Twenty years of the Fabry Outcome Survey (FOS): insights, achievements, and lessons learned from a global patient registry.

Background: Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients.

Assessment of plasma lyso-Gb for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease.

Purpose: To assess the utility of globotriaosylsphingosine (lyso-Gb) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat.

Methods: A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups.

Generation of osteoclasts from type 1 Gaucher patients and correlation with clinical and genetic features of disease.

Gaucher disease (GD) is a rare autosomal recessive disorder caused by deficient activity of β-glucocerebrosidase resulting in the accumulation of glucosylceramide. Bone disease is a common feature with radiological evidence in up to 93% of patients. Severity of bone involvement ranges from osteoporosis to pathological fractures.

Impact of sphingolipids on osteoblast and osteoclast activity in Gaucher disease.

Gaucher disease (GD) is an inherited disorder in which mutations in the GBA1 gene lead to deficient β-glucocerebrosidase activity and accumulation of its substrate glucosylceramide. Bone disease is present in around 84% of GD patients, ranging from bone loss including osteopenia and osteonecrosis to abnormal bone remodelling in the form of Erlenmeyer flask formation. The range of severity and variety of types of bone disease found in GD patients indicate the involvement of several mechanisms.

The utility of the FIPI score in predicting long-term clinical outcomes in patients with Fabry disease receiving enzyme replacement therapy with agalsidase alfa.

Fabry disease is a rare X-linked lysosomal storage disorder in which there is deficiency of alpha galactosidase A. Enzyme replacement therapy (ERT) is commercially available and has been demonstrated to improve cardiac and renal outcomes. Predictive scores, such as the Fabry International Prognostic Index (FIPI), have been developed to stratify disease severity; however, these have not been validated to predict outcomes in patients receiving ERT.

Difficulties and barriers in diagnosing Fabry disease: what can be learnt from the literature?

Introduction: Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by deficiency of the lysosomal enzyme alpha galactosidase A. Clinical features include neuropathic pain, rash, proteinuria renal failure, stroke and cardiomyopathy accompanied by a reduced life expectancy. Patients report an average delay of > 10 years between symptom onset and diagnosis.

Gaucher disease: outcome following total hip replacements and effect of enzyme replacement therapy in a cohort of UK patients.

Only a limited number of reports of total hip replacements (THRs) in patients with Gaucher disease (GD) have been published, with the majority showing high rates of early aseptic loosening as well as an increased number of peri-operative complications. We present a series of twelve THRs in nine affected patients, with a mean age of 39 years at the time of surgery (median 37 years; range 27-60 years). We examine the medium- to long-term results and present the outcome scores, survival, and assess the effect of enzyme replacement therapy (ERT).

Functional analysis of variant lysosomal acid glycosidases of Anderson-Fabry and Pompe disease in a human embryonic kidney epithelial cell line (HEK 293 T).

The functional significance of missense mutations in genes encoding acid glycosidases of lysosomal storage disorders (LSDs) is not always clear. Here we describe a method of investigating functional properties of variant enzymes in vitro using a human embryonic kidney epithelial cell line. Site-directed mutagenesis was performed on the parental plasmids containing cDNA encoding for alpha-galactosidase A (α-Gal A) and acid maltase (α-Glu) to prepare plasmids encoding relevant point mutations.

Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson-Fabry Disease survey.

Objectives: The prevalence of Anderson-Fabry disease (AFD) in patients presenting with unexplained left ventricular hypertrophy (LVH) is controversial. The aim of this study was to determine the prevalence of AFD in a large, consecutive cohort of patients with hypertrophic cardiomyopathy (HCM) using rapid mutation screening.

Design, Setting And Patients: A European multicentre cross-sectional study involving 13 referral centres.

An unusual case of transient dermatological reaction to bortezomib in AL amyloidosis.

We report an unusual dermatological reaction to bortezomib in a 61-year-old man with AL amyloidosis. Systemic AL amyloidosis is a rare complication of monoclonal gammopathy or myeloma in which abnormally unstable free light chains cause fibrillary deposits in organs leading to multisystem disease. The treatment of AL amyloidosis is directed at the underlying plasma cell dyscrasia and most regimes have been adapted from myeloma, but drug toxicity is more common in AL amyloidosis because of the more extensive nature of the disease.

A validated disease severity scoring system for Fabry disease.

Fabry disease is a lysosomal storage disorder with onset of adverse signs and symptoms usually during childhood and progressive life-threatening decline in organ functions. A validated and feasible Fabry disease severity scoring system (DS3) is needed to reliably quantify the disease burden, monitor disease progression and treatment response, and compare disease status among patient cohorts in clinical studies. We developed a new Fabry DS3 and tested its reliability and validity using a combination of expert consensus formation and statistical techniques.

Glucosylceramide synthase inhibitors sensitise CLL cells to cytotoxic agents without reversing P-gp functional activity.

Malignant B-cells from most chronic lymphocytic leukaemia (CLL) patients over-express MDR1 encoded P-glycoprotein (P-gp) multidrug efflux pump. Inhibition of glucosylceramide (GC) synthesis has been shown in cell lines to correlate with the expression and function of P-gp and sensitise cancer cells to cytotoxic agents. We investigated the hypothesis that reducing intracellular GC levels will reduce P-gp expression in malignant cells from CLL patients.

