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ABSTRACT:Fabry disease is an X-linked lysosomal disease caused by deficiency of ␣-galactosidase A. Signs and symptoms of Fabry disease occurring during childhood and adolescence were characterized in 352 Fabry Registry patients. At enrollment (median age 12 year), 77% of males and 51% of females reported symptoms. The median age of symptom onset was 6 year in males and 9 year in females. The most frequent symptom, neuropathic pain, was reported by 59% of males (median age 7 year) and 41% of females (median age 9 year). Gastrointestinal symptoms were reported by 18% of children (median age 5 year in males and 9.5 year in females). Males exhibited height and weight values below the US 50th percentile. Females had weight values above the US 50th percentile. A few patients had serious renal and cardiac manifestations, stage 2 or 3 chronic kidney disease (n ϭ 3), arrhythmia (n ϭ 9), and left ventricular hypertrophy (n ϭ 3). Thus, many pediatric Fabry patients report early symptoms, particularly pain, gastrointestinal symptoms, and impaired quality of life. Some children experience major complications during the pediatric years. (Pediatr Res 64: 550-555, 2008)

IntroductionGaucher disease, a relatively common recessively inherited lysosomal storage disorder, is caused by a deficiency in the enzyme glucocerebrosidase, encoded by the GBA gene. 1 Deficient enzymatic activity of glucocerebrosidase results in the lysosomal accumulation of its substrate glucosylceramide, most prominently in macrophages. Three variants of Gaucher disease are generally distinguished based on the absence (type 1) or presence of central nervous system involvement 1 (types 2 and 3). In the much more common type 1 variant of Gaucher disease, glycosphingolipidladen macrophages, referred to as Gaucher cells, accumulate in the visceral tissues liver, spleen, and bone marrow, inducing a pleiotropic array of symptoms, including hepatosplenomegaly and pancytopenia. In addition, type 1 Gaucher patients often develop bone complications: bone pain and crises, avascular necrosis, and pathologic fractures. 1 Two different types of therapeutic intervention are available for type 1 patients. One relies on chronic intravenous administration of recombinant glucocerebrosidase, denoted enzyme replacement therapy (ERT). 2 Two recombinant enzyme preparations are now registered for ERT in type 1 Gaucher disease: imiglucerase (Cerezyme; Genzyme Corp) and velaglucerase alfa (Vpriv; Shire HGT). 3 A third enzyme, a plant-cellexpressed recombinant glucocerebrosidase, is under clinical development (Taliglucerase; Protalix/Pfizer). 3 The other therapeutic intervention is based on oral administration of the iminosugar N-butyldeoxinojirimycin (Miglustat; Zavesca, Actelion). 4 This compound is thought to effectively lower synthesis of the accumulating metabolite, glucosylceramide, by inhibiting its synthesizing enzyme, glucosylceramide synthase. 5 The clinical responses to ERT are fast and impressive, such as significant corrections in hepatosplenomegaly, improvement of hematologic parameters and reduction of bone marrow infiltration as seen by magnetic resonance imaging. 6 The response to miglustat treatment is less prominent, and its use is authorized for mildly to moderately affected patients who are unsuitable for ERT (EMA) or in whom ERT is not a therapeutic option (FDA). 7 Future use of such small compounds for treating patients with a neuronopathic course of Gaucher disease is appealing given their potential to penetrate the brain (in contrast to recombinant enzyme). 8 The availability of costly therapies has stimulated searches for plasma biomarkers that can assist in clinical management of individual patients. Several circulating protein markers for Gaucher cells have meanwhile been identified (for a review see Aerts et al 9 ). It has been demonstrated that the enzyme chitotriosidase 10 and the chemokine CCL18 11 are produced by Gaucher cells and secreted into the circulation. Both proteins are candidate biomarkers since their plasma concentrations are markedly increased in symptomatic type 1 Gaucher patients and vary This article contains a data supplement.The publication costs of this article were defrayed in part b...

IntroductionFabry 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.MethodsA 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.ResultsFor 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 m2) 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.ConclusionThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0253-6) contains supplementary material, which is available to authorized users.

Mucopolysaccharidosis type II (MPS II) is a rare, life-limiting, X-linked recessive disease characterised by deficiency of the lysosomal enzyme iduronate-2-sulfatase. Consequent accumulation of glycosaminoglycans leads to pathological changes in multiple body systems. Age at onset, signs and symptoms, and disease progression are heterogeneous, and patients may present with many different manifestations to a wide range of specialists. Expertise in diagnosing and managing MPS II varies widely between countries, and substantial delays between disease onset and diagnosis can occur. In recent years, disease-specific treatments such as enzyme replacement therapy and stem cell transplantation have helped to address the underlying enzyme deficiency in patients with MPS II. However, the multisystem nature of this disorder and the irreversibility of some manifestations mean that most patients require substantial medical support from many different specialists, even if they are receiving treatment. This article presents an overview of how to recognise, diagnose, and care for patients with MPS II. Particular focus is given to the multidisciplinary nature of patient management, which requires input from paediatricians, specialist nurses, otorhinolaryngologists, orthopaedic surgeons, ophthalmologists, cardiologists, pneumologists, anaesthesiologists, neurologists, physiotherapists, occupational therapists, speech therapists, psychologists, social workers, homecare companies and patient societies.Take-home messageExpertise in recognising and treating patients with MPS II varies widely between countries. This article presents pan-European recommendations for the diagnosis and management of this life-limiting disease.