Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.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 cessation of ERT in patients with FD.A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement.For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped.The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.Ministry of Health (ZonMw

Extent, impact, and predictors of diagnostic delay in Pompe disease: A combined survey approach to unveil the diagnostic odyssey

Background Early diagnosis is of substantial benefit for patients with Pompe disease. Yet underdiagnosing and substantial diagnostic delay are still frequent and the determinants of this are unknown. This study is the first to systematically investigate the diagnostic odyssey in Pompe disease from patients', parents', and physicians' perspectives. Methods Patients with infantile or late onset Pompe disease, their parents as well as their metabolic experts were invited to fill in respective surveys. The survey addressed perceived disease symptoms at onset and during the course of the disease, specialties of involved physicians, activities of patient-initiated search for diagnosis and the perceived impact of time to diagnosis on outcome. Results of experts' and patients'/parents' surveys were compared and expressed by descriptive statistics. Results and Discussion We collected data on 15 males and 17 females including 9 infantile and 23 late onset Pompe patients. All received the correct diagnosis at a metabolic or musculoskeletal expert center. Patients with direct referral to the expert center had the lowest diagnostic delay, while patients who were seen by several physicians, received the correct diagnosis after 44%-200% longer delay. The proportion of direct referral varied strongly between pediatricians (57%) and other disciplines (18%-36%). Conclusion Our study highlights a substantially larger diagnostic delay in Pompe patients that are not directly referred to expert centers for diagnostic work. Our findings may be used to develop more successful strategies for early diagnosis. Synopsis Diagnostic delay in Pompe disease is substantial particularly in patients that are not directly referred to expert centers for diagnostic workup, so facilitating direct referral may be a new strategy for early diagnosis

Analysis of Renal and Cardiac Outcomes in Male Participants in the Fabry Outcome Survey Starting Agalsidase Alfa Enzyme Replacement Therapy Before and After 18 Years of Age

To determine the impact of initiating enzyme replacement therapy (ERT) with agalsidase alfa early in the course of Fabry disease, we evaluated renal and cardiac outcomes for ≤10 years after ERT initiation in males from the Fabry Outcome Survey (FOS). Male patients from FOS were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1), >18 and ≤30 years (cohort 2), and >30 years (cohort 3). Analysis included age at symptom onset, diagnosis, and ERT initiation; ERT duration; FOS-Mainz Severity Score Index (FOS-MSSI); estimated glomerular filtration rate (eGFR); proteinuria level; and left ventricular mass indexed to height (LVMI). Mixed-effect models estimated renal and cardiac outcomes during follow-up between and within cohorts. The analysis included 560 male patients: 151 (27.0%) in cohort 1, 155 (27.7%) in cohort 2, and 254 (45.4%) in cohort 3. Mean±SD duration of ERT for cohorts 1, 2, and 3 was 6.3±4.3, 8.6±4.9, and 7.9±4.9 years, respectively. Mean±SD baseline FOS-MSSI scores increased with age from 9.8±7.2 in cohort 1 to 24.7±11.4 in cohort 3. Cohort 3 showed the lowest baseline mean±SD value for eGFR (87.1±29.0 mL/min/1.73m 2) and highest baseline mean±SD values for proteinuria (801.9±952.6 mg/day) and LVMI (56.7±16.0 g/m 2.7) among the three cohorts. Evaluation of mean annual rates of change in eGFR, proteinuria, and LVMI revealed no significant differences in any parameter for cohort 1. For cohort 2, proteinuria and LVMI remained stable, whereas eGFR significantly deteriorated annually (-1.12 mL/min/1.73m 2 ; P <0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (-2.60 mL/min/1.73m 2 ; P <0.001), proteinuria (+34.10 mg/day; P <0.001), and LVMI (+0.59 g/m 2.7 ; P =0.001). Renal and/or cardiac disease progression appears attenuated in patients starting ERT in childhood or early adulthood versus patients starting ERT in later adulthood. These findings support early ERT initiation in Fabry disease. ClinicalTrials.gov identifier: NCT0328906

Paediatric Fabry disease: prognostic significance of ocular changes for disease severity

BACKGROUND: Ocular signs of Fabry disease can be seen in the first decade of life. METHODS: We examined the occurrence of ocular signs in 232 paediatric patients in the Fabry Outcome Survey (FOS) international registry and looked for relationships between the presence of eye findings and disease severity as measured by the FOS Mainz severity score index (FOS-MSSI). RESULTS: At least one ocular sign was found in 55/101 (54.5%) girls and 62/131 (47.3%) boys: cornea verticillata in 53/101 (52.5%) girls and 55/131 (42.0%) boys, vessel tortuosity in 17/98 (17.3%) girls and 32/131 (24.4%) boys, and posterior spoke-like lens opacities in 3/97 (3.1%) girls and 2/130 (1.5%) boys. Summary statistics showed higher median (range) age-adjusted FOS-MSSI total score indicating more severe disease in children with eye findings versus those without eye findings (0.5 [-11.0, 20.7] versus -2.3 [-11.1, 18.8]). At least one eye finding was observed in 59.1% of treated and 37.9% of untreated children. CONCLUSIONS: We conclude that the presence of ocular signs, particularly cornea verticillata, correlates with more severe disease as indicated by FOS-MSSI scores in paediatric patients with Fabry disease. Ocular signs appear in roughly half of school-aged children with Fabry disease and are well-recognised as a valuable tool for diagnosis of Fabry disease in children; they also may help identify patients who are at risk for developing early severe manifestations of Fabry disease and who should be further evaluated and closely followed up

