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Introduction
Skills and Expertise
Current institution
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November 1986 - present
Publications
Publications (418)
Background
The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5–87 years with Gaucher disease in the United Kingdom—an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of...
Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat‐treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9‐month...
Background
The Gaucher Investigative Therapy Evaluation (GAUCHERITE) is a national clinical cohort of 250 patients aged 5–87 years with Gaucher disease - an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly...
Background
Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls.
Methods
We performed...
Background
Gaucher disease (GD) manifests heterogeneously and other conditions are often misdiagnosed in its place, leading to diagnostic delays. The Gaucher Earlier Diagnosis Consensus (GED‐C) initiative proposed a point‐scoring system (PSS) based on the signs and covariables that are most indicative of GD to help clinicians identify which individ...
Background:
Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease-modifying therapies.
Objective:
Cross-sectional and longitudinal survey of prodromal PD si...
Alpha-galactosidase A mutations on chromosome Xq22.1 lead to a reduction in cognate enzyme activity, with resultant accumulation of globotriaosylceramide, and the clinical features of Fabry disease (OMIM 301500). Genotype-phenotype relationship is not straightforward. Disease-specific therapy involves intravenous enzyme infusion or more recently or...
Background
Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognize the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities.
Aims
The Gaucher Earlier Diagnosis Consensus (GED‐C) initiative aimed to ide...
The association between Gaucher disease (GD) and PD (PD)has been described for almost two decades. In the biallelic state (homozygous or compound heterozygous) mutations in the glucocerebrosidase gene (GBA) may cause GD, in which glucosylceramide, the sphingolipid substrate of the glucocerebrosidase enzyme (GCase), accumulates in visceral organs le...
Objectives:
The authors sought to explore the Fabry myocardium in relation to storage, age, sex, structure, function, electrocardiogram changes, blood biomarkers, and inflammation/fibrosis.
Background:
Fabry disease (FD) is a rare, x-linked lysosomal storage disorder. Mortality is mainly cardiovascular with men exhibiting cardiac symptoms earlie...
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 attenuate...
Correlation analyses.
plasma α-Gal A activity and age for males: (A) N215S (n = 36), (B) non-N215S (n = 49), and females: (C) N215S (n = 46), non-N215S (n = 102); ns = not significant.
(TIF)
Mutations included in the non-N215S group.
(PDF)
Correlation analyses.
(A-D) GFR and: (a) plasma α-Gal A activity for males non-N215S (A; n = 42) and females non-N215S (B; n = 94), (b) leukocyte α-Gal A activity for non-N215S males (C; n = 28) and non-N215S females (D; n = 44). (E-H) LVMI and: (a) plasma α-Gal A activity for males (E; n = 44) and non-N215S females (F; n = 76), (b) leukocyte α-Gal...
Correlation analyses.
Plasma globotriaosylsphingosine (Lyso-Gb3) and age for Non-N215S males (blue; n = 9) and non-N215S females (red; n = 36); ns = not significant.
(TIF)
Treatment of Gaucher Disease (GD) is now beset with the abundance of therapeutic options for an individual patient, making the choice of therapy complex for both expert and non‐expert clinicians. The pathogenesis of all disease manifestations is a gene mutation‐driven deficiency of glucocerebrosidase, but the clinical expression and response of eac...
Background
Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes.
Methods
In this multicentre retrospe...
Fabry disease, a lysosomal storage disorder, is a rare inborn error of metabolism caused by deficiency of the enzyme alpha galactosidase A and resulting accumulation of globotriaosylceramide. The symptoms of Fabry disease are heterogeneous including renal failure, cardiac hypertrophy, and stroke and may not be well recognized by non-specialist phys...
Background
Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of α-galactosidase A and the resulting accumulation of the glycosphingolipid globotriaosylceramide (Gb3) and its derivatives, including globotriaosylsphingosine (Lyso-Gb3). Increased cellular and plasma levels of Gb3 and Lyso-Gb3 affect multiple organs,...
Quality of life (QoL) is decreased in patients with Fabry disease (FD). To improve QoL, it is important to understand the influence of FD related characteristics, symptoms, and complications. In this retrospective cohort study we explored the effect of pain (measured by the Brief Pain Inventory), phenotype, treatment, and FD-related complications o...
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 dis...
Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and...
Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease co...
Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to exp...
LysoGb3 in women non-classical men.
(PDF)
Phenotypic classification.
A detailed description of the phenotypic classification method used.
(PDF)
Distribution and number of events per phenotype.
(PDF)
Multivariate analysis with eGFR as dichotomous variable.
(PDF)
Individual eGFR slopes per patient obtained from the linear mixed model.
(PDF)
Statistical analysis.
Formulas and detailed description of the analysis.
(PDF)
Multivariate analysis, excluding renal events.
(PDF)
Estimates of the change in LVM from baseline after 1 year per patient, results from the linear mixed model of the change in LVM.
(PDF)
Background:
The level of plasma globotriaosylsphingosine (lysoGb3) is an indication of disease severity in Fabry disease (FD) and its decrease during enzyme replacement therapy could be a reflection of treatment efficacy. Early treatment of FD may improve clinical outcome, but data to support this hypothesis are scarce. In this study we compared l...
Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype,...
