Fabry disease (FD) is an X-linked genetic disorder caused by the deficient activity of lysosomal α-galactosidase (α-Gal). While males are usually severely affected, clinical presentation in female patients may be more variable ranging from asymptomatic to, occasionally, as severely affected as male patients. The aim of this study was to evaluate the existence of skewed X-chromosome inactivation (XCI) in females with FD, its concordance between tissues, and its contribution to the phenotype. Fifty-six females with FD were enrolled. Clinical and biological work-up included two global scores [Mainz Severity Score Index (MSSI) and DS3], cardiac magnetic resonance imaging, measured glomerular filtration rate, and measurement of α-Gal activity. XCI was analyzed in four tissues using DNA methylation studies. Skewed XCI was found in 29% of the study population. A correlation was found in XCI patterns between blood and the other analyzed tissues although some punctual variability was detected. Significant differences in residual α-Gal levels, severity scores, progression of cardiomyopathy and deterioration of kidney function, depending on the direction and degree of skewing of XCI were evidenced. XCI significantly impacts the phenotype and natural history of FD in females.

We propose an updated PS including renal and neurological features and adaptation of follow-up according to the genetic and ethnic status of PXE-affected patients.Genet Med advance online publication 19 January 2017.

Fabry disease (FD) (OMIM 301500) is a rare disorder in which globotriaosylceramide and other glycosphingolipids accumulate within lysosomes because of insufficient activity of α-galactosidase A. 1,2 Over time, the glycosphingolipid substrate progressively accumulates within blood vessels and various other cell types throughout the body. The initial signs and symptoms of FD frequently include neuropathic pain in the extremities, hypohidrosis, angiokeratomas, and gastrointestinal discomfort. 3 Over a period of decades, the accumulation of glycosphingolipids impairs vital organ function, putting patients at risk of developing renal failure, stroke, and cardiovascular dysfunction. [4][5][6] Because it is an X-linked disorder, hemizygous males typically experience the most severe manifestations of FD, 1 but heterozygous females can also develop serious complications. [4][5][6][7] The cardiovascular manifestations of FD can include leftventricular hypertrophy (LVH), atrial and left-ventricular arrhythmias, heart block, valvular dysfunction, angina, and arterial wall thickening. 4,5,[8][9][10][11][12][13] As the disease progresses, the hypertrophy becomes more severe, including the development of myocardial fibrosis and serious cardiac events including cardiac-related death. 4,5,8,11 Agalsidase-β, a recombinant form of human α-galactosidase A (Fabrazyme, Genzyme a Sanofi Company, Cambridge, MA), is approved for use as enzyme replacement therapy (ERT) for FD. In clinical studies, agalsidase-β at a dose of 1 mg/kg/2 weeks cleared microvascular endothelial glycosphingolipid deposits from the heart, as well as from kidney and skin, within 5 months. 14 It also provided long-term stabilization of renal function in patients with mild renal involvement 15 and delayed time to renal, cardiovascular, and cerebrovascular events in patients with more advanced FD. 16 Because it is a rare disorder, the randomized clinical trials of agalsidase-β included a relatively limited number of subjects with FD. 14,16 Several prospective, observational studies have reported cardiac data from patients treated with agalsidase-β, but these also involved only small numbers of patients. 17,18 Purpose: The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-β (recombinant human α-galactosidase A) on left ventricular hypertrophy. Methods:Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-β (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression.Results: For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was −3.6 g/year (n = 31) compared with +9.5 g/year in untr...