Screening for Fabry disease in male patients with end-stage renal disease in western France.

CONTEXT: Fabry disease is a rare X-linked genetic disease due to pathogenic variants in the GLA gene. Classic Fabry disease is characterized by glycosphingolipids accumulation in all organs including the kidney, resulting in end-stage renal disease in a subset of male patients. Fabry disease should therefore be considered in the differential diagnosis of patients with unexplained end-stage renal disease. OBJECTIVE: We performed a prospective screening study in Western France to determine the prevalence of Fabry disease in a large population of dialyzed and transplanted patients. PATIENTS AND METHODS: Patients meeting the inclusion criteria (males, 18-70 years with end-stage renal disease of unknown or vascular origin) were selected from the REIN® registry and the CRISTAL® database. Screening on filter papers was performed after patient consent was obtained during either a dialysis session or a transplantation follow-up visit. RESULTS: One thousand five hundred and sixty-one end-stage renal disease male patients were screened and 819 consented (dialysis: n=242; transplant: n=577). One single patient was found with decreased alpha-galactosidase levels <25%. GLA sequencing identified the p.Phe113Leu variant in favor of an unknown superimposed kidney disease responsible for end-stage renal disease since this GLA pathogenic variant is associated with a later-onset cardiac form of Fabry disease with minimal kidney involvement. Family cascade genotyping revealed a previously undiagnosed affected brother. CONCLUSION: The prevalence of Fabry disease in end-stage renal disease patients was 0.12%, questioning the efficacy of this screening strategy with respect to the low prevalence. However, beside the benefit for the patient and his family, the increased awareness of Fabry disease among participating nephrologists may be of interest for future patients.

[Ehlers-Danlos syndromes]. / Les syndromes d'Ehlers-Danlos.

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inheritable connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and cutaneous fragility with delayed wound healing. Over and above these common features, they differ in the presence or absence of various organ and tissue abnormalities, and differences in genetic causal mechanisms and degree of severity. They are complex and multisystem diseases, with the majority being highly disabling because of major joint problems and neurosensory deficiencies, and in some cases, they may be life-threatening due to associated complications, especially vascular disorders. In 1997, the Villefranche classification defined 6 subtypes of EDS. However, many other new variants have been described over the last years. The "historical" EDS were characterized by abnormalities in fibrillar collagen protein synthesis. More recently, disorders of synthesis and organization of the extracellular matrix have been shown to be responsible for other types of EDS. Thus, many EDS are in fact metabolic diseases related to enzymatic defects. While there is no curative treatment for any type of EDS, early diagnosis is of utmost importance in order to optimize the symptomatic management of patients and to prevent avoidable complications. Patients must be treated and monitored by multidisciplinary teams in highly specialized reference centers. In this article, we present the current state of knowledge on these diseases that continue to be elucidated thanks to new molecular genetic techniques.

Basilar Artery Changes in Fabry Disease.

BACKGROUND AND PURPOSE: Dolichoectasia of the basilar artery is a characteristic finding of Fabry disease. However, its prevalence, severity, and course have been poorly studied. This study quantitatively evaluated, by MRA, a panel of basilar artery parameters in a large cohort of patients with Fabry disease. MATERIALS AND METHODS: Basilar artery mean diameter, curved length, "origin-to-end" linear distance (linear length), and tortuosity index ([curved length ÷ linear length] - 1) were retrospectively measured on 1.5T MRA studies of 110 patients with Fabry disease (mean age, 39.4 ± 18.6 years; 40 males) and 108 control patients (mean age, 42.0 ± 18.2 years; 40 males). RESULTS: Patients with Fabry disease had increased basilar artery mean diameter (P < .001) and basilar artery linear length (P = .02) compared with control patients. Basilar artery curved length and tortuosity index correlated with age in both groups (P < .001), whereas basilar artery linear length correlated with age only in patients with Fabry disease (P = .002). Patients with Fabry disease showed a basilar artery curved length mean increase of 4.2% (9.7% in male patients with Fabry disease versus male control patients), whereas the basilar artery mean diameter had a mean increase of 12.4% (14.3% in male patients with Fabry disease versus male control patients). Male patients with Fabry disease had increased basilar artery mean diameter, curved length, and tortuosity index compared with female patients with Fabry disease (P = .04, P = .02, and P < .001, respectively) and male control patients (P < .001, P = .01, and P = .006, respectively). Female patients with Fabry disease demonstrated an age-dependent increase of basilar artery mean diameter that became significant (P < .001) compared with female control patients above the age of 45 years. CONCLUSIONS: The basilar artery of patients with FD is subjected to major remodeling that differs according to age and sex, thus providing interesting clues about the pathophysiology of cerebral vessels in Fabry disease.

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.

[Genetic aspects of mucopolysaccharidoses]. / Génétique des mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are inherited metabolic diseases caused by mutations in the genes coding for one of the eleven enzymes involved in lysosomal catabolism of different glycosaminoglycans (or mucopolysaccharides). The different enzyme deficiencies result in a total of seven distinct mucopolysaccharidoses (I to IV, VI, VII and IX). This review considers the genetic and molecular aspects of the seven types of MPS.

A Phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects.

BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally every other day (QOD) to females with FD. METHODS: This was an open-label, uncontrolled, Phase 2 study of 12 weeks with extension to 48 weeks in nine females with FD. Doses of 50mg, 150 mg and 250 mg were given QOD. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Each individual GLA mutation was retrospectively categorized as being amenable or not to migalastat HCl based on an in vitro α-Gal A transfection assay developed in human embryonic kidney (HEK)-293 cells. RESULTS: Migalastat HCl was generally well tolerated. Patients with amenable mutations seem to demonstrate greater pharmacodynamic response to migalastat HCl compared to patients with non-amenable mutations. The greatest declines in urine GL-3 were observed in the three patients with amenable GLA mutations that were treated with 150 or 250 mg migalastat HCl QOD. Additionally, these three patients all demonstrated decreases in GL-3 inclusions in kidney peri-tubular capillaries. CONCLUSIONS: Migalastat HCl is a candidate oral pharmacological chaperone that provides a potential novel genotype-specific treatment for FD. Treatment resulted in GL-3 substrate decrease in female patients with amenable GLA mutations. Phase 3 studies are ongoing.

Fabry disease: a review of current management strategies.

Fabry disease is an X-linked inherited condition due to the absence or reduction of alpha-galactosidase activity in lysosomes, that results in accumulation of globotriaosylceramide (Gb3) and related neutral glycosphingolipids. Manifestations of Fabry disease include serious and progressive impairment of renal and cardiac function. In addition, patients experience pain, gastrointestinal disturbance, transient ischaemic attacks and strokes. Additional effects on the skin, eyes, ears, lungs and bones are often seen. The first symptoms of classic Fabry disease usually appear in childhood. Despite being X-linked, females can suffer the same severity of symptoms as males, and life expectancy is reduced in both females and males. Enzyme replacement therapy (ERT) can stabilize the progression of the disease. The rarity of the classic form of Fabry disease, however, means that there is a need to improve the knowledge and understanding that the majority of physicians have concerning Fabry disease, in order to avoid misdiagnosis and/or delayed diagnosis. This review aims to raise awareness of the signs and symptoms of Fabry disease; to provide a general diagnostic algorithm and to give an overview of the effects of ERT and concomitant treatments. We highlight a need to develop comprehensive international guidelines to optimize ERT and adjunctive therapy in patients with Fabry disease, including females and children.

[Azoospermia as a new feature of Fabry disease]. / Azoospermie: un nouveau signe d'appel de la maladie de Fabry.

This case report describes two cases of azoospermia in men suffering from Fabry disease. Testicular biopsies revealed characteristic aspects of trihexosid ceramid deposit in the Leydig cells by optic and electronic microscopic analysis. Using TESE and ICSI, sperm retrieval led to pregnancies and deliveries of healthy children. Azoospermia should be considered as a possible complication of Fabry disease and we recommend a routine sperm analysis in the follow up of young patients with Fabry disease. As we do not know the efficacy of the agalsidase therapy on the genital issue of the Fabry disease, consideration of sperm cryopreservation is suggested.

[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.

[Fabry disease: enzymatic screening using dried blood spots on filter paper]. / Dépistage de la maladie de Fabry par mesure de l'activité enzymatique de gouttes de sang séché sur papier filtre.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, which leads to a deficient activity of α-galactosidase A. α-galactosidase A activity can be assayed on dried blood spots on filter paper but the original method has been associated with a number of false positive due in great part to quenching of fluorescence. Here, we describe an adaptation of the original fluorimetric method reducing quenching of the fluorescence. RESULTS: A simple and sensitive fluorimetric method has been described for the determination of the α-galactosidase A activity in dried blood spots on filter paper, convenient for screening of FD in at-risk populations. The procedure uses 4-methylumbelliferyl-α-D-galactose, as a synthetic substrate for the enzyme. In this study, protein precipitation was added after incubation both to stop the enzymatic reaction and eliminate interfering proteins. With the novel method the risk of false-positive due to fluorescence quenching was minimized. A cut-off level of 2.1 µmol.h(-1).L(-1) (control values: 5.6 ± 2.0 µmol.h(-1).L(-1), mean ± SD) was chosen corresponding to 40 % of median control value. In all 60 hemizygotes males, α-gal A activities were below 1.1 µmol.h(-1).L(-1) (0.11 ± 0.2 µmol.h(-1).L(-1)). In the 68 heterozygous females, α-gal A activity ranged from 0 to 7.8 µmol.h(-1).L(-1) (2.2 ± 1.7 µmol.h(-1).L(-1)). Using the improved methodology, one third of the females were not identified using the enzymatic assay, due to significant residual enzyme activity. CONCLUSION: This improved method for the assay of α-gal A was robust and reduced the number of false-positive results. It can be applied for the screening of at-risk populations. α-galactosidase A enzymatic assay should not be used for screening for FD in women or, if used, should be interpreted cautiously together with the results of genotyping.

