[Respiratory manifestations of Ehlers-Danlos syndromes]. / Manifestations respiratoires des syndromes d'Ehlers-Danlos.

Ehlers-Danlos syndromes (EDS) represent a heterogeneous group of heritable connective tissue disorders characterized by the clinical "triad" consisting in joint hypermobility, skin hyperextensibility and tissue fragility. Respiratory manifestations associated with EDS are frequent and variable. They vary mainly according to the type of EDS. In hypermobile and classical EDS, the most frequent non-vascular types, dyspnea is a common symptom. Its etiologies are wide-ranging and can coexist in the same patient: asthma, respiratory muscle weakness, chest wall abnormalities, upper and lower airway collapse. The prevalence of obstructive sleep apnea syndrome in nvEDS is high. Identification of the relevant dyspnea mechanism is essential to providing appropriate therapeutic measures. In vascular EDS (vEDS), the main pulmonary complications are pneumothorax, hemothorax and hemoptysis. As they frequently precede the diagnosis of vEDS by several years, it is imperative to raise the possibility of vEDS in a young patient with spontaneous pneumothorax or hemothorax. The presence of suggestive computed tomography parenchymal abnormalities (emphysema, clusters of calcified nodules, cavitated nodule) can be an aid to diagnosis. Treatment is based on the usual approaches, which must be carried out with caution by an experienced operator fully informed of the diagnosis. Better knowledge of respiratory manifestations of EDS by the pneumological community would improve patient care and pave the way for further research.

[Ocular manifestations in Ehlers-Danlos Syndromes: Clinical study of 21 patients]. / Manifestations ophtalmologiques des syndromes d'Ehlers­Danlos : à propos d'une cohorte de 21 patients.

INTRODUCTION: The goal of this study was to describe and analyze the ophthalmological manifestations found in 21 patients followed for Ehlers-Danlos Syndrome in our department. METHODS: This retrospective study analyzed 21 consecutive patients (17 women and 4 men) with Ehlers-Danlos syndrome seen in the Necker hospital, Paris, between April 2016 and November 2017. The mean age was 25.95 years (12-47). A complete evaluation was performed searching for symptoms, orthoptic evaluation and complete ophthalmologic examination with slit lamp examination of the anterior segment, pachymetry and fundus examination with fundus photography and OCT. RESULTS: Nineteen patients presented ophthalmological signs (90.5%). The most frequent ophthalmological signs were: ocular motility disorders in 15 patients (71.4%), with convergence insufficiency in 13 of them, blue sclera in 8 patients (38%) and dry eye syndrome in 7 patients (33%, with 2 patients with reduced Break-Up Time<10seconds and 5 with very reduced Break-Up Time<5seconds). Mean pachymetry was 539.25µm (365-612). One patient presented with bilateral keratoglobus (4.8%). High myopia was present in 2 patients (9.5%) and associated with retinal tears in one patient (4.8%). No patients presented with angioid streaks. DISCUSSION: In this study, the main ophthalmological sign was convergence insufficiency present in more than 60% of the patients. This highlights the importance of an orthoptic examination in patients with Ehlers-Danlos syndrome. Dry eye syndrome with tear film instability was frequent, even though the patients were young. Blue sclera was seen in 38% of the patients. We reported two patients with high myopia and one patient with keratoglobus in our cohort. No patients presented with angioid streaks, and mean pachymetry was normal in our series. CONCLUSION: An ophthalmological and orthoptic evaluation should be performed in all patients with Ehlers-Danlos syndrome to detect and treat ocular manifestations. If Ehlers-Danlos syndrome is suspected, ophthalmological examination can also provide support for the diagnosis.

X-chromosome inactivation in female patients with Fabry disease.

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.

[Vestibular and cochlear manifestations in Fabry's disease]. / Manifestations ORL de la maladie de Fabry.

Anderson-Fabry's disease corresponds to an inherited disorder transmitted by an X-linked recessive gene. The disease is caused by an alpha-galactosidase deficiency leading to an abnormal glycosphingolipid metabolism, resulting in glycosphingolipids deposits all over the body. The disease affects all organs over the body and can be responsible for central nervous system or renal failure, heart attack, which can lead for early death in absence of diagnosis and treatment. In addition to these life-threatening manifestations, other problems which may have a profound impact on quality of life, such as hearing loss, have been relatively neglected. Thus, a large proportion of patients with Fabry's disease suffer from sensorineural hearing loss, with both progressive hearing impairment and sudden deafness, and peripheral vestibular deficits with dizziness and vertigo. The exact pathophysiologic mechanism(s) of those otological complications is still studied, but both cochleo-vestibular disorder and vascular origin seems to be involved. For many years, only symptomatic treatment has been available. For the past ten years, the introduction of enzyme replacement therapy with recombinant agalsidase-α or -ß provides new prospect for these patients, decreasing the risk of complications. Still on study, it may also be active both on hearing loss and vestibular disturbances.

