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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., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Extraction and purification of an acid β-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., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

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 -β 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., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

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).

Evidence-based therapeutic goals have been developed by European and North American experts in the field of Gaucher disease (GD, lysosomal acid beta glucosidase deficiency, OMIM 230 800) in an attempt to reverse the entire disease phenotype, improve quality of life and prevent life-threatening complications. Patients with GD usually have maximal clinical benefit when enzyme replacement treatment (ERT) efficiency is administered at the optimal time i.e. generally during the asymptomatic phase of the disease. Currently, imiglucerase is the standard of care for type 1 GD due to its high efficiency at improving bleeding tendencies, anemia, reversing heptosplenomegaly and part of skeletal damages and eliminating bone crises. ERT has also demonstrated a remarkable safety profile with tolerability at 3 years greater than 99%. Treatment of GD is a lifelong treatment that patients should not interrupt without a careful monitoring of the disease evolution.

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.

Hypertrophic cardiomyopathies have an estimated prevalence of 1/500. The analysis of the genes coding for the 10 most commonly involved sarcomeric proteins, fails to detect a mutation in about one third of cases. In some of these cases, cardiomyopathy can be attributed to a genetics storage disease with enlarged glycogen vacuolss (PRKAG2 deficiency, Danon disease, Pompe disease) and/or lysosomol vacuoles (Donon disease, Pompe disease, Fabry disease). These diseases all have in common a short PR interval. PRKAG2 deficiency is due to a dominant mutation of the gamma2 subunit of the cardiac AMP kinose. It leads to a storage cardiomyopathy which may be associated with sudden death in 10% of cases, due to ventricular arrhythmia or auriculoventricular blocks. Danon disease is an X-linked dominant inherited disease characterized by cardiomyopathy, squeletal myopathy and mental retardation. Cardiac transplantation is indicated in both affected men and women. In the infantile form of Pompe disease, enzyme replacement therapy with olglucosidase alpha shows efficacy on cardiac failure with a significant regression of ventricular hypertrophy on ECG, echocardiography and radiography

Moss spectrometry proceeds from the generation of gas-phase ions from the molecules present in a sample. Recent ionisation methods make use of a focalized energy transfer onto a surface, allowing the localized analysis of a solid sample. The signals recorded are all the more intense as the corresponding molecules are more abundant. The point-by-point recording of mass spectra thus enables to generate ion images inasmuch as the translation of ionic intensity variations in a colour code creates the visible contrast. By applying mass spectrometry imaging to thin tissue slices originating, for example, from biopsies, it is possible to detect and locate simultaneously on the tissue surface a variety of biomolecules such as lipids, metabolites, drugs or proteins. This method can either play a role of support to the clinical diagnostic or emerge as a new tool in metabolomic and proteomic studies. The particular case of the Fabry disease is presented here in order to illustrate the present capabilities of this novel chemical imaging approach.

Progressive decline in kidney function is a cardinal manifestation of Fbry disease. Proteinuria is usually the earliest biological marker of renal involvement. Renoprotection should associate both effective Enzyme Replocement Therapy (ERT) and non-specific anti-proteinuric therapy as recommended for all chronic kidney diseases. ERT has demonstrated high efficiency in the early clearing of globotriaosylceromide deposits, however the functional protecting effect on GFR decrease remains to be validated, especially in patients with CKD stage 3 or higher Estimation of GFR should be very cautious using creatinine based formulas, leading to measure GFR whenever possible in order to characterize the progression of CKD in Fabry patients.

Preclinical and phase I/II studies gave the proof of principle of enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A through the demonstration of the clearance of the accumulated subtrate from plasma and tissues. In a multicenter, randomized, placebo-controlled, double-blind phase Ill study, the biological efficacy of recombinant alpha-galactosidose A (agalsidase beta 1 mg/kg/714 days) was demonstrated on the basis of complete clearance of accumulated globotriaosylceramide from the endothelia of the kidney, heart and skin. The phase III extension study data gives additional results: kidney function appears to be stabilized after 54 to 60 months of treatment with agolsidase beta in most patients. Intent-to-treat analysis of a double-blind, randomized, placebo-controlled, phase IV study, showed that, adjusted for on imbalance in baseline proteinuria, agalsidase beta significantly reduces by 53% the risk of a first clinical event (renal, cardiac and cerebrovascular), compared with placebo. Clinical benefits of ERT depend on patients' clinical status at baseline, therefore prompting for onset of ERT before irreversible damage occur and underlying the need to stratify patients' populations to better understand the outcome of ERT.

Fabry disease (FD, OMIM 301500) is an X-linked inborn error of metabolism due to mutations in the gene encoding a-galactosidase A, a lysosomal enzyme. FD is an X-linked disease and affected males are more severely affected than females. In Fabry disease, the penetrance and the severity index of the phenotype are high in males, while expressivity and severity index appears highly variable and often "intermediate" in heterozygous females. Classic definitions of X-linked recessive and dominant inheritance neither reflect the variable expressivity, nor take into account the multiple mechanisms that can lead to disease expression in heterozygous females. The use of the terms X-linked recessive and dominant should probably be abandoned, and Fabry disease simply described as following 'X-linked' inheritance. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. Molecular testing of females at-risk to be carriers is therefore mandatory for accurate genetic counselling. The GLA gene has been cloned and more than 300 mutations have been identified. Most of them are private and have been identified in only one family

Due to its high sensitivity and specificity, determination of the c-galactosidase A activity in leukocytes is the gold standard to confirm the diagnosis of Fabry disease in hemizygous moles. In contrast, heterozygous females cannot be dependably diagnosed by this method and genotyping should always be carried out. Two recent breakthroughs have contributed to the rise of screening programs for Fabry disease: first, the use of filter papers to collect blood or urine spots from individuals in at-risk populations for Fabry disease, second, the development of moss spectrometry Substrate accumulation and enzyme activity can be measured on urine and blood samples, respectively Moss spectrometry allows the qualitative and quantitative determination of the accumulation of the undegraded substrate (globotriaosylceromide) in urine, but also the measurement of enzyme activities in blood samples for the simultaneous diagnosis of several inborn errors of metabolism, among which lysosomal storage diseases and in particular Fabry disease.

