Clinical efficacy of Enzyme Replacement Therapy in paediatric Hunter patients, an independent study of 3.5 years

BACKGROUND: Hunter Syndrome is an X-linked lysosomal storage disorder due to the deficit of iduronate 2-sulfatase, an enzyme catalysing the degradation of the glycosaminoglycans (GAG) dermatan- and heparan-sulfate. Treatment of the disease is mainly performed by Enzyme Replacement Therapy (ERT) with idursulfase, in use since 2006. Clinical efficacy of ERT has been monitored mainly by the Hunter Outcome Survey (HOS) while very few independent studies have been so far conducted. The present study is a 3.5-years independent follow-up of 27 Hunter patients, starting ERT between 1.6 and 27 years of age, with the primary aim to evaluate efficacy of the therapy started at an early age (<12 years). METHODS: In this study, we evaluated: urinary GAG content, hepato/splenomegaly, heart valvulopathies, otorinolaryngological symptoms, joint range of motion, growth, distance covered in the 6-minute walk test, neurological involvement. For data analysis, the 27 patients were divided into three groups according to the age at start of ERT: ≤5 years, >5 and ≤ 12 years and > 12 years. Patients were analysed both as 3 separate groups and also as one group; in addition, the 20 patients who started ERT up to 12 years of age were analysed as one group. Finally, patients presenting a “severe” phenotype were compared with “attenuated” ones. RESULTS: Data analysis revealed a statistically significant reduction of the urinary GAG in patients ≤5 years and ≤ 12 years and of the hepatomegaly in the group aged >5 and ≤ 12 years. Although other clinical signs improved in some of the patients monitored, statistical analysis of their variation did not reveal any significant changes following enzyme administration. The evaluation of ERT efficacy in relation to the severity of the disease evidenced slightly higher improvements as for hepatomegaly, splenomegaly, otological disorders and adenotonsillar hypertrophy in severe vs attenuated patients. CONCLUSIONS: Although the present protocol of idursulfase administration may result efficacious in delaying the MPS II somatic disease progression at some extent, in this study we observed that several signs and symptoms did not improve during the therapy. Therefore, a strict monitoring of the efficacy obtained in the patients under ERT is becoming mandatory for clinical, ethical and economic reasons. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-014-0129-1) contains supplementary material, which is available to authorized users

A rapid testing procedure for Fabry disease: alpha-galadosidase A assay in dried blood spots

Background: Fabry disease is a rare X-linked disorder characterized by complete deficiency or reduced activity of the lysosomal enzyme -galactosidase A. Patients with Fabry disease present with a heterogeneous spectrum of symptoms due to the progressive accumulation of glycosphingolipids in bodily tissues. Clinical onset usually occurs during late childhood or adolescence, but the correct diagnosis is rarely reached before the third decade of life. Enzyme replacement therapy is available for the treatment of patients with confirmed -galactosidase A deficiency. Aim: To report on a rapid testing procedure for measuring -galactosidase A activity in dried blood spots. Methods and results: Dried blood spots represent a convenient and cost-effective way to collect blood samples. We analysed five different populations: 116 healthy adults, 147 newborns, three hemizygous males and four heterozygous females with Fabry disease, and ten individuals affected by other lysosomal storage diseases (LSDs). We obtained the following enzyme activity ranges: healthy adults, 6.0\u201321.4 pmoles/punch/h; newborns, 5.0\u201352.3 pmoles/ punch/h; hemizygous males, 0.3\u20133.2 pmoles/punch/h; heterozygous females, 5.4\u201310.3 pmoles/punch/h; individuals affected by other LSDs, 5.9\u201319.4 pmoles/punch/h. The dried blood spot test was able to differentiate male patients with Fabry disease, but not females, from healthy volunteers. Conclusion: Given that the prevalence of Fabry disease appears to be underestimated, especially in patients with cardiac and renal dysfunction, we propose this microassay as a non-invasive, cost-effective and quick method for screening at-risk adult populations

Clinical efficacy of Enzyme Replacement Therapy in paediatric Hunter patients, an independent study of 3.5\ua0years

Hunter Syndrome is an X-linked lysosomal storage disorder due to the deficit of iduronate 2-sulfatase, an enzyme catalysing the degradation of the glycosaminoglycans (GAG) dermatan- and heparan-sulfate. Treatment of the disease is mainly performed by Enzyme Replacement Therapy (ERT) with idursulfase, in use since 2006. Clinical efficacy of ERT has been monitored mainly by the Hunter Outcome Survey (HOS) while very few independent studies have been so far conducted. The present study is a 3.5-years independent follow-up of 27 Hunter patients, starting ERT between 1.6 and 27 years of age, with the primary aim to evaluate efficacy of the therapy started at an early age (<12 years). METHODS: In this study, we evaluated: urinary GAG content, hepato/splenomegaly, heart valvulopathies, otorinolaryngological symptoms, joint range of motion, growth, distance covered in the 6-minute walk test, neurological involvement. For data analysis, the 27 patients were divided into three groups according to the age at start of ERT: 645 years, >5 and\u2009 64\u200912 years and\u2009>\u200912 years. Patients were analysed both as 3 separate groups and also as one group; in addition, the 20 patients who started ERT up to 12 years of age were analysed as one group. Finally, patients presenting a "severe" phenotype were compared with "attenuated" ones. RESULTS: Data analysis revealed a statistically significant reduction of the urinary GAG in patients 645 years and\u2009 64\u200912 years and of the hepatomegaly in the group aged >5 and\u2009 64\u200912 years. Although other clinical signs improved in some of the patients monitored, statistical analysis of their variation did not reveal any significant changes following enzyme administration. The evaluation of ERT efficacy in relation to the severity of the disease evidenced slightly higher improvements as for hepatomegaly, splenomegaly, otological disorders and adenotonsillar hypertrophy in severe vs attenuated patients. CONCLUSIONS: Although the present protocol of idursulfase administration may result efficacious in delaying the MPS II somatic disease progression at some extent, in this study we observed that several signs and symptoms did not improve during the therapy. Therefore, a strict monitoring of the efficacy obtained in the patients under ERT is becoming mandatory for clinical, ethical and economic reasons