X-linked Disorder (X-link + disorder)

Distribution by Scientific Domains

Selected Abstracts

Fabry disease: overall effects of agalsidase alfa treatment

M. Beck
Abstract Background, Fabry disease is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme ,-galactosidase A. Progressive accumulation of the substrate globotriaosylceramide in cells throughout the body leads to major organ failure and premature death. The Fabry Outcome Survey (FOS) is a European outcomes database which was established to collect data on the natural history of this little-known disease and to monitor the long-term efficacy and safety of enzyme replacement therapy (ERT) with agalsidase alfa. This paper presents the first analysis of the FOS database on the effects of ERT on renal function, heart size, pain and quality of life. Design, The effects of 1 and 2 years of ERT with agalsidase alfa on renal function (assessed by estimated glomerular filtration rate), heart size (assessed by echocardiography), pain (assessed by the Brief Pain Inventory) and quality of life (assessed by the European Quality of Life Questionnaire EQ-5D) were analyzed in a cohort of 545 patients, 314 of whom were receiving treatment (188 for at least 12 months and 92 for at least 24 months; mean duration of treatment, 17 months; maximum duration, 56 months). Results, Treatment with agalsidase alfa stabilized renal function in patients with a mild or moderate deterioration in renal function at baseline, reduced left ventricular size in patients who had an enlarged heart at baseline, and improved pain scores and quality of life. These improvements were similar in hemizygous men and heterozygous women with Fabry disease. Conclusions, Enzyme replacement therapy with agalsidase alfa leads to significant clinical benefits in patients with Fabry disease, and treatment is likely to alter the natural history of this disorder. [source]

Suppression of liver regeneration and hepatocyte proliferation in hepatocyte-targeted glypican 3 transgenic mice,

HEPATOLOGY, Issue 3 2010
Bowen Liu
Glypican 3 (GPC3) belongs to a family of glycosylphosphatidylinositol-anchored, cell-surface heparan sulfate proteoglycans. GPC3 is overexpressed in hepatocellular carcinoma. Loss-of-function mutations of GPC3 result in Simpson-Golabi-Behmel syndrome, an X-linked disorder characterized by overgrowth of multiple organs, including the liver. Our previous study showed that GPC3 plays a negative regulatory role in hepatocyte proliferation, and this effect may involve CD81, a cell membrane tetraspanin. To further investigate GPC3 in vivo, we engineered transgenic (TG) mice overexpressing GPC3 in the liver under the control of the albumin promoter. GPC3 TG mice with hepatocyte-targeted, overexpressed GPC3 developed normally in comparison with their nontransgenic littermates but had a suppressed rate of hepatocyte proliferation and liver regeneration after partial hepatectomy. Moreover, gene array analysis revealed a series of changes in the gene expression profiles in TG mice (both in normal mice and during liver regeneration). In unoperated GPC3 TG mice, there was overexpression of runt related transcription factor 3 (7.6-fold), CCAAT/enhancer binding protein alpha (2.5-fold), GABA A receptor (2.9-fold), and wingless-related MMTV integration site 7B (2.8-fold). There was down-regulation of insulin-like growth factor binding protein 1 (8.4-fold), Rab2 (5.6-fold), beta-catenin (1.7-fold), transforming growth factor beta type I (3.1-fold), nodal (1.8-fold), and yes-associated protein (1.4-fold). Changes after hepatectomy included decreased expression in several cell cycle,related genes. Conclusion: Our results indicate that in GPC3 TG mice, hepatocyte overexpression of GPC3 suppresses hepatocyte proliferation and liver regeneration and alters gene expression profiles, and potential cell cycle,related proteins and multiple other pathways are involved and affected. (HEPATOLOGY 2010;52:1060,1067) [source]

Fabry disease during childhood: clinical manifestations and treatment with agalsidase alfa

Uma Ramaswami
Abstract Fabry disease is a rare X-linked disorder that leads to widespread and progressive disease manifestations, with patients at risk of premature mortality as a result of renal, cardiovascular or cerebrovascular complications. In recent years there has been a growing awareness that the first signs and symptoms of Fabry disease may begin during childhood. Studies show that clinical manifestations such as pain, hypohidrosis, gastrointestinal disturbances, angiokeratomas, cornea verticillata and acroparaesthesiae may be common in childhood and that such manifestations may become apparent during the first few years of life. Despite the early onset of these signs and symptoms, however, diagnosis is often delayed. Interest is now focused on whether enzyme replacement therapy can slow or prevent the onset of these disease manifestations. Preliminary data from two studies suggest that treatment with agalsidase alfa is well tolerated in children and that it may have beneficial clinical effects; however, further research is needed to determine whether enzyme replacement therapy can prevent the development of disease manifestations. Conclusion: The manifestations of Fabry disease first become apparent during childhood. It is well known that disease-associated manifestations are progressive; however, it has yet to be determined whether specific treatment with enzyme replacement therapy can prevent the development of the associated severe and life-threatening complications. [source]

Enzyme replacement therapy with agalsidase alfa in a cohort of Italian patients with Anderson,Fabry disease: testing the effects with the Mainz Severity Score Index

R Parini
Anderson,Fabry disease (AFD) is a rare X-linked disorder caused by lysosomal storage of several glycosphingolipids, affecting virtually all organs and systems. Enzyme replacement therapy (ERT) for AFD has been available since 2001. Due to the highly variable nature of clinical manifestations in patients with AFD, it is very difficult to assess disease progression and the effects of therapy. We used the Mainz Severity Score Index (MSSI) as a measure of disease severity to study the effects of ERT in a population of 30 patients treated with agalsidase alfa for a median of 2.9 years (range, 1.0,6.2 years). Our data show that the MSSI captures the correlation between disease severity and both gender and age (1 , males performing worse than females at baseline and 2 , severity of diseases progresses with age in both sex). Furthermore, after at least 1 year of ERT, total MSSI scores were significantly lower than those at baseline (p < 0.001), suggesting a marked clinical improvement under ERT. In conclusion, the MSSI is a sensitive and useful tool for monitoring disease progression and assessing the effects of ERT in a population of patients from different treatment centres. [source]

The Mainz Severity Score Index: a new instrument for quantifying the Anderson,Fabry disease phenotype, and the response of patients to enzyme replacement therapy

C Whybra
Anderson,Fabry disease (AFD) is an X-linked disorder caused by deficient activity of the lysosomal enzyme ,-galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system , the Mainz Severity Score Index (MSSI) , to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty-nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained from 23 patients in whom AFD was excluded. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. The MSSI indicated that, although more men than women had symptoms classified as severe, overall, the median total severity scores were not significantly different between male and female patients. One year of ERT with agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the MSSI score may be a useful, specific measure for objectively assessing the severity of AFD and for monitoring ERT-related treatment effects. [source]