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...

Features of the pain in hypermobile Ehlers‐Danlos syndrome (hEDS) are complex and insufficiently known by clinicians. We enrolled 37 hEDS patients. Disease status was ascertained using revised 2017 International Classification criteria, in the EDS French National Reference Center. Patients were evaluated with a clinical examination, quantitative sensory testing, and validated questionnaires. Thirty‐seven patients were evaluated. Pain had appeared at 10 ± 5 years old and became chronic at 20 ± 9 years old. hEDS was diagnosed at only 24 ± 10 years old. Ninety‐seven percent of them had severe chronic pain, which gradually increased over time in 75% of them. The main location of pain was in joints and predominated in lower limbs. Patients with a generalized presentation of pain had older chronic pain and a higher impact on the affective component. Neuropathic pain was frequent in the most painful joint and associated with heat hypoesthesia. An asymmetric proprioception was found in one third of the patients. A very high rate of attempted suicide was observed. To conclude, pain in hEDS is severe, chronic, and disabling. Sensorial and proprioceptive sensibilities are also affected. Peripheral neuropathic pain is frequent and central sensitization appears to be a key step in the evolution of disease.

Immunogenicity of recombinant human acid-alpha glucosidase (rhGAA) in enzyme replacement therapy (ERT) is a safety and efficacy concern in the management of late-onset Pompe disease (LOPD). However, long-term effects of ERT on humoral and cellular responses to rhGAA are still poorly understood. To better understand the impact of immunogenicity of rhGAA on the efficacy of ERT, clinical data and blood samples from LOPD patients undergoing ERT for >4 years (n = 28) or untreated (n = 10) were collected and analyzed. In treated LOPD patients, anti-rhGAA antibodies peaked within the first 1000 days of ERT, while long-term exposure to rhGAA resulted in clearance of antibodies with residual production of non-neutralizing IgG. Analysis of  T cell responses to rhGAA showed detectable T cell reactivity only after in vitro restimulation. Upregulation of several cytokines and chemokines was detectable in both treated and untreated LOPD subjects, while IL2 secretion was detectable only in subjects who received ERT. These results indicate that long-term ERT in LOPD patients results in a decrease in antibody titers and residual production of non-inhibitory IgGs. Immune responses to GAA following long-term ERT do not seem to affect efficacy of ERT and are consistent with an immunomodulatory effect possibly mediated by regulatory T cells.

Topical STS appears to be a promising treatment for ectopic calcifications secondary to HFTC or HHS.

No abstract

Periodontal Ehlers–Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early‐onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non‐invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.