Ocular Signs Correlate Well with Disease Severity and Genotype in Fabry Disease

<div><p>Ocular signs in Fabry disease have generally been regarded to be primarily of diagnostic value. We explored whether ocular findings, alone or in particular in combination with the α-galactosidase A gene mutation, have predictive value for disease severity. Data from the Fabry Outcome Survey (FOS), a large, global database sponsored by Shire, were selected for adult patients who had undergone ophthalmological examination. Three ocular signs were assessed: cornea verticillata, tortuous conjunctival and/or retinal vessels, and cataract. Fabry disease severity was measured using FOS Mainz Severity Score Index and modifications thereof. Ophthalmological data were available for 1203 (699 female, 504 male) adult patients with eye findings characteristic of Fabry disease in 55.1%. Cornea verticillata had a similar distribution in women (51.1%) and men (50.8%), whereas tortuous vessels and Fabry cataract were somewhat more frequent in men than in women. Patients with cornea verticillata, selected as the principal ocular sign for this study, had more severe disease (median score, 20.0) versus those without ocular signs (11.0; <i>P</i><0.001). This finding could be confirmed by applying age adjusted severity scores. Moreover, the prevalence of cornea verticillata was significantly higher in patients with null (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (<i>P</i><0.01). Our analyses show a correlation between the prevalence of ocular changes in Fabry disease and disease severity. Consequently, information on ocular findings and α-galactosidase A gene mutation may help assess the risk for more severe Fabry disease. These observed findings are of notable clinical importance, as Fabry disease is characterized by high clinical course variability and only weak genotype-phenotype correlation at the individual patient level. Further confirmatory studies are needed.</p></div

Representative ocular changes seen in patients with Fabry disease.

<p>Representative ocular changes include (A) cornea verticillata, (B) increased tortuosity of conjunctival vessels, and (C) increased tortuosity of retinal vessels.</p

Paediatric Fabry disease : prognostic significance of ocular changes for disease severity

Altres ajuts: Medical writing support was provided by Margit Rezabek, DVM, PhD, of Excel Scientific Solutions and was funded by Shire. Shire was given the opportunity to review the manuscript.Ocular signs of Fabry disease can be seen in the first decade of life. We examined the occurrence of ocular signs in 232 paediatric patients in the Fabry Outcome Survey (FOS) international registry and looked for relationships between the presence of eye findings and disease severity as measured by the FOS Mainz severity score index (FOS-MSSI). At least one ocular sign was found in 55/101 (54.5%) girls and 62/131 (47.3%) boys: cornea verticillata in 53/101 (52.5%) girls and 55/131 (42.0%) boys, vessel tortuosity in 17/98 (17.3%) girls and 32/131 (24.4%) boys, and posterior spoke-like lens opacities in 3/97 (3.1%) girls and 2/130 (1.5%) boys. Summary statistics showed higher median (range) age-adjusted FOS-MSSI total score indicating more severe disease in children with eye findings versus those without eye findings (0.5 [−11.0, 20.7] versus −2.3 [−11.1, 18.8]). At least one eye finding was observed in 59.1% of treated and 37.9% of untreated children. We conclude that the presence of ocular signs, particularly cornea verticillata, correlates with more severe disease as indicated by FOS-MSSI scores in paediatric patients with Fabry disease. Ocular signs appear in roughly half of school-aged children with Fabry disease and are well-recognised as a valuable tool for diagnosis of Fabry disease in children; they also may help identify patients who are at risk for developing early severe manifestations of Fabry disease and who should be further evaluated and closely followed up. The online version of this article (doi:10.1186/s12886-016-0374-2) contains supplementary material, which is available to authorized users

A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations

<p>Abstract</p> <p>Background</p> <p>Pompe disease (Glycogen storage disease type II, GSD II, acid alpha-glucosidase deficiency, acid maltase deficiency, OMIM # 232300) is an autosomal-recessive lysosomal storage disorder due to a deficiency of acid alpha-glucosidase (GAA, acid maltase, EC 3.2.1.20, Swiss-Prot P10253). Clinical manifestations are dominated by progressive weakness of skeletal muscle throughout the clinical spectrum. In addition, the classic infantile form is characterised by hypertrophic cardiomyopathy.</p> <p>Methods</p> <p>In a cross-sectional single-centre study we clinically assessed 3 patients with classic infantile Pompe disease and 39 patients with non-classic presentations, measured their acid alpha-glucosidase activities and analysed their GAA genes.</p> <p>Results</p> <p>Classic infantile patients had nearly absent residual enzyme activities and a typical clinical course with hypertrophic cardiomyopathy until the beginning of therapy. The disease manifestations in non-classic patients were heterogeneous. There was a broad variability in the decline of locomotive and respiratory function. The age of onset ranged from birth to late adulthood and correlated with enzyme activities. Molecular analysis revealed as many as 33 different mutations, 14 of which are novel. All classic infantile patients had two severe mutations. The most common mutation in the non-classic group was c.-32-13 T > G. It was associated with a milder course in this subgroup.</p> <p>Conclusions</p> <p>Disease manifestation strongly correlates with the nature of the GAA mutations, while the variable progression in non-classic Pompe disease is likely to be explained by yet unknown modifying factors. This study provides the first comprehensive dataset on the clinical course and the mutational spectrum of Pompe disease in Germany.</p