[Enzyme replacement therapy of lysosomal storage diseases]. / Thérapies enzymatiques substitutives des maladies lysosomales.

Extraction and purification of an acid ß-glucosidase from human placenta (alglucerase) for the treatment of Gaucher disease, replaced a few years later by a recombinant enzyme (imiglucérase, Cerezyme(®)), has paved the way to the development of enzyme replacement therapies (ERT) for the treatment of lysosomal storage diseases (LSD) among which Fabry disease for which the long-term efficacy of the two currently available preparations (agalsidase alfa, Replagal(®) and Fabrazyme(®)) is still being investigated. Mucopolysaccharidosis (MPS) type I (Hurler and Scheie diseases), II (Hunter syndrome) and VI (Maroteaux-Lamy disease) also benefit from ERT using laronidase (Aldurazyme(®)), idursulfase (Elaprase(®)) and galsulfase (Naglazyme(®)), respectively. ERT reduces the hepatosplenomegaly and improves the physical and respiratory capacities of MPS patients with a globally acceptable safety profile although the possibility of infusion-associated should always be kept in mind. Alglucosidase alpha (Myozyme(®)) improves the cardiomyopathy and life expectancy of infants suffering from Pompe disease and is under evaluation for the treatment of the juvenile and adult forms of the disease. CNS involvement remains a major challenge for many LSD and innovative research and approaches are needed to address the fact that recombinant enzymes do not cross the blood-brain barrier and therefore are not expected to lead to any improvement in CNS damages, except if alternative routes such as intrathecal administration would be developed. Molecular chaperones (e.g. migalastat for Fabry disease) and inhibitors of glucosylceramide synthesis (e.g. eliglustat tartrate for Gaucher disease) are currently under investigation in various clinical trials.

[Prenatal diagnosis of Gaucher disease]. / Le diagnostic prénatal de la maladie de Gaucher.

Gaucher disease (GD, OMIM #230800, 230900, 231000) is a lysosomal surcharge disorder caused by a deficiency in glucocerebrosidase, a lysosomal enzyme also referred to as acid beta-glucosidase or, in rare cases, by a deficiency in the activator protein saposin C. Partial deficiency of acid beta-glucosidase is associated with the presence of glucosylceramide, also known as glucocerebroside (Gb1), deposits in the reticuloendothelial cells of the liver, spleen and bone marrow, in non-neuronopathic type 1, GD. Profound deficiency of acid beta-glucosidase caused by disabling mutations is additionally associated with neurological manifestations in the less common type 2 and type 3 Gaucher diseases. Type 2 GD culminates in early death as a result of devastating neurological disease. Congenital ichtyosis with a collodion baby phenotype is also part of the spectrum of clinical presentations of type 2 GD. Recombinant glucocerebrosidase (imiglucerase) is an effective mean of treating type 1 GD and should be initiated early on in life. Although imiglucerase has recently been approved for the treatment of type 3 GD, enzyme replacement therapy cannot reverse the neurological manifestations in type 2 or type 3 GD. Following genetic counseling and informed consent, direct enzymatic assay of acid beta-glucosidase and molecular testing of the GBA mutations on chorionic villi samples (CVS) can be offered to families in which type 2 or type 3 GD has been diagnosed. Improvement in substrate deprivation therapy or gene therapy may provide a cure for patients with these disorders in the future.

[The cochlea in Fabry disease: a sensorineural hearing loss model of vascular origin?]. / La maladie de Fabry: l'atteinte vasculaire multi-organe pourrait également intéresser la cochlée.

PURPOSE: Fabry disease is an inborn error of metabolism due to a deficient activity of the lysosomal enzyme alpha-galactosidase A. The enzyme defect leads to the systemic accumulation of neutral glycosphingolipids in tissues, mainly in the vascular endothelium. STRONG POINT: The aim of this paper is to present a review of the auditory manifestations in Fabry disease, and to discuss hypothesis on the vascular origin of deafness. PERSPECTIVES: Sensorineural hearing loss in Fabry disease could be the first documented vascular pathology of the inner ear.