Heterozygote GBA (glucosylceramidase beta) mutations increase the risk of Parkinson's disease (PD). Data based on the measured frequencies of GBA mutated alleles in the healthy population suggest that severe GBA mutations are associated with even higher risk for PD. These data, however, are prone to methodological biases resulting from the rarity o...
The introduction of a home therapy option during clinical trials of velaglucerase alfa in patients with type 1 Gaucher disease marked the first time that home infusions have been permitted during a clinical trial for an investigational drug for Gaucher disease. Home infusions were an available option in 4 open-label velaglucerase alfa clinical stud...
Taliglucerase alfa is an [intravenous] enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell–expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to...
Supporting Information
Introduction
Une analyse en sous-groupes de l’efficacite et la tolerance de la velaglucerase alfa chez les patients adultes (≥ 18 ans) atteints de la maladie de Gaucher de type 1 (MG1) qui ont participe a une etude d’extension HGT-GCB 044 et qui etaient tous naifs de traitement avant leur participation dans deux etudes (principales) de phase III re...
Introduction
Determiner l’efficacite et la tolerance a long terme des patients atteints de la maladie de Gaucher de type 1 qui ont switche de l’imiglucerase vers la velaglucerase alfa.
Materiels et methodes
Les patients inclus dans cette analyse avaient recu une perfusion de velaglucerase alfa tous les 15 jours dans l’etude HGT-GCB-044, une etude d...
Introduction: Factors relating to clinical variability in Anderson-Fabry
disease (AFD) heterozygotes are not fully known. Understanding
molecular pathways related to onset, progression and severity
of disease in individuals would be valuable in genetic counselling
of patients, optimising treatment to limit progression of renal, cardiac
and cerebrov...
Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published stu...
Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and...
Supporting Information
Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long-term disease-specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirty-eight of 40 patients (aged 9-71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alf...
To estimate the prevalence of prodromal clinical features of neurodegeneration in patients with Anderson-Fabry disease (AFD) in comparison to age-matched controls.
This is a single-center, prospective, cross-sectional study in 167 participants (60 heterozygous females and 50 hemizygous males with genetically confirmed AFD, 57 age-matched controls)...
Supplementary table 1. Annualized rate of change in eGFR for male patients (stratified by baseline eGFR and urine protein level).
Supplementary table 2. Annualized rate of change in eGFR for female patients (stratified by baseline eGFR and urine protein level).
Supplementary table 3. Annualized rate of change in LVMI (stratified by gender and basel...
Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities and, additionally in children, growth failure. Fifty-seven patients aged 3-62 years at the baseline of two phase III trials for velaglucerase alfa tre...
Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published stu...
Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed.
To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1.
Phase 3, randomized, double-blind...
Anderson-Fabry Disease (AFD) is an X linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Some mutations are associated with prominent and, in many cases, exclusive cardiac involvement. The primary aims of this study were to determine the incidence of major cardiac events in AFD and to identify clinical and genetic p...
Importance
Numerically, the most important genetic risk factor for the development of Parkinson disease (PD) is the presence of a glucocerebrosidase gene (GBA) mutation.Objective
To evaluate longitudinally and clinically a GBA mutation–positive cohort and the evolution of the prodromal features of PD.Design, Setting, and Participants
Participant...
Introduction: Factors relating to clinical variability in Anderson-Fabry
disease (AFD) heterozygotes are not fully known. Understanding
molecular pathways related to onset, progression and severity
of disease in individuals would be valuable in genetic counselling
of patients, optimising treatment to limit progression of renal, cardiac
and cerebrov...
Cardiovascular magnetic resonance (CMR) derived native myocardial T1 is decreased in patients with Fabry disease even before left ventricular hypertrophy (LVH) occurs and may be the first non-invasive measure of myocyte sphingolipid storage. The relationship of native T1 lowering prior to hypertrophy and other candidate early phenotype markers are...
Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson's disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson's disease, are also present in GBA-positive individuals-both with and without...
Gaucher disease (GD) is an autosomal recessive lysosomal storage disease, caused by deficiency of the enzyme glucocerebrosidase, required for the degradation of glycosphingolipids. Clinical manifestations include hepatosplenomegaly, thrombocytopenia, bone disease and a bleeding diathesis, frequently resulting in presentation to haematologists. Hist...
Pregnancy and delivery are affected by and - in turn - impact signs and symptoms of Gaucher disease (GD). Prior to enzyme replacement therapy (ERT), the reported missed abortions rate was 25%, with worsening of anemia and thrombocytopenia, with increased frequency of post-partum hemorrhage, puerperal fever and bone crises during pregnancy. ERT with...
Gaucher disease is caused by mutations in the glucocerebrosidase gene, which encodes the lysosomal hydrolase glucosylceramidase. Patients with Gaucher disease and heterozygous glucocerebrosidase mutation carriers are at increased risk of developing Parkinson's disease. Indeed, glucocerebrosidase mutations are the most frequent risk factor for Parki...
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...
Gaucher disease (GD) is an autosomal recessive disorder caused by deficiency of β-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 des...
Purpose:
Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease.
Methods:
M...
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....
Treating patients or families with Fabry disease is challenging. Males with this X-linked disease experience life-threatening organ damage to the heart, kidney and cerebrovascular system, and may have advanced disease at presentation; in addition, treatment with enzyme-replacement therapy (ERT) is not only extremely expensive, it is of limited effe...
