Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation.

BACKGROUND: Fabry disease (FD) results from X-linked inheritance of a mutation in the GLA gene, encoding for alpha galactosidase A, and is characterized by heterogeneous clinical manifestations. Two phenotypes have been described "Classic" and "late onset" which cannot be predicted exclusively by genotype. The latter has been considered an attenuated form of the disease often affecting a single organ system commonly the heart. Recent studies have demonstrated that cardiac outcomes are similar in patients with classic and late onset mutations. In this study we investigate the relationship between clinical heterogeneity and plasma lyso-Gb3 in a large single centre cohort of N215S patients and compare this to patients with other mutations. METHODS: In this single-centre, retrospective, cross-sectional study we analysed a cohort of 251 FD patients: 84 N215S mutation (37 males) and 167 non-N215S mutations (58 males). The Mainz severity score index (MSSI) was used as an index of overall disease severity. Cardiac function and morphology were assessed by electrocardiogram and echocardiogram. Left ventricular mass was calculated using the Devereux formula and the left ventricular mass index (LVMI) calculated to adjust for height (g/m2.7). The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). GFR was measured by radio-isotope (chromium-EDTA) method and adjusted for patient height (ml/min/m2.7), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients. RESULTS: N215S patients showed later symptom onset (males: p< 0.0001, females: p<0.03), later development of left ventricular hypertrophy (LVH) (median survival without LVH: 41 (non-N215S) vs. 64 (N215S) years, p< 0.0001), later development of proteinuria (median survival without proteinuria 43 (non-N215S) vs 71 years (N215S), p< 0.0001), later occurrence of cerebrovascular events (stroke/ Transient Ischaemic Attacks (TIA); median survival without stroke: 74 years (non-N215S) vs. not reached (N215S), p< 0.02), later decline in renal function to GFR <60 ml/min/1.73m2 (median survival: 56 (non-N215S) vs. 72 (N215S) years, p< 0.01), and greater overall survival (median survival 81 (N215S) vs. 66 (non-N215S) years, p< 0.0006). Lyso-Gb3 was found to be less elevated in N215S compared to non-N215S male and female patients. However, the N215S population eventually reached an overall severity measured by MSSI comparable to the non-N215S without equivalent elevation of lyso-Gb3 (means: 6.7 vs. 74.3 nmol/L, p < 0.001). In addition, N215S patients showed strong correlations between lyso-Gb3 levels and LVMI, GFR, and MSSI. These associations became stronger when we investigated individuals' life time exposure to lyso-Gb3 (calculated as [lyso-Gb3]*age): MSSI (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001). CONCLUSION: These results demonstrate that the N215S mutation results in a late onset phenotype involving the heart and other organs. Correlations between clinical manifestations and plasma lyso-Gb3 variations in this group suggest a Fabry-relevant disease mechanism for the heterogeneity observed in this group.

A randomised, double-blind, placebo-controlled, crossover study to assess the efficacy and safety of three dosing schedules of agalsidase alfa enzyme replacement therapy for Fabry disease.

Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule.

Enhanced differentiation of osteoclasts from mononuclear precursors in patients with Gaucher disease.

Gaucher disease (GD) is an autosomal recessive disorder caused by deficiency of ß-glucocerebrosidase. Storage of glucosylceramide in reticuloendothelial cells results in multiorgan pathology including bone disease. Established skeletal disease may remain problematic despite Gaucher-specific treatment. Both osteopenia and osteonecrosis have been described but the underlying pathophysiology, in particular the role of monocyte-derived osteoclasts is not well defined. The objective of this study was to explore the effect of glucocerebrosidase deficiency, inhibition and replacement on osteoclast development and function. In cultures derived from GD patients, or where GBA was chemically inhibited multinucleate giant cells expressing markers of osteoclast differentiation occurred earlier and in greater numbers compared to normal controls and the functional capacity of osteoclasts for bone resorption was enhanced. Increases in osteoclast number and activity correlated with radiological markers of active bone disease. Abnormalities were reversed by addition of specific therapies and were attenuated by co-culture with cells derived from healthy controls (HCs). Numbers of osteoblast lineage cells in the peripheral blood were mismatched to osteoclast precursors indicating uncoupling of osteoblast-osteoclast regulation which may further impact on bone remodelling. Elucidation of the underlying mechanisms of these changes will suggest rational therapies for the most disabling aspect of this condition.

