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Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized.

Rhabdomyolysis is a serious and potentially life threatening condition. Although consensus criteria for rhabdomyolysis is lacking, a reasonable definition is elevation of serum creatine kinase activity of at least 10 times the upper limit of normal followed by a rapid decrease of the sCK level to (near) normal values. The clinical presentation can vary widely, classical features are myalgia, weakness and pigmenturia. However, this classic triad is seen in less than 10% of patients. Acute renal failure due to acute tubular necrosis as a result of mechanical obstruction by myoglobin is the most common complication, in particular if sCK is >16.000 IU/l, which may be as high as 100,000 IU/1. Mortality rate is approximately 10% and significantly higher in patients with acute renal failure. Timely recognition of rhabdomyolysis is key for treatment. In the acute phase, treatment should be aimed at preserving renal function, resolving compartment syndrome, restoring metabolic derangements, and volume replacement. Most patients experience only one episode of rhabdomyolysis, mostly by substance abuse, medication, trauma or epileptic seizures. In case of recurrent rhabdomyolysis, a history of exercise intolerance or a positive family history for neuromuscular disorders, further investigations are needed to identify the underlying, often genetic, disorder. We propose a diagnostic algorithm for use in clinical practice. (C) 2014 Elsevier B.V. All rights reserved.

Little is known on the impact of growing up with Fabry disease (FD) on psychosocial development. Children with FD may suffer from severe recurrent pains in hands and feet, gastro-intestinal symptoms and heat intolerance. These symptoms may influence quality of life and may interfere with a normal psychosocial development. It is important to evaluate psychosocial outcomes of patients with FD into adulthood to be able to optimize support of children with FD. The current cross-sectional questionnaire study investigated psychosocial development and quality of life of 28 young adults with FD, aged 18-35 years (9 males, 19 females), using the Course of Life questionnaire and the Short Form-36 questionnaire for quality of life. The results were compared with an age-matched normative population. We found significant differences in the achievement of milestones in social development of male Fabry patients. The milestones that were affected were 'going out to bars' and 'participation in sports activities'. Other than that FD patients appear to be able to achieve a rather normal psychosocial development until adulthood. Quality of life was decreased in Fabry males in the domains of physical functioning and bodily pain and of general health perception in females.

There are only a few reports on the histology of placental tissue of pregnancies from mothers with Fabry disease. Fabry disease is a lysosomal disorder caused by alpha-galactosidase A deficiency. Extensive glycosphingolipid (GSL) accumulation in fetal and maternal placenta tissue obtained from a Fabry mother and her affected male newborn has previously been reported. Here we report the evaluation of placenta tissue of two pregnancies in Fabry mothers, one of an unaffected male newborn (placenta A) and one of an affected female newborn (placenta B). The mother of the female affected offspring was treated with recombinant alpha-galactosidase A (enzyme replacement therapy. ERT) during the pregnancy (placenta B). Storage material was only detected in smooth muscle cells of the umbilical cord of placenta B. No accumulation was seen in both placentae. Combing these results with the outcome in two earlier described placentae, a heterogeneous picture emerges. This may be due to differences in disease severity in the mothers or severity of disease in their offspring. In addition, a possible effect of ERT on placental GSL accumulation could also explain lack of GSL storage in placenta B. (C) 2010 Elsevier Ltd. All rights reserved

Although thrombopoietin (Tpo) was already described in the early sixties, it took more than 30 years before it was cloned. It became possible after the recognition and cloning of its receptor, Mpl. In the past few years new information about Tpo and Mpl has accumulated rapidly. Structure, biosynthesis and tissue expression have been elucidated. The central role of Tpo in the regulation of megakaryocytopoiesis and platelet production has become clear, as has the way in which this is accomplished. Tpo appears to be an important growth factor for haematopoietic stem cells as well. Thus, it may become one of the most important factors in stem cell transplantation. Finally, the signal transduction mechanisms involved and the way in which Tpo affects platelets and their precursors functionally have been studied in detail. The cloning and characterization of thrombopoietin and its receptor Mpl is one of the most important advances in the haematology of the nineties.

