Fabry and Cardiomyopathy (FaCard)
Fabry and Cardiomyopathy (FaCard)
Primary objective and endpoint is the analysis of the long-term course of lyso-Gb3 and its
 clinical correlation to the progression of the cardiomyopathy in N215S-Fabry patients.
Fabry disease is an X-linked lysosomal disorder that leads to excessive deposition of neutral
 glycosphingolipids in the vascular endothelium of several organs in the body. Progressive
 endothelial accumulation of glycosphingolipids accounts for the associated clinical
 abnormalities of skin, eye, kidney, heart, brain, and peripheral nervous system. Fabry
 disease manifesting predominantly in men. Female heterozygotes also present with features of
 Fabry disease. It is suggested that the mean age of hemizygotic men at the onset of
 symptomatic stroke is 29 - 34 years. The mean age of female heterozygotes at the onset of
 symptomatic strokes is 40 - 43 years.In Europe the prevalence of Fabry disease seems to be
 massively underrepresented; actual textbooks describe 1 per 40.000. However, recent data (Lin
 HY, et al., 2009) demonstrate the identification of eight different mutations in the
 alpha-galactosidase A (alpha-Gal A) gene in 110 027 newborns who were screened by assaying
 the alpha-Gal A activity followed by genetic analysis. Hwu and co-workers (2009) have shown
 in 90,288 male newborns screened for Fabry disease that 73 males had GLA gene mutations.
 Surprisingly, 86% had the c.936+919G>A (also called IVS4+919G>A) splice mutation. In
 contrast, screening 81,689 females detected two heterozygotes. Summarizing, newborn screening
 identified a surprisingly high frequency of Taiwanese males with Fabry disease (approximately
 1 in 1,250), 86% having the IVS4+919G>A mutation previously found in later-onset cardiac
 phenotype patients.The late-onset mutation N215S is discussed to be a so-called cardiac
 variant (Perry Elliott, 2006; Eng et al., 1993, Sachdev et al., 2002). The prevalence of most
 mutations is low, i.e. Fabry disease spontaneously and individually inheriting so-called
 private mutations. However, there are some mutations that occur more frequent. Besides for
 instance R112H, A143T and R227X, also N215S belongs to this group (Dobrovolny et al., ASHG
 Abstract, 2008). The enzyme activity is only moderately affected, but hemizygous patients
 display a clearly decreased activity in leucocytes and fibroblasts.

 In 2005, Young and colleagues (Acta Paediatr Suppl.) concluded that Gb3 is not an ideal
 biomarker using the example of N215S. All heterozygotes were unconspicuous and only 50% of
 the examined hemizygotes had increased levels. However, globotraosylceramid (lyso Gb3) seems
 to reveal all (genetically) found patients with a pathologically elevated level (with a mean
 of 1,17ng/ml (females) and 2,43ng/ml (males) respectively).

 In a case study from 2004 (Meehan et al., American Journal of Kidney Diseases) was shown that
 a hemizygous male 75 years of age had a renal manifestation of mild proteinuria and a mildly
 decreased renal function due to high Gb3 accumulation in podocytes, to a lesser extent in
 tubular endothelial cells. Furthermore, he had mild congestive heart failure, a reduced left
 ventricular ejection fraction, and hypercholesterolemia. Thus, it is obvious that in Fabry
 patients with the N215S mutation disease progression can be mono- to oligosymptomatic, but
 show a tendency for the cardiac and renal phenotype rather than classical manifestation.
Inclusion Criteria:

 -  All patients of both gender from 18 years of age with a diagnosis of Fabry disease
 with the mutation N215S

 -  Written informed consent from patient

 Exclusion Criteria:

 -  Patients without a diagnosis of Fabry disease

 -  No written informed consent