Diagnosing Gaucher disease: an on-going need for increased awareness amongst haematologists.

Gaucher disease (GD) is an inherited enzyme deficiency characterised by progressive cytopenias, hepatosplenomegaly and destructive bone disease. It is diagnosed by demonstration of beta glucosidase deficiency but may be suspected in presence of abnormal storage cells on tissue biopsy. Specific treatment is available in the form of enzyme replacement (ERT) and is effective in reversing many disease features. Delayed treatment has been associated with increased disease complications. This retrospective review of a single centre cohort of 86 patients was undertaken to ascertain if the diagnostic journey had improved since the introduction of ERT and commissioning of services. Fifty-six percent of patients presented primarily with features related to thrombocytopenia or splenomegaly with a median time from symptom onset to diagnosis of 2years (range 0.5-26years), 19% experiencing delays of 5 or more years. Seventy-five percent of patients were diagnosed by haematologists, 68% following an abnormal bone marrow biopsy. Raised serum ACE levels, low HDL cholesterol and raised ferritin were identified as prevalent laboratory abnormalities at the time of diagnosis. These features, coupled with the relative preservation of haemoglobin and white cell counts compared to the platelet count, help identify patients presenting to haematologists with a possible diagnosis of GD earlier in the diagnostic pathway.

Left atrial spindle cell sarcoma - case report.

Primary spindle cell sarcoma of the left atrium is an extremely rare tumour. Surgical excision is the mainstay of treatment since it responds poorly to chemotherapy or radiotherapy. In spite of all the treatment, the prognosis remains poor due to inadvertent delay in diagnosis, few therapeutic options and propensity to metastasize. We present a 47-year-old male who underwent a surgical excision of a left atrial mass in February 2010. It was proved to be a high-grade spindle cell sarcoma on histopathology. He presented again in October 2010 with recurrence of the tumour for which he was re-operated. However, the tumour recurred again within one month, to which the patient succumbed.

Late-onset Fabry disease associated with angiokeratoma of Fordyce and multiple cherry angiomas.

Fabry disease (FD) is a lysosomal storage disorder. The prevalence and clinical spectrum is higher than previously thought. The average time between onset of symptoms and diagnosis is 10 years. Early identification of patients is essential to institute enzyme therapy and reduce morbidity. We report the case of a 76-year-old man, who presented with loss of consciousness following exertional chest pain. He was found to have tortuous corneal vessels, > 100 cherry angiomas on his trunk, and angiokeratomas on his scrotum. The latter were indistinguishable from angiokeratoma of Fordyce, a diagnosis reported in 15% of men over the age of 50 years, and generally ignored by them. The patient's α-galactosidase levels were low, and a mutation in exon 5 of the GLA gene was identified on DNA analysis, confirming the diagnosis of FD. This case highlights the importance of considering a diagnosis of FD in all male patients with angiokeratoma. It also raises the question of whether the presence of multiple cherry angiomas in patients with cardiac disease should raise the possible diagnosis of FD.

Long-term outcomes of liver transplantation in type 1 Gaucher disease.

Gaucher disease (GD) is the most prevalent lysosomal storage disorder. Enzyme replacement therapy (ERT) has demonstrable efficacy in reversing clinical and pathological manifestations of GD. We report four patients with GD and severe hepatic impairment who were successfully treated by orthotopic liver transplantation. Liver failure resulted from GD in two patients and due to a comorbidity in two others (HCV and autoimmune chronic active hepatitis). Following successful liver transplantation, patients received long-term ERT. Liver transplantation is a life-saving treatment for end-stage liver disease in patients with Gaucher disease. All four patients have had excellent outcomes from liver transplantation for up to 10 years postprocedure with no evidence of Gaucher-related pathology in the graft.