The cloning and characterization of thrombopoietin and its receptor Mpl in the past few years has been a major advance in haematology. It opens new ways of studying congenital and acquired platelet disorders, leading to new insights in the pathogenesis and treatment of this group of diseases. The Tpo level of the blood appears to be a useful marker for the differentiation between thrombocytopenia due to peripheral destruction and that due to thrombocytopoietic failure. No simple clinical parameter exist for this important differential diagnostic problem. When recombinant thrombopoietin becomes available for therapy it will rapidly become the drug of choice for many of our patients. However, because of all the legal and commercial issues at stake it is expected that it will still take a few more years before general availability is realized. Short peptides with Tpo activity ( Cwirla et al, 1997 ; Kimura et al, 1997 ), which can be synthesized chemically, may form a more easily obtainable alternative.

The availability of enzyme replacement therapy for Fabry disease, deficiency of alpha-galactosidase (αGal) A, has increased awareness for this disorder and stimulated the conduction of additional screening ([1][1]). Several studies have shown that patients with renal insufficiency, cerebral

found that there was more robust clearance of GL-3 in plasma and urine in patients treated with the recom­ mended dose of agalsidase beta (1 mg/kg) compared with those treated with agalsidase alfa or agalsidase beta 0.2 mg/kg. Treatment with a higher dose could overcome the negative influence of antiagalsidase antibodies on plasma and urine GL-3 that is seen with the lower dose (0.2 mg/kg every other week). However, the clinical sig­ nificance of more robust urinary and plasma GL-3 clearance is unknown. Currently, various treatment strategies are being studied with agalsidase alfa (0.2 mg/kg weekly and 0.4 mg/kg every other week) and with agalsidase beta (6 months of 1 mg/kg every other week followed by 0.3 mg/kg every other week). The outcome of 1 of these studies was recently published 9 ; results from the other study are eagerly awaited. In addition, in an ongoing Canadian study, patients were randomized to receive either 0.2-mg/kg agalsidase alfa or I-mg/kg agalsidase beta every other week. lo Results from these patients will be analyzed and compared using several clinical and bio­ chemical end points. These research efforts should lead to more informed decisions regarding the timing of Fabry disease treatment as well as the choice of preparation or dose. Moreover, the goal of future studies will be to confirm whether anti­ body formation against the infused enzyme is dose related and whether the emergence of antibodies might result in reduced therapeutic efficacy. ACKNOWLEDG M ENTS

Background The cost-effectiveness of enzyme replacement therapy (ERT) compared to standard medical care was evaluated in the Dutch cohort of patients with Fabry disease. Methods Cost-effectiveness analysis was performed using a life-time state-transition model. Transition probabilities, effectiveness data and costs were derived from retrospective data and prospective follow-up of the Dutch study cohort consisting of males and females aged 5–78 years. Intervention with ERT (either agalsidase alfa or agalsidase beta) was compared to the standard medical care. The main outcome measures were years without end organ damage (renal, cardiac en cerebrovascular complications), quality adjusted life years (QALYs), and costs. Results Over a 70 year lifetime, an untreated Fabry patient will generate 55.0 years free of end-organ damage (53.5 years in males, 56.9 years in females) and 48.6 QALYs (47.8 in males, 49.7 in females). Starting ERT in a symptomatic patient increases the number of years free of end-organ damage by 1.5 year (1.6 in males, 1.3 in females), while the number of QALYs gained increases by a similar amount (1.7 in males, 1.4 in females). The costs of ERT starting in the symptomatic stage are between €9 - €10 million (£ 7.9 - £ 8.8 million, $13.0- $14.5 million) during a patient’s lifetime. Consequently, the extra costs per additional year free of end-organ damage and the extra costs per additional QALY range from €5.5 - €7.5 million (£ 4.8 – £ 6.6 million, $ 8.0 – $ 10.8 million), undiscounted. Conclusions In symptomatic patients with Fabry disease, ERT has limited effect on quality of life and progression to end organ damage. The pharmaco-economic evaluation shows that this modest effectiveness drives the costs per QALY and the costs per year free of end-organ damage to millions of euros. Differentiation of patients who may benefit from ERT should be improved to enhance cost-effectiveness.