[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.

Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical studies.

Many genetic disorders are due to protein misfolding and excessive premature degradation in the endoplasmic reticulum (ER). When a gene mutation does not affect the functionality of the protein, it may still promote the premature clearance of the protein by ER-associated degradation (ERAD), resulting in a loss of function. Competitive inhibitors are often effective active-site-specific chaperones when used at sub-inhibitory concentrations. Active-site-specific chaperones assist in the folding of mutant lysosomal enzymes in the ER, thereby promoting their escape from ERAD, enhancing trafficking to the lysosome and increasing the level of residual enzyme activity. In Fabry disease, degradation of various mutant forms of a-galactosidase A (alpha-gal A) has been shown to take place in the ER as a result of protein misfolding. One of the most potent inhibitors of alpha-gal A, 1-deoxygalactonojirimycin, has also been shown to be effective in enhancing residual alpha-gal A activity in cultured fibroblasts and lymphoblasts established from patients with Fabry disease caused by a variety of missense mutations. Oral administration of 1-deoxygalactonojirimycin to transgenic mice expressing a mutant form of human alpha-gal A (R301Q) yielded higher alpha-gal A activity in major tissues, compared with untreated transgenic mice.

[Niemann-Pick disease type B identified following an episode of bronchopneumonia]. / Maladie de Niemann-Pick de type B révélée par une atteinte bronchopulmonaire.

Niemann Pick disease type B (NPD type B) is a rare autosomal recessive lipid storage disorder, characterized by a partial deficiency of sphingomyelinase. We report the case of an adult male patient affected by NPD type B and diagnosed at 39-years-of age. Pulmonary CT scan revealed a cranio-caudal gradient with nodular centrilobular ground glass opacities and thickening of the interlobular septa. Pathological examination of the bronchoalveolar lavage showed foamy alveolar macrophages and vacuolated bronchial epithelial cells on bronchial biopsy. Diagnostic confirmation was achieved by a decrease in cell lysosomal enzyme activity and by the presence of the homozygous DeltaR608 mutation in the acid sphingomyelinase gene (SMPD1).

Natural history of the respiratory involvement in Anderson-Fabry disease.

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity of enzyme alpha-galactosidase A, resulting in the accumulation of glycosphingolipids within lysosomes. Pulmonary involvement in AFD has previously been documented, but until now has been studied only in a few series of patients without any longitudinal follow-up. The aim of this study was to compare spirometric changes in AFD patients with a matched control population and to follow the subsequent progression of the disease. MATERIALS AND METHODS: Fifty individuals (27 women, 23 men, mean age 40 +/- 14 years) with AFD from 14 families underwent a static spirometric examination under standard conditions. A set of indices was compared with that of the control population. Out of this cohort, 39 individuals not receiving enzyme replacement therapy were longitudinally evaluated (median follow-up time 24 months). RESULTS: A clinically significant reduction in spirometric parameters, corresponding to mild to severe airway obstruction, was observed in 26% of women and 61% of men. During the serial follow-up, a significant (p < 0.05) age-dependent reduction of predicted %FVC and %FEV1 values was observed in male patients, while the influence of age was not seen in female patients. The %FEF(25-75) values decreased by similar degrees in men and women and in older and younger patients, indicating that progressive bronchial disease affects the small airways first. CONCLUSIONS: We have demonstrated a clinically relevant age- and sex-dependent progressive pulmonary involvement in AFD patients. The effects of enzyme replacement therapy on pulmonary involvement remain to be demonstrated.

Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry.

The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a centralized, confidential database. This report describes the baseline demographic and clinical characteristics of the first 1765 patients (54% males (16% aged < 20 years) and 46% females (13% < 20 years)) enrolled in the Fabry Registry. The median ages at symptom onset and diagnosis were 9 and 23 years (males) and 13 and 32 years (females), respectively, indicating diagnostic delays in both sexes. Frequent presenting symptoms in males included neurological pain (62%), skin signs (31%), gastroenterological symptoms (19%), renal signs (unspecified) (17%), and ophthalmological signs (11%). First symptoms in females included neurological pain (41%), gastroenterological symptoms (13%), ophthalmological (12%), and skin signs (12%). For those patients reporting renal progression, the median age at occurrence was 38 years for both sexes, but onset of cerebrovascular and cardiovascular events was later in females (median 43 and 47 years, respectively) than in males (38 and 41 years, respectively). This paper demonstrates that in spite of the considerable burden of disease in both sexes that begins to manifest in childhood or adolescence, the recognition of the underlying diagnosis is delayed by 14 years in males and 19 years in females. The Fabry Registry provides data that can increase awareness of common symptoms in all age groups, as well as insight into treated and untreated disease course, leading to improved recognition and earlier treatment, and possibly to improved outcomes for affected individuals.

[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.