Anderson-Fabry disease: developments in diagnosis and treatment.

Anderson-Fabry disease (commonly known as Fabry disease) is an X-linked disorder that is caused by deficiency of the lysosomal enzyme a-galactosidase A. The resulting accumulation of globotriaosylceramide leads to a wide spectrum of clinical signs and symptoms that affect many organs, including the kidneys, heart and brain. In recent years, our understanding of the natural history of Fabry disease has improved considerably, as have methods of clinical characterization and diagnosis. It is now apparent that this disorder may be much more common than previously suspected. The long-term efficacy of enzyme replacement therapy (ERT) in reducing disease burden in patients with Fabry disease continues to be demonstrated in clinical trials and observational studies; however, it is clear that ERT has limitations. This review provides an overview of current issues in the diagnosis and treatment of patients with Fabry disease and considers what may lie ahead in this rapidly evolving therapeutic area.

Patients with Gaucher disease living in England show a high prevalence of vitamin D insufficiency with correlation to osteodensitometry.

AIM: Gaucher disease type 1 (GD-1) is the most prevalent lysosomal storage disorder and frequently causes osteopenia and osteoporosis. Adequate vitamin D levels are essential for bone health. The present study retrospectively analyzed 25-hydroxyvitamin D (25[OH]D) in outpatients with GD-1. PATIENTS AND METHODS: Sixty GD-1 patients living at home and with residence in southern or central England (34 men, 26 women), aged 17-85 years (mean 45.0 years) were seen at routine follow-up visits (range: 1-9, mean: 4.4) between January 2003 and July 2007. Overall, 264 blood samples, collected at different seasons of the year, were present for laboratory testing. The retrospective interpretation of vitamin D deficiency was based on different cut-off levels of 25(OH)D (<25 nmol/L, <50 nmol/L, <80 nmol/L) and the seasons of the year. Vitamin D sufficiency was defined as 25(OH)D >80 nmol/L. RESULTS: The mean+/-SD of 25(OH)D was 58.2+/-30.3. Degrees of vitamin D deficiency (<25 nmol/L, <50 nmol/L, <80 nmol/L) were present in 9.1%, 44.3%, 83.0%, vitamin D sufficiency (>80 nmol/L) in only 17.0%, respectively. A significant seasonal variation of 25(OH)D was present. Results of vitamin D deficiency for December-May were 15.7%, 63.8%, 92.9%, and for June-November 2.9%, 26.3%, 73.7%. The 25(OH)D values representing the seasonal nadir observed during the season December-May showed a significant correlation with T-scores and Z-scores of the lumbar spine and hip. Parathyroid hormone and 25(OH)D were inversely correlated. CONCLUSIONS: Vitamin D deficiency is frequent among GD-1 patients. To optimize treatment of GD-1 vitamin D supplementation should be recommended.

Is there a role for scintigraphic imaging of bone manifestations in Gaucher disease? A review of the literature.

Gaucher disease is the most prevalent inherited, lysosomal storage disease and is caused by deficient activity of the enzyme beta-glucocerebrosidase. Bone and bone marrow alterations are frequent in the most prevalent non-neuronopathic form of Gaucher disease. Imaging of bone manifestations in Gaucher disease is performed by a variety of imaging methods, conventional X-ray and MRI as the most frequently and most important ones. However, different modalities of scintigraphic imaging have also been used. This article gives an overview on scintigraphic imaging with respect to bone manifestations in Gaucher disease discussing the advantages and limitations of scintigraphic imaging in comparison to other imaging methods.

Changes of bone metabolism in seven patients with Gaucher disease treated consecutively with imiglucerase and miglustat.

