of macrophages. In this manuscript, we investigated the effects of glycolipids accumulation on lysosomal and mitochondrial function, inflammasome activation and efferocytosis capacity in a THP-1 macrophage model of Gaucher disease. In addition, the beneficial effects of coenzyme Q10 (CoQ) supplementation on cellular alterations were evaluated. Chemically-induced Gaucher macrophages were developed by differentiateing THP-1 monocytes to macrophages by treatment with phorbol 12-myristate 13-acetate (PMA) and then inhibiting intracellular GCase with conduritol B-epoxide (CBE), a specific irreversible inhibitor of GCase activity, and supplementing the medium with exogenous GlcCer. This cell model accumulated up to 16-fold more GlcCer compared with control THP-1 cells. RESULTS: Chemically-induced Gaucher macrophages showed impaired autophagy flux associated with mitochondrial dysfunction and increased oxidative stress, inflammasome activation and impaired efferocytosis. All abnormalities were partially restored by supplementation with CoQ. CONCLUSION: These data suggest that targeting mitochondria function and oxidative stress by CoQ can ameliorate the pathological phenotype of Gaucher cells. Chemically-induced Gaucher macrophages provide cellular models that can be used to investigate disease pathogenesis and explore new therapeutics for GD.

Combination therapy in a patient with chronic neuronopathic Gaucher disease: a case report.

BACKGROUND: The variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease. CASE PRESENTATION: We report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment. CONCLUSIONS: This case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

Successful switch from enzyme replacement therapy to miglustat in an adult patient with type 1 Gaucher disease: a case report.

BACKGROUND: Gaucher disease is one of the most common lipid-storage disorders, affecting approximately 1 in 75,000 births. Enzyme replacement therapy with recombinant glucocerebrosidase is currently considered the first-line treatment choice for patients with symptomatic Gaucher disease type 1. Oral substrate reduction therapy is generally considered a second-line treatment option for adult patients with mild to moderate Gaucher disease type 1 who are unable or unwilling to receive lifelong intravenous enzyme infusions. The efficacy and safety of the oral substrate reduction therapy miglustat (Zavesca®) in patients with Gaucher disease type 1 have been established in both short-term clinical trials and long-term, open-label extension studies. Published data indicate that miglustat can be used as maintenance therapy in patients with stable Gaucher disease type 1 switched from previous enzyme replacement therapy. CASE PRESENTATION: We report a case of a 44-year-old Caucasian man with Gaucher disease type 1 who was initially treated with enzyme replacement therapy but, owing to repeated cutaneous allergic reactions, had to be switched to miglustat after several attempts with enzyme replacement therapy. Despite many attempts, desensitization treatment did not result in improved toleration of imiglucerase infusions, and the patient became unwilling to continue with any intravenous enzyme replacement therapy. He subsequently agreed to switch to oral substrate reduction therapy with miglustat 100 mg twice daily titrated up to 100 mg three times daily over a short period. Long-term miglustat treatment maintained both hemoglobin and platelet levels within acceptable ranges over 8 years. The patient's spleen volume decreased, his plasma chitotriosidase levels stayed at reduced levels, and his bone mineral density findings have remained stable throughout follow-up. The patient's quality of life has remained satisfactory. Miglustat showed good gastrointestinal tolerability in this patient, and no adverse events have been reported. CONCLUSIONS: Oral miglustat therapy proved to be a valid alternative treatment to intravenous enzyme replacement therapy for long-term maintenance in this patient with Gaucher disease type 1, who showed persistent allergic intolerance to imiglucerase infusions. This report exemplifies the type of patient with Gaucher disease type 1 who can benefit from switching from enzyme replacement therapy to substrate reduction therapy.

Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease.

To study the neuronal deficits in neuronopathic Gaucher Disease (nGD), the chronological behavioral profiles and the age of onset of brain abnormalities were characterized in a chronic nGD mouse model (9V/null). Progressive accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) in the brain of 9V/null mice were observed at as early as 6 and 3 months of age for GC and GS, respectively. Abnormal accumulation of α-synuclein was present in the 9V/null brain as detected by immunofluorescence and Western blot analysis. In a repeated open-field test, the 9V/null mice (9 months and older) displayed significantly less environmental habituation and spent more time exploring the open-field than age-matched WT group, indicating the onset of short-term spatial memory deficits. In the marble burying test, the 9V/null group had a shorter latency to initiate burying activity at 3 months of age, whereas the latency increased significantly at ≥12 months of age; 9V/null females buried significantly more marbles to completion than the WT group, suggesting an abnormal response to the instinctive behavior and an abnormal activity in non-associative anxiety-like behavior. In the conditional fear test, only the 9V/null males exhibited a significant decrease in response to contextual fear, but both genders showed less response to auditory-cued fear compared to age- and gender-matched WT at 12 months of age. These results indicate hippocampus-related emotional memory defects. Abnormal gait emerged in 9V/null mice with wider front-paw and hind-paw widths, as well as longer stride in a gender-dependent manner with different ages of onset. Significantly higher liver- and spleen-to-body weight ratios were detected in 9V/null mice with different ages of onsets. These data provide temporal evaluation of neurobehavioral dysfunctions and brain pathology in 9V/null mice that can be used for experimental designs to evaluate novel therapies for nGD.