Olivier Lidove

Fabry disease and the skin: data from FOS, the Fabry outcome survey

Background  Fabry disease (also known as Anderson–Fabry disease) is a rare, X‐linked lysosomal storage disorder that is characterized by accumulation of globotriaosylceramide throughout a range of tissues in the body.

Clinical results of enzyme replacement therapy in Fabry disease: a comprehensive review of literature

Enzyme replacement therapy (ERT) has been used to treat Fabry disease – a progressive lysosomal storage disorder – since 2001. Two preparations of the enzyme α‐galactosidase A are available in Europe: agalsidase alpha, produced in a human cell line, and agalsidase beta, produced in Chinese hamster ovary cells. To review critically the published evidence for the clinical efficacy of these two enzyme preparations. A systematic literature search was undertaken to identify open or randomised controlled trials published on Fabry disease since 2001. Eleven trials fulfilled the criteria for inclusion in this review, of a total of 586 references on Fabry disease. To date, no direct comparisons exists between the two available enzyme preparations. Significant clinical benefits compared with placebo, however, have been demonstrated with ERT, with positive effects on the heart, kidneys, nervous system and quality of life. The quality of most of these publications was less than optimal. Further prospective studies are required to confirm the long‐term clinical benefits of ERT. More studies are also needed on the effects of ERT in women and on the use of ERT early in the course of Fabry disease, to prevent organ damage. Large national and international outcomes databases will also be invaluable in evaluating treatment effects and safety.

The pulvinar sign: frequency and clinical correlations in Fabry disease

Fabry disease is an X-linked lysosomal deficiency of α-galactosidase A that results in cellular accumulation of galactoconjugates, mainly globotriaosylceramide, particularly in blood vessels. Neuroradiological findings include ischemic stroke, white matter lesions, vascular abnormalities (vertebrobasilar dolichoectasia and vessel tortuosity), and posterior thalamus involvement (the so called pulvinar sign). The purpose of our study was to investigate the presence of the increased pulvinar signal intensity on T1-weighted imaging – pulvinar sign and its relationship with other clinical findings, in a non-selected cohort of Fabry patients.MethodsWe performed a prospective analysis of two populations of patients (36 subjects) with Fabry disease. Patients were followed-up at the Department of Internal Medicine of the Bichat Hospital in Paris (France) and at the Neurological Clinic of the University Hospital of Padova (Italy). Brain MR studies of each patient included T1- and T2- weighted images, FLAIR sequences, and in some cases diffusion weighted images.ResultsA total of 36 patients (16 males, 20 females) were investigated in 14 families. The pulvinar sign was found in 5 male patients, but not in female patients. Seven patients had had at least one stroke (territorial or lacunar). There was no correlation between stroke and the pulvinar sign. All patients with the pulvinar sign had hypertrophic cardiomyopathy. Four patients out of five with the pulvinar sign were on dialysis or had a kidney transplantation.ConclusionsOur findings suggest that the pulvinar sign is a highly specific sign of Fabry disease, found in male patients with cardiac signs and severe kidney involvement.

Fabry disease ‘The New Great Imposter’: results of the French Observatoire in Internal Medicine Departments (FIMeD)

Lidove O, Kaminsky P, Hachulla E, Leguy‐Seguin V, Lavigne C, Marie I, Maillot F, Serratrice C, Masseau A, Chérin P, Cabane J, Noel E; on behalf of the FIMeD investigators. Fabry disease ‘The New Great Imposter’: results of the French Observatoire in Internal Medicine Departments (FIMeD).

Fabry nephropathy: 5 years of enzyme replacement therapy—a short review

Fabry disease is an X-linked lysosomal storage disease, resulting from a deficiency of the enzyme α-galactosidase A and subsequent cellular storage of the enzyme substrate globotriaosylceramide (Gb3) [1]. Estimates of the incidence of Fabry disease vary markedly, from 1:<5000 male births in a newborn screening study in Italy [2] to 1:117 000 male births in Australia [3] and 1:833 000 male births in northern Portugal [4]. In general, hemizygous males are more severely affected than heterozygous females. In males, life expectancy is reduced by an average of 20 years [5] and in females by 15 years [6]. Although males tend to suffer symptoms earlier than females, both boys and girls can be affected from an early age [7]. Death usually occurs due to renal, cardiovascular or cerebrovascular complications [5,6,8], with renal dysfunction being the main cause of death in men before the development of renal failure requiring dialysis and transplantation [9]. As enzyme replacement therapy (ERT) has recently become available, it is important to recognize the signs and symptoms of Fabry disease so that early treatment can be started before irreversible organ damage occurs. This short review outlines the renal manifestations of Fabry disease and the results of ERT.

Imaging Features of Fabry Disease

OBJECTIVE Our objective was to describe the various imaging patterns of Fabry disease, including cerebrovascular, renal, cardiac, and other organ involvement. Fabry disease, an X-linked inborn error of glycosphingolipid catabolism resulting from a deficient activity of the hydrolase alpha-galactosidase A, displays more complications in men than in heterozygous women. CONCLUSION It is up to radiologists to evoke the diagnosis, help practitioners in treating patients early with enzyme replacement therapy, and monitor its efficacy.