Bone manifestations are frequent in Gaucher disease (GD), the most prevalent lysosomal storage disorder. Currently, therapy with enzyme replacement (ERT) or substrate reduction (SRT) is available. We investigated changes of laboratory parameters associated with bone metabolism in GD patients switching from ERT to SRT. Seven GD patients consecutively treated with ERT and SRT were studied. All patients had different degrees of bone involvement. Laboratory results were acquired at the time of change from ERT to SRT (0 months) and while on SRT (6 months, 12-18 months). Markers of GD activity remained stable or showed statistically insignificant increases. Six patients had stable skeletal manifestations and reported no bone-associated symptoms. One patient presented progressive bone manifestations on magnetic resonance imaging and experienced increasing bone pain. Osteocalcin, alkaline phosphatase, and C-terminal telopeptide of collagen I were initially within the lower part of the normal range and decreased during SRT (alkaline phosphatase P = 0.0169, osteocalcin nonsignificant, C-terminal telopeptide of collagen I nonsignificant). Tartrate-resistant acid phosphatase 5b was initially normal or slightly increased, and macrophage colony-stimulating factor was within the normal lower range; both parameters remained stable. Interleukin-6 was elevated only in the patient with progressive bone disease. Macrophage inflammatory protein 1alpha (MIP-1alpha) was elevated without change after switching to SRT. MIP-1beta was within the normal range, and no values were above 85 ng/mL, indicative of active skeletal disease. From a clinical and metabolic point of view, most skeletal manifestations and bone-associated laboratory parameters remain stable after switch from ERT to SRT.

Safety and efficacy of indigenously developed and manufactured bivalirudin in moderate/high-risk Indian patients undergoing percutaneous coronary intervention: the Bivaflo Registry.

BACKGROUND: Current treatment strategies for percutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) include concomitant use of glycoprotein IIb/IIIa inhibitors (GPI) and antithrombotic therapy such as aspirin, clopidogrel, and unfractionated or low-molecular-weight heparin. The "direct thrombin inhibitor" bivalirudin has been associated with better efficacy and safety than heparin. OBJECTIVE: The present study is performed to evaluate the safety and efficacy of an indigenously developed and manufactured bivalirudin (Bivaflo; Sun Pharmaceutical Industries Ltd., Mumbai) as the primary anticoagulation strategy during PCI in moderate-high risk patients with only provisional use of GPI. METHODS: This prospective multicentered registry enrolled 439 patients in 11 tertiary care centers across India. Patients who had ACS or other clinical/angiographic characteristics, which increase risk during PCI, were enrolled in the registry. Bivaflo was administered as a bolus dose of 0.75 mg/kg, followed by infusion at a rate of 1.75 mg/kg/h during the procedure and optionally 0.25 mg/kg/h for 4 hours after the procedure at investigator's discretion. GPI use was discouraged except as bailout. The primary endpoints were composite and individual incidences of death, myocardial infarction (MI), urgent revascularization, subacute stent thrombosis (SAT), or bleeding at day 7/hospital discharge, whichever was earlier. The secondary endpoints were 30-day composite and individual incidences of death, MI, urgent revascularization, and SAT. RESULTS: The mean age of the group was 58 +/- 10 years and 83% were males. Bivaflo was administered for a mean duration of 102 +/- 79 minutes, and 65% patients received Bivaflo infusion post-PCI. ACT values measured at 10 minutes after bolus and at the end of the PCI were found to be 339 +/- 110 and 336 +/- 104 seconds, respectively. GPI was provisionally used in only 4% (16) patients mostly due to new or suspected thrombus and obstructive dissection with decreased flow. At day 7/hospital discharge, there were no incidences of major adverse cardiac events or major bleeding. Minor bleeding occurred in only 4 patients (0.9%). The 30-day composite major adverse cardiac event rate was 0.68%. One death and two subacute thrombosis occurred during the 30-day follow-up. CONCLUSION: Bivaflo is safe and effective sole anticoagulation strategy during PCI of moderate-high risk patients. Bivaflo administration was associated with no major bleeding events and extremely low in hospital and 30-day MACE rate. These rates were lower than expected MACE rates for such a subgroup of patients based on historical controls.

Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa.

