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.

Bone loss and hematological malignancies in adults: a pilot study.

PURPOSE: Bone loss-osteopenia and osteoporosis-is a recognized consequence of solid tumors in adults, of pediatric hematological malignancies, and of the treatment for these diseases, but little research has been published on the adverse effects of hematological malignancies on the bone in adults. The aim of this study is to identify hematological diseases that are associated with the highest prevalence and severity of osteoporosis. METHODS: We evaluated DXA (dual-energy X-ray absorptiometry) in a cross-section of 181 adult patients with hematological neoplasms, excluding multiple myeloma. All patients were over 18 years of age, signed a local institutional review board (IRB)-approved consent form, and had completed a questionnaire regarding predisposing factors to osteoporosis. This data was supplemented by hospital charts. RESULTS: Bone loss as measured by DXA T scores was found in 65% of patients, of whom 38% had osteopenia and 27% osteoporosis. DXA Z scores under - 2.0 were found in 11.4% of patients, compared to the expected 2.5% of the normal population. The DXA Z scores varied by diagnosis, showing bone loss in 49% of chronic lymphocytic leukemia/small lymphocytic lymphoma, compared to 67% of non-Hodgkin lymphoma and 88% of Hodgkin disease; the scores were not affected by the duration of time from diagnosis to DXA (3.6, 2.0, and 1.6 years, respectively). CONCLUSION: Adult patients with hematological malignancies have significant bone loss compared to a normal age-matched population. The type of diagnosis is more important than the time from diagnosis in predicting risk for bone loss. Recognition of bone loss in these patients may warrant prophylactic measures and lifestyle changes before, during, and after therapy.

Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study.

We evaluated clinical and safety outcomes in adult patients with type 1 Gaucher disease receiving miglustat in clinical practice settings. An observational, retrospective cohort study was conducted in centers across the EU and the USA. Medical chart data were collected from consecutive patients between the 20th November 2002 and 31st December 2008. A total of 115 patients were included; 34 (30%) were enzyme replacement therapy-naïve ('naïve') and 81 (70%) were enzyme pretreated ('pretreated'). Median (range) miglustat exposures in these groups were 15.1 (0.6-52.9)months and 15.2 (0.3-62.1)months, respectively. Low numbers of patients were anemic (10/101) or thrombocytopenic (21/101) at initiation of miglustat therapy. The median (range) hemoglobin concentration at miglustat initiation was 12.8 (10.2-16.4)g/dl in naïve patients and 13.6 (7.3-17.4)g/dl in pretreated patients; median (range) changes in hemoglobin were 0.3 (-2.5-3.6) and -0.3 (-4-4.6)g/dl, respectively. The median (range) platelet counts at miglustat initiation were 101 (37-730)×10(9)/l in naïve patients and 173 (43-382)×10(9)/l in pretreated patients; median (range) changes in platelet count were 8 (-77-145)×10(9)/l and -10 (-144-434)×10(9)/l, respectively. Plasma chitotriosidase was substantially reduced in naïve but not in pretreated patients. Organ volumes were not routinely monitored. Forty-nine (43%) patients discontinued miglustat; most due to gastrointestinal manifestations and some due to tremor. Overall, hemoglobin and platelet counts tended to increase in naïve patients treated with miglustat, and to remain stable or decrease slightly in pretreated patients. The profile of safety and tolerability observed with miglustat in the current study is similar to previous studies.

Acupuncture for symptoms of Gaucher disease.

OBJECTIVE: The purpose of this study was to examine the effect of acupuncture on bone/joint pain, headache and fatigue, as well as quality of life in patients with Gaucher disease (GD), within the framework of an integrated treatment programme. METHODS: Patients with GD suffering from any of the above symptoms were offered a series of 10-12 weekly acupuncture treatment sessions. Prior to initiation of treatment, participants were asked to score the severity of pain, as well as to complete the Functional Assessment of Chronic Illness Therapy-Fatigue measure (FACIT-F) and the Medical Outcomes Study (MOS) Short-Form (SF) questionnaire. These tools were evaluated again at the end of the treatment period. RESULTS: A total of 12 patients were evaluated. While the only pain outcome reduced by acupuncture was knee pain, a significant improvement was observed with respect to nearly all FACIT-Fatigue measures, including the Physical Well Being (PWB) subscales and the SF-12 Physical Composite Score (PCS), though not for the Mental Composite Score (MCS). Patients reported satisfaction with the treatment process, and no significant side effects were reported. CONCLUSION: Acupuncture may play a beneficial role for patients with GD when used in conjunction with conventional therapy, reducing fatigue and improving physical function. The preliminary finding of this observational study should encourage further research.

Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease.

Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously - usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase - and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed.

A plant-derived recombinant human glucocerebrosidase enzyme--a preclinical and phase I investigation.

UNLABELLED: Gaucher disease is a progressive lysosomal storage disorder caused by the deficiency of glucocerebrosidase leading to the dysfunction in multiple organ systems. Intravenous enzyme replacement is the accepted standard of treatment. In the current report, we evaluate the safety and pharmacokinetics of a novel human recombinant glucocerebrosidase enzyme expressed in transformed plant cells (prGCD), administered to primates and human subjects. Short term (28 days) and long term (9 months) repeated injections with a standard dose of 60 Units/kg and a high dose of 300 Units/kg were administered to monkeys (n = 4/sex/dose). Neither clinical drug-related adverse effects nor neutralizing antibodies were detected in the animals. In a phase I clinical trial, six healthy volunteers were treated by intravenous infusions with escalating single doses of prGCD. Doses of up to 60 Units/kg were administered at weekly intervals. prGCD infusions were very well tolerated. Anti-prGCD antibodies were not detected. The pharmacokinetic profile of the prGCD revealed a prolonged half-life compared to imiglucerase, the commercial enzyme that is manufactured in a costly mammalian cell system. These studies demonstrate the safety and lack of immunogenicity of prGCD. Following these encouraging results, a pivotal phase III clinical trial for prGCD was FDA approved and is currently ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT00258778.

Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies.

BACKGROUND: Bone manifestations are a source of disability among patients with Gaucher disease (GD) and a focus of disease management. The effect of enzyme replacement therapy (ERT) on GD bone disease can be limited and may take up to 8 years to become manifest. Miglustat, a glucosylceramide synthase inhibitor, may have a positive influence on GD bone disease. OBJECTIVES: The aim of this analysis was to evaluate the effects of miglustat on bone manifestations and bone mineral density (BMD) in patients with type 1 GD. METHODS: This was a pooled analysis of data collected prospectively over an observation period of 2 years from patients who participated in 3 multinational, open-label clinical trials evaluating the efficacy and tolerability of miglustat 100 mg TID (the currently approved therapeutic dose). Bone manifestations were assessed qualitatively and in relation to treatment and spleen status. The effects of miglustat on BMD were assessed by dual-energy x-ray absorptiometry at the lumbar spine and/or femoral neck. Bone response was defined as a positive change in BMD, based on the change in BMD Z-score from baseline to months 6, 12, and 24. Changes in BMD were also analyzed according to spleen status and baseline severity of osteopenia. RESULTS: The analysis involved 72 patients, including 41 (57%) who had received previous ERT and 20 (28%) who had undergone splenectomy. Patients' mean (SD) age was 41.2 (13.1) years. The most frequent bone-related manifestations at study entry were osteoporosis (43/63 [68%] patients) and bone pain (41/65 [63%] patients). At 2 years, 54/65 (83%) patients reported no bone pain. The reductions in bone pain were comparable among all subgroups, including high-risk patients (ie, splenectomized). No new cases of bone crisis, avascular necrosis, or pathologic fractures were reported. BMD Z-scores were improved from baseline at both the lumbar spine and femoral neck at each time point (months 6, 12, and 24) (P < 0.001). As early as 6 months after the initiation of miglustat monotherapy, significant increases from baseline in the BMD Z-score were observed at both the lumbar spine (mean, 0.15; P = 0.022) and femoral neck (0.23; P < 0.001); the increases remained significant at 12 months (0.19 [P = 0.012] and 0.21 [P = 0.017], respectively) and 24 months (0.21 [P = 0.015] and 0.18 [P = 0.039]). Significant increases in BMD Z-scores were observed at the femoral neck in splenectomized patients (P < 0.001) and at both sites in osteoporotic patients (lumbar spine: P < 0.001; femoral neck: P = 0.006). CONCLUSION: This pooled analysis of 3 open-label studies of miglustat 100 mg TID suggests that miglustat monotherapy may reduce the incidence of bone pain and improve BMD in patients with type 1 GD, including those with a history of splenectomy and/or osteoporosis.

Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement.

Enzyme replacement therapy (ERT) with imiglucerase reduces hepatosplenomegaly and improves hematologic parameters in Gaucher disease type 1 within 6-24 months. Miglustat reduces organomegaly, improves hematologic parameters, and reverses bone marrow infiltration. This trial evaluates miglustat in patients clinically stable on ERT. Tolerability of miglustat and imiglucerase, alone and in combination, pharmacokinetic profile, organ reduction, and chitotriosidase activity were assessed. Thirty-six patients stable on imiglucerase were randomized into this phase II, open-label trial. Statistically significant changes from baseline were assessed (paired t test) on primary objectives with secondary analyses on biochemical and safety parameters. Liver and spleen volume were unchanged in switched patients. No significant differences were seen between groups regarding mean change in hemoglobin. Mean change in platelet counts was only significant between miglustat and imiglucerase groups (P = .035). Chitotriosidase activity remained stable. In trial extension, clinical endpoints were generally maintained. Miglustat was well tolerated alone or in combination. Miglustat's safety profile was consistent with previous trials; moreover, no new cases of peripheral neuropathy were observed. Gaucher disease type 1 (GD1) parameters were stable in most switched patients. Combination therapy did not show benefit. Findings suggest miglustat could be an effective maintenance therapy in stabilized patients with GD1.

Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.

PURPOSE: Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. METHODS: For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. RESULTS: In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. CONCLUSIONS: It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy.

Orthopedic considerations in Gaucher disease since the advent of enzyme replacement therapy.

Gaucher disease, the most prevalent lysosomal storage disorder, is characterized by hepatosplenomegaly, hypersplenism, and rarely, neurological involvement. The most variable symptoms relate to skeletal disease, and both onset and progression are difficult to predict on the basis of genotype. This review describes findings from a large referral clinic (> 500 patients) and from the literature in the decade since the advent of specific enzyme replacement therapy. Such therapy is effective in reducing visceral and hematological involvement, but its greatest advantage as regards the skeleton is prevention of irreversible damage. Avascular necrosis of the joints-particularly the hips but also the knees and shoulders-and pathological fractures of the long bones including the ribs, as well as episodic "crises' of bone pain in children and young adults, are common manifestations. Various imaging modalities should be performed at baseline for life-long monitoring, and then as required because of specific complaints. Surgical interventions such as joint arthroplasties are important adjuvant treatments in this population; presurgical hematological profiling plus antibiotic cover and postoperative pain control are equally critical. Opportunities for orthopedic consultations with senior surgeons are not abused by our patients. These reflect disease-related morbidity, with greater numbers of requests being made by patients requiring enzyme therapy, who by definition have more severe disease characteristics.

Gaucher disease and the clinical experience with substrate reduction therapy.

Gaucher disease is caused by an enzymatic defect with consequent accumulation of glucocerebroside. Type I, the non-neuronopathic form, is rather common and panethnic. Patients may present with hepatosplenomegaly, anaemia, thrombocytopenia and skeletal or lung involvement. Enzyme replacement therapy ameliorates disease symptoms and signs; however, it involves lifelong intravenous therapy, is costly and is incapable of crossing the blood-brain barrier. Substrate reduction with N-butyldeoxynojirimycin (OGT 918) is a harbinger of oral iminosugars for glycolipid storage disorders. Long-term data in the seminal trial (100 mg three times per day), demonstrate safety and efficacy in adult type I patients naive to enzyme therapy, and suggest its application in patients unwilling or unable to receive enzyme replacement and tolerating side effects, including diarrhoea, weight loss, tremor and peripheral neuropathy (mostly reversible with dose reduction or withdrawal). Dose dependency was demonstrated with 50 mg three times per day. In patients stabilized on enzyme therapy switched from or in combination with enzyme, no deterioration in disease parameters was seen but side effects were as above. Although efficacy is less dramatic than enzyme treatment, it may be that plateaux are achieved asymptotically so therapeutic outcomes with OGT 918 may ultimately be comparable. Yet, given the above side effects and the lack of long-term experience, patients with very mild manifestations would probably not be appropriate candidates.