Multidimensional analysis of clinical symptoms in patients with Fabry’s disease

Aim:  Fabry’s disease is an X‐linked inherited lysosomal storage disorder caused by the deficient activity of alpha‐galactosidase A. The interrelationships between clinical symptoms in Fabry patients have not yet been fully established. Using cluster and multivariate analysis, the aim of the study was to determine the relationships among clinical symptoms and organ involvement, and predictive clinical symptoms for disease severity.

Letter Regarding Brouns et al, Baptista et al, and Wozniak et al

To The Editor: We congratulate the authors of the 3 recent studies addressing the prevalence of Fabry disease (FD) in stroke.1,–,3 Previous studies provided conflicting results with no practical conclusion.4,5 However, early diagnosis of FD could be crucial because enzyme replacement therapy may prevent severe disease manifestations.6 The 3 studies differ according to populations enrolled.1,–,3 Two studies considered ischemic or hemorrhagic strokes,1,2 although the relation between FD and hemorrhagic stroke is unclear. Moreover, these 2 studies included patients regardless of stroke etiology, which may have led to underestimation of FD. The other study considered cryptogenic ischemic strokes only, but there was no definition for cryptogenic stroke.3 Women were investigated in 2 studies only.1,2 The studies also differed according …

Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency

Disclaimer:This diagnostic guideline is intended as an educational resource and represents the opinions of the authors, and is not representative of recommendations or policy of the American College of Medical Genetics and Genomics (ACMG). The information should be considered a consensus based on expert opinion, as more comprehensive levels of evidence were not available in the literature in all cases.Background:Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease. The underlying metabolic defect is deficiency of the enzyme acid sphingomyelinase that results in progressive accumulation of sphingomyelin in target tissues. ASMD manifests as a spectrum of severity ranging from rapidly progressive severe neurovisceral disease that is uniformly fatal to more slowly progressive chronic neurovisceral and chronic visceral forms. Disease management is aimed at symptom control and regular assessments for multisystem involvement.Purpose and methods:An international panel of experts in the clinical and laboratory evaluation, diagnosis, treatment/management, and genetic aspects of ASMD convened to review the evidence base and share personal experience in order to develop a guideline for diagnosis of the various ASMD phenotypes.Conclusions:Although care of ASMD patients is typically provided by metabolic disease specialists, the guideline is directed at a wide range of providers because it is important for primary care providers (e.g., pediatricians and internists) and specialists (e.g., pulmonologists, hepatologists, and hematologists) to be able to identify ASMD.Genet Med advance online publication 13 April 2017

Impact of imiglucerase supply constraint on the therapeutic management and course of disease in French patients with Gaucher disease type 1

BackgroundIn 2009, a worldwide supply constraint of imiglucerase led to treatment modifications or interruptions for patients with Gaucher disease (GD) type 1. In France, joint treatment recommendations were issued to protect the most vulnerable patients. This observational study evaluated the impact of imiglucerase treatment modifications on the clinical and biological course of GD.MethodsRetrospective data on patients’ characteristics, treatment, clinical and biological parameters from 01 June 2009 to 31 October 2010 were collected during a single visit.ResultsNinety-nine GD1 patients, aged 7–84 years, were included (median age 47 years); 10 were children. Patients experienced a median of 4 different treatment modifications. Median change from pre-supply constraint dose (92 U/kg/4-weeks) was −69, −51, −29 and −60 U/kg/4-weeks at 3, 6, 9 and 12 months after first modification, respectively, with imiglucerase discontinuation reported for 70%, 47%, 29% and 55% of patients at these timepoints. Replacement with another ERT was reported for 35 patients. Results show a statistically significant decrease in hemoglobin (−0.8 g/L/month) and platelets (−5905.103/mm3/month) and an increase in chitotriosidase (+537 nmol/mL/h/month) and angiotensin-converting enzyme (+4 IU/L/month) in the subgroup of 61 patients who discontinued treatment for at least 3 months; this magnitude of change was not seen in the subgroup (32 patients) treated with reduced imiglucerase for at least 3 consecutive months. GD-related events were spontaneously reported by the study investigators for 39% of the whole study population, including asthenia/fatigue (8%), bone infarction and bone pain (4% each), and hepatomegaly (3%). A Kaplan-Meier estimate of the probability for a patient to present a bone, hematological or visceral event during the constraint was 37% for patients who discontinued the treatment and 10% for patients treated with a reduced imiglucerase dose.ConclusionThe release of recommendations and individuals’ close follow-up allowed satisfactory management of patients during the imiglucerase supply constraint in France. This study suggests that during this period, lowering the dose of imiglucerase had less impact on the outcomes of patients than interrupting treatment. However, general effects (such as fatigue, bone pain) reported in some patients, emphasize the importance of maintaining appropriate individualized dosing.