BACKGROUND: Anderson-Fabry disease is an X-linked glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide (Gb(3)) in the lysosomes of cells throughout the body that ultimately results in premature death from renal, cardiac or cerebrovascular complications. Until recently, there was no effective therapy available for this disease. The present study was designed to assess the safety and efficacy of enzyme replacement therapy with agalsidase alfa on the cardiac manifestations of Anderson-Fabry disease. METHOD: The effects of therapy with agalsidase alfa on cardiac structure and function were assessed in a randomised, double-blind, placebo-controlled study of 15 adult male patients with Anderson-Fabry disease. The following parameters were measured at baseline and 6 months: left ventricular mass, QRS duration and levels of Gb(3) in cardiac tissue, urine sediment and plasma. After 6 months of the randomised trial patients were enrolled in a 2-year open-label extension study. RESULTS: Left ventricular mass, as measured by MRI, was significantly reduced following 6 months of treatment with agalsidase alfa compared with placebo (p = 0.041). A mean 20% reduction in myocardial Gb(3) content as assessed by serial transvenous endomyocardial biopsies was demonstrated over the 6 months of enzyme replacement compared to a mean 10% increase in patients receiving placebo (p = 0.42) CONCLUSION: Enzyme replacement therapy with agalsidase alfa resulted in regression of the hypertrophic cardiomyopathy associated with Anderson-Fabry disease.

Access to expensive drugs in the NHS: myths and realities for cancer patients.

SETTING: Patient support organisation (Myeloma UK) and Hospital Myeloma Clinic. TYPE OF STUDY: Case review of two patients, one whose treatment is funded by a private insurance company in the UK, and the other who is funded by the National Health Service (NHS) and questionnaire survey of 51 haematologists from Myeloma UK database. RESULTS: The treatment options available for private patients with myeloma in the UK are broader and more in line with national and international practice than are options available to UK NHS patients. 22/41 (54%) of respondents had received refusals to fund bortezomib by NHS funding agencies; all the rejections had been from Primary Care Trusts in England, which are governed by guidance issued from a different regulator than the other UK countries and subject to divergent local funding arrangements; 19/46 (41%) felt that it was currently (May 2007) more difficult to obtain funding approval for one treatment, bortezomib, than in September 2006, when it received a negative recommendation from the National Institute for health and Clinical Excellence and 15/17 doctors who prescribe on the NHS and privately felt it was easier to obtain bortezomib for a private patient than an NHS patient in the UK. CONCLUSION: The current funding arrangements for new drugs to treat myeloma in the UK are inequitable and do not lend themselves to achieve the best possible outcome for patients.

Multiple myeloma: causes and consequences of delay in diagnosis.

BACKGROUND: Myeloma is a serious and usually fatal haematological malignancy with reported mortality of 10-20% within the first 2 months of presentation. Symptoms are non-specific, and patients thus present to a range of medical practitioners. AIM: To analyse the causes and consequences of a delay in diagnosis of myeloma. DESIGN: Retrospective case review. METHODS: The number and type of disease-related complications present at diagnosis of 92 patients with myeloma were categorized according to the medical practitioner to whom the patient initially presented, the time before diagnosis and the status of the patient at study end in 2006. Overall and disease-free survival were analysed. RESULTS: Duration of symptoms >6 months prior to diagnosis was seen in 40% of the patients, of whom >50% had initially consulted a general practitioner. The most common presenting symptom (67%) was bone pain. The most common complications present at diagnosis were anaemia (54%), bone disease (45%) and renal failure (36%), with the highest frequency of complications in the group experiencing symptoms for >6 months. All patients in this group had two or more complications, while 40% in the group with symptoms for <3 months had no complications. A prolonged time to diagnosis had a significant effect on disease-free survival from both onset of first symptoms (p = 0.043) and from diagnosis (p = 0.003), but not on overall survival. DISCUSSION: A prolonged delay before diagnosis is associated with a significant impact on the clinical course of multiple myeloma. There is a need to raise awareness of the presentation of this condition, especially among general practitioners.