Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder due to deficiency of alpha-Galactosidase A, causing accumulation of globotriaosylceramide and elevated plasma globotriaosylsphingosine (lysoGb3). The diagnostic value and clinical relevance of plasma lysoGb3 concentration was investigated. All male and adult female patients with classical Fabry disease could be discerned by an elevated plasma lysoGb3. In young pre-symptomatic Fabry heterozygotes, lysoGb3 levels can be normal. Individuals carrying the R112H and P60L mutations, without classical Fabry symptoms, showed no elevated plasma lysoGb3. Multiple regression analysis showed that there is no correlation of plasma lysoGb3 concentration with total disease severity score in Fabry males. However, plasma lysoGb3 concentration did correlate with white matter lesions (odds ratio: 6.1 per 100 nM lysoGb3 increase (95% CI: 1.4-25.9, p=0.015). In females, plasma lysoGb3 concentration correlated with overall disease severity. Furthermore, plasma lysoGb3 level was related to left ventricular mass (19.5+/-5.5 g increase per 10 nM lysoGb3 increase; p=0.001). In addition, it was assessed whether lifetime exposure to lysoGb3 correlates with disease manifestations. Male Fabry patients with a high lysoGb3 exposure (>10,000 U), were moderately or severely affected, only one mildly. Female patients with a low exposure (<1000 U) were asymptomatic or mildly affected. A large proportion of the females with an exposure >1000 U showed disease complications. Plasma lysoGb3 is useful for the diagnosis of Fabry disease. LysoGb3 is an independent risk factor for development of cerebrovascular white matter lesions in male patients and left ventricular hypertrophy in females. Disease severity correlates with exposure to plasma lysoGb3.

Analysis of placental tissue in Fabry disease with and without enzyme replacement therapy.

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.

Screening for Fabry disease in high-risk populations: a systematic review.

INTRODUCTION: Fabry disease (FD) may present with left ventricular hypertrophy (LVH), renal insufficiency or stroke. Several studies investigated FD prevalence in populations expressing these symptoms. A systematic review was conducted to calculate the overall prevalence of FD in these cohorts. METHODS: Online databases were searched for studies on screening for FD. Study population selection, screening methods and outcome of screening were recorded. RESULTS: 20 studies were identified, 10 of which included both male and female patients. In all (n=19) studies with male and almost all (n=10) with female patients, alpha-galactosidase A (alpha-Gal A) activity was used as the screening method. In men on dialysis (10 studies), overall FD prevalence was 0.33% (95% CI 0.20% to 0.47%) and in women (6 studies) 0.10% (95% CI 0% to 0.19%). Combined prevalence of FD in patients with renal transplant was 0.38% in men (95% CI 0.07% to 0.69%) and 0% in women. In patients with LVH, selection of study population and differences in the method of screening hampered the calculation of an overall prevalence (ranging from 0.9% to 3.9% in men and 1.1% to 11.8% in women). In premature strokes (n=2 studies), overall FD prevalence was 4.2% (95% CI 2.4% to 6.0%) in men and 2.1% (95% CI 0.5% to 3.7%) in women. DISCUSSION: The prevalence of FD in dialysis patients is 0.33% for men and 0.10% for women. The prevalence of FD in LVH is at least 1% for both genders. In women, most studies were performed with alpha-Gal A activity measurements as the screening tool, although this method fails to detect one third of female patients with FD, underestimating the overall prevalence in women.