Prevalence and clinical significance of cardiac arrhythmia in Anderson-Fabry disease.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme alpha-galactosidase A. More than 60% of patients with AFD have evidence for cardiac involvement; the prevalence and clinical significance of arrhythmia in AFD are unknown. Seventy-eight consecutive patients (mean age 43.

Rituximab in the treatment of refractory autoimmune cytopenias in adults.

We report the results of four cycles of rituximab therapy in eleven patients with chronic warm antibody type autoimmune hemolytic anemia (AIHA) and six patients with chronic idiopathic thrombocytopenia (ITP). The overall response rate was 64% in the AIHA group (3 complete responses and 4 partial responses) and 83% in the ITP group (4 complete responses, 1 partial response). Responses in AIHA patients with underlying lymphoproliferative disorders receiving rituximab with chemotherapy were generally better sustained, whereas responses in ITP were often transient.

Haemorheology in Gaucher disease.

Unlabelled: In Gaucher disease, a deficiency of glucocerebrosidase results in the accumulation of glucocerebroside within the lysosomes of the monocyte-macrophage system. Prior to the availability of enzyme replacement therapy (ERT), splenectomy was often indicated for hypersplenism. Haemorheological abnormalities could be expected in view of the anaemia and abnormal lipid metabolism in these patients and the role of the spleen in controlling erythrocyte quality.

Selective apoptotic killing of malignant hemopoietic cells by antibody-targeted delivery of an amphipathic peptide.

The alpha-helical amphipathic peptide D-(KLAKLAK)2 is toxic to eukaryotic cells if internalized by a suitable targeting mechanism. We have targeted this peptide to malignant hemopoietic cells via conjugation to monoclonal antibodies, which recognize lineage-specific cell surface molecules. An anti-CD19/peptide conjugate efficiently killed 3/3 B lymphoid lines.

Clinical effects and P-glycoprotein inhibition in patients with acute myeloid leukemia treated with zosuquidar trihydrochloride, daunorubicin and cytarabine.

Background And Objectives: P-glycoprotein (P-gp) is a major cause of multidrug resistance (MDR) in acute myelogenous leukemia (AML) and is thought to contribute to the failure of chemotherapy. Zosuquidar trihydochloride (Z.3HCL) is a potent and selective inhibitor of P-gp which rapidly and effectively inhibits drug efflux.

V(H) gene usage differs in germline and mutated B-cell chronic lymphocytic leukemia.

Background And Objectives: Given the prognostic relevance that the identification of mutated and germline subgroups of chronic lymphocytic leukemia (CLL) has recently acquired we set out to analyze in depth individual VH gene usage rearrangements in patients with mutated and germline CLL.

Design And Methods: Using sequence analysis of FR1/JH polymerase chain reaction products, the VH immunoglobulin gene configuration was analyzed in 159 rearranged IgH alleles from 154 CLL patients. Having previously identified a spatial relationship between VH gene usage and JH proximity in patients with acute lymphocytic leukemia (ALL), we performed linear and Poisson regression analysis on patients with germline and mutated CLL against VH rearrangements from normal peripheral blood.

Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs.

We studied the actions of geldanamycin (GA) and herbimycin A (HMA), inhibitors of the chaperone proteins Hsp90 and GRP94, on B chronic lymphocytic leukemia (CLL) cells in vitro. Both drugs induced apoptosis of the majority of CLL isolates studied. Whereas exposure to 4-hour pulses of 30 to 100 nM GA killed normal B lymphocytes and CLL cells with similar dose responses, T lymphocytes from healthy donors as well as those present in the CLL isolates were relatively resistant.

Cytotoxic drugs enhance the ex vivo sensitivity of malignant cells from a subset of acute myeloid leukaemia patients to apoptosis induction by tumour necrosis factor receptor-related apoptosis-inducing ligand.

We have studied the actions of tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) on cells isolated from patients with acute myeloid leukaemia (AML). Apoptosis induction was initially assessed by quantitative morphological analysis. Only 2/19 isolates showed a > 10% increase in apoptotic cells following TRAIL treatment.

Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis.

Activation of the phosphatidylinositol 3- kinase/AKT pathway antagonizes apoptosis in diverse cellular systems. We previously showed that human plasma activated AKT and potently blocked the ability of chlorambucil or gamma radiation to induce apoptosis of B-chronic lymphocytic leukemia (CLL) cells. Here we report experiments that identify albumin as the major component of plasma that blocks CLL cell killing by chlorambucil or radiation.

Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro.

Background And Objectives: The staurosporine derivative PKC412 (CGP41251) is a more selective inhibitor of the conventional isoforms of protein kinase C (PKC) than is the parent compound. In addition to its growth inhibitory properties, PKC412 reverses the efflux function of the multidrug resistance (MDR)-1 gene product, P-glycoprotein (P-gp).

Design And Methods: The in vitro actions of PKC412 were investigated in peripheral blood lymphocytes (PBL) from 4 normal volunteers, B-cell isolates from 3 normal tonsils and 31 patients with B-cell chronic lymphocytic leukemia (B-CLL).

Infusional 5-fluorouracil in Cutaneous Leukaemia: a Novel Palliative Therapy in Haematological Malignancy; Malignancy.

We describe the management of a woman suffering from acute myelomonocytic leukaemia with cutaneous involvement. Following treatment with conventional chemotherapy she was in complete remission, but then suffered an isolated skin relapse. In order to limit side effects and myelotoxicity, an experimental therapy using a continuous infusion of 5-fluorouracil was employed.