Treatment of Fabry Disease: Outcome of a Comparative Trial with Agalsidase Alfa or Beta at a Dose of 0.2 mg/kg

Two different enzyme preparations, agalsidase alfa (Replagal(TM), Shire) and beta (Fabrazyme(TM), Genzyme), are registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a randomized controlled open label trial.Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both agalsidase alfa). The occurrence of treatment failures did not differ between the two treatment groups; chi(2) = 0.38 p = 0.54.Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly. Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease.International Standard Randomized Clinical Trial ISRCTN45178534 [http://www.controlled-trials.com/ISRCTN45178534]

Does peer victimization predict low self-esteem, or does low self-esteem predict peer victimization? Meta-analyses on longitudinal studies

In the current study two meta-analyses are performed on longitudinal studies on peer victimization and self-esteem. The goal of these meta-analyses was to analyze whether a low self-esteem predicts future peer victimization, or whether peer victimization predicts future low self-esteem. The databases PsycINFO, MEDLINE, and ERIC were searched for relevant literature. Two authors independently went through the retrieved articles and found four doctoral dissertations and 14 peer reviewed articles eligible for inclusion in the meta-analysis. Articles were independently coded by two authors, with good interrater agreement. A total of 16,230 youth were included in the meta-analysis on peer victimization and self-esteem, and a total of 16,394 youth were included in the meta-analysis on self-esteem and peer victimization. Significant prospective pathways were found from peer victimization to self-esteem, and from self-esteem to peer victimization, which suggests that peer victimization and self-esteem are related in a transactional manner. Analyses suggested a negligible role of publication bias in the obtained results. Moderator analyses revealed that effect sizes were smaller for studies that used peer reports, and for studies that considered longer time-spans. The results of the current study suggest that peer victimization could have long lasting negative effects on self-esteem, but also point out that children may become victims because of low self-esteem.Development Psychopathology in context: clinical setting

Foster Parent Stress as Key Factor Relating to Foster Children’s Mental Health: A 1-Year Prospective Longitudinal Study

AbstractBackgroundFoster children are reported to often have mental health difficulties. To optimize foster children’s development chances, we need to know more about the characteristics that are predictive of foster children’s mental health.ObjectiveIn the current study, we aimed to establish what accounts for the differences in foster children’s mental health, by examining the change and predictors of change in foster children’s mental health. Insight into foster children’s mental health outcomes and their predictors could inform the design of targeted interventions and support for foster children and foster families.MethodIn a sample of 432 foster children between 4 and 17 years old (M = 10.90) we examined a multivariate model in which characteristics of the foster child, the child’s care experiences, foster family, and foster placement were included as predictors of foster children’s mental health (internalizing, externalizing, and prosocial behaviors) using a three-wave longitudinal designResultsResults showed that levels of mental health were generally stable over time. Differences between foster children’s developmental outcomes were mainly predicted by foster parent stress.ConclusionsFoster parent stress levels were high and consistently found to be the strongest predictor of foster children’s mental health outcomes. Given this finding it is important for researchers and practitioners to consider foster parent stress in screening as a point of attention in creating conditions conducive to foster children’s mental health.</jats:sec

Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers

Introduction. Recently, a method to analyse dried whole blood spots to diagnose Fabry disease (deficiency of the lysosomal enzyme alphaGal A) was described. However given its X-linked inheritance female Fabry patients can exhibit normal alphaGal A activities. This could lead to underestimation in screening females for Fabry disease using this method. Methods. aGal A activity was measured in dried whole blood spots of 21 females with documented Fabry disease. Results. Only 13/21 (67%) had reduced aGal A activities, concluding that one-third of female carriers would not be identified during screening. Additional determination of alphaGlucosidase activity (alphaGlu) and the construction of an alphaGal/alphaGlu ratio did not increase sensitivity of the assay. Conclusion. Assays using alphaGal activity for determination of Fabry disease in females have a high false-negative value. Screening for a-Gal A deficiency by means of whole blood spots should not be performed in a females. (C) 2004 Elsevier B.V. All rights reserve

Novel therapeutic targets for the treatment of Fabry disease

Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of alpha-galactosidase A. The traditional concept that is used to explain the complications of the disease involves progressive accumulation of globotriaosylceramide in endothelial and smooth muscle cells, resulting in vascular damage. Clinically, progressive renal insufficiency, cardiac involvement and brain pathology evolves. Two pharmaceutical companies have developed enzyme replacement therapy in Fabry disease. Although the first clinical trials showed great promise, it is clear that long-term effects are not as robust as was anticipated. Stabilisation of renal function and decreases in cardiac hypertrophy has been observed, but some patients may experience progressive complications. As there are recent indications that serum components contribute to the pathophysiology of Fabry disease, fundamental studies are needed to unravel the precise role and identity of these factors. Combination of these basic studies with clinical follow up may ultimately reveal when the 'point of no return' is reached. Advanced renal insufficiency seems to be a clinical indicator of lack of response, but other signs and symptoms are probably related to adverse outcome. It is anticipated that in the future controlled studies in early symptomatic or presymptomatic patients will be required. In addition, alternative strategies such as substrate reduction or chaperone therapy, either alone or in combination with enzyme replacement therapy, should be explored. Because Fabry disease is rare, collaborative efforts should be undertaken and openness of data should be strived fo

Three-dimensional face shape in Fabry disease

Facial dysmorphology is an important feature in several lysosomal storage disorders. Although in Fabry disease facial dysmorphism is not a prominent sign, minor facial abnormalities have been previously reported. By analysing three-dimensional images of faces, we quantified facial dysmorphology in a cohort of both male and female Fabry patients. Morphometric analysis of different regions of the face revealed significant differences in face shape in male patients and to a lesser extent in female patients. In male patients, the most prominent abnormalities were located in the peri-orbital region. Pattern recognition techniques achieved a discrimination accuracy of up to 85% for male patients compared with healthy controls. The discrimination accuracy in female patients achieved only 67%. This objective method for facial dysmorphology assessment provided evidence for significant differences in face shape in both male and female Fabry patients compared with controls. However, because discrimination from healthy controls is too low, no key role in the diagnostic process can be expecte

Home treatment for Fabry disease: practice guidelines based on 3 years experience in The Netherlands

INTRODUCTION: Recently, chronic supplementation with alpha-galactosidase A (alphaGal A) has been approved as a treatment modality for Fabry disease. The aim of the current study was to investigate the feasibility of home therapy for Fabry disease during a follow-up of >3 years and to make a proposal for practice guidelines. METHODS: Based on experience in previous clinical trials, an algorithm for home treatment eligibility was developed. The number of successful and uneventful infusions was recorded, as well as adverse and infusion-associated events. The presence and titre of recombinant human (rh)-alphaGal A antibodies were monitored every 3 months. RESULTS: Thirty of the 36 patients eligible for home treatment received a total of 1418 infusions at home (median 44 infusions, range 1-108), between March 2001 and July 2005. Mean age was 44.7 years (17-71). Seventeen patients receiving home treatment (57%) were male. The majority of patients (27 out of 30, 90%) undergoing home treatment received 0.2 mg/kg agalsidase alpha or beta. Six male patients developed an infusion-associated event, of which three developed these at home. All patients with an infusion-associated event were anti-rh-alphaGal A IgG positive at 3 months, but three patients with rh-alphaGal A antibodies did not develop side effects. Antibody titres between these patients did not differ. None of the events was life-threatening or necessitated urgent admission. CONCLUSION: Home treatment with rh-alphaGal A for Fabry disease with 0.2 mg/kg for males and both 1.0 and 2.0 mg/kg for females is feasible and safe, and reduces both the burden related to chronic intravenous therapy and health care costs. Whether this can also be applied for male patients treated with 1.0 mg/kg has not yet been determine

Family Reunification Decision-Making in Dutch Family Foster Care: A Dual Perspective Approach

Abstract Background An important responsibility of the child welfare system, is taking decisions on the reunification of children with their birth parents after the children have lived in foster families. We currently lack evidence-based knowledge to guide the reunification decision-making process. Objective The present study uses concept mapping as an exploratory method, to identify themes that seem to be used by two groups of professionals in their judgement and decision making on reunification. Method First, we consulted 78 foster care workers and studied 172 legal cases to examine criteria important for reunification. Next, unique criteria were grouped and rated by 35 foster care workers and also by 12 family judges separately. The data was analysed with multidimensional scaling and cluster analysis which resulted in a concept map for each group of professionals. Results Both foster care workers and family judges suggested the following themes in the reunification decision-making process: (a) birth parents’ functioning and parenting abilities, (b) birth parents’ acceptance of support, and (c) the child’s functioning, developmental needs and wishes. Besides parallel themes, both foster care workers and family judges also seem to consider unique themes. Conclusions The suggested similarities and differences between the two groups of professionals possibly reflect different professional frameworks. The foster care workers’ considerations seem to have an orientation towards permanency planning while the family judges’ considerations seem to be linked to the legal framework. Gaining insight in the perspective of different groups of professionals involved in the process of reunification, is a small but important step towards reaching consensus through discussion in order to achieve the optimal implementation of the decisions considered in the best interest of children’s future. </jats:sec