The advent of innovative techniques in mass spectrometry, especially in the area of imaging, prompted us to evaluate two promising techniques: secondary ion mass spectrometry (SIMS) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. For this purpose, sections of cutaneous biopsies from patients affected by Fabry's disease and control patients were analyzed. In the course of this disease, two physiological glycosphingolipids [globotriasylceramide (Gb3) and the galabiosylceramide (Ga2)] accumulate in certain tissues owing to a catabolism failure. The ability of these techniques to localize sites of accumulation in body tissues and their capacity to identify the accumulated lipid structures by mass spectra were evaluated. Results demonstrated that these two techniques provide complementary information:-secondary ion mass spectrometry enabled precise localization of areas of accumulation with lateral resolution in the micrometer range;-the signal obtained with matrix-assisted laser desorption/ionization mass spectrometry was high enough to identify these structures according to their molecular weight.

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.

Fabry disease is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Progressive accumulation in lysosomes of the undegraded glycosphingolipids leads to a multi-system disease with dermatological, ocular, renal, cardiac, and neurological manifestations. Peripheral nerve involvement, neuropathic pain and chronic acroparesthesiae, are frequent and early-onset signs revealing the disease. They are due to the involvement of small nerve fiber, thus explaining the normality of electroneuromyography. Cochleo-vestibular and autonomic nervous system involvement is frequent. Besides rare aseptic meningitis, central nervous system involvement is essentially represented by cerebrovascular events (stroke, transient ischemic attack). Affecting essentially the posterior circulation, their etiologies have to be clarified: progressive stenosis of small vessels with globotriasocylceramide deposits, arterial remodeling, endothelial dysfunction, pro-thrombotic state, cerebral hypoperfusion consecutive to dysautonaumy, cardiac embolism. MRI shows numerous silent lesions, increasing with age, mainly in small perforant arteries (periventricular white matter, brainstem, cerebellum, basal ganglia). Pulvinar calcifications, due to an increase in cerebral hyperperfusion, could be specific of Fabry disease. Positon tomography analysis shows a reduced cerebral flow velocity and impaired cerebral autoregulation, secondary to the glycosphingolipid storage in vascular endothelial cells. Enzyme replacement therapy has to be carefully monitored.

Evidence-based therapeutic goals have been developed by several European and American experts in Gaucher disease in order to attempt to reverse the entire Type 1 Gaucher phenotype, prevent complications, improve quality of life and prevent life-threatening complications. Patients with Gaucher disease will benefit by maximum enzyme replacement treatment (ERT) efficiency if it is given at the optimal time i.e. generally during the asymptomatic phase of the disease. Currently, Cerezyme is the standard of care for all severities of type 1 Gaucher disease due to its high efficiency at ameliorating bleeding tendencies, reversing organomegaly and part of skeletal damages and eliminating bone crises. ERT has also demonstrated a remarkable safety profile with tolerability at 3 years greater than 99%. Treatment of Gaucher disease is a long-life treatment that the patient should not interrupt without a careful monitoring of the disease evolution.

The Gaucher phenotype is very complex and it cannot be simply evaluated on the basis of blood counts or splenomegaly, but by the analysis of all disease compartments. To establish the diagnosis of Gaucher disease, biochemical assay of glucocerebrosidase activity is the most reliable method. However, it can be supplemented by molecular diagnosis, which may be helpful to predict the severity and the rate of progression of clinical manifestations. The genotype-phenotype correlations are very complex with a high inter-individual variability in the severity of clinical manifestations within a same genotype. Genetic modifiers may play an important role in determining the eventual Gaucher phenotype. Despite of some devastating complications, which can arise with advancing age, Gaucher disease worsen progressively in the majority of patients homozygous for the N370S mutation. The analysis of the data of the International Collaborative Gaucher Group registry should provide a better understanding of the natural history of the Gaucher disease.

Gaucher disease (GD) is one of the most prevalent lysosomal storage disorders and one of the rare genetic diseases for which therapy is now available. Partial deficiency of glucocerebrosidase is associated with parenchymal disease of the liver, spleen, and bone marrow with concomitant anaemia and thrombocytopenia in non-neuronopathic, type 1, Gaucher disease. Severe deficiency of glucocerebrosidase caused by disabling mutation is additionally associated with neurological manifestations in the less common type 2 and type 3 Gaucher diseases. Outside of the Ashkenazi Jewish community, a high molecular diversity is observed. Clarification of genotype-phenotype relationship and the identification of modifier loci that impact on Gaucher disease phenotypes remain a critical area for research. Recombinant glucocerebrosidase (imiglucerase) is an effective mean of treating type 1 Gaucher disease and should be initiated early on in life. Amelioration of hepatosplenomegaly and of haematological manifestations is usually apparent within six months. Bone disease responds more slowly. Imiglucerase has recently been approved for the treatment of type 3 Gaucher disease. Enzyme replacement therapy cannot reverse the neurological deficits in type 2 or type 3 Gaucher disease. This should prompt further research on substrate deprivation and gene therapy.

Fabry disease is a hereditary metabolic disease, with an X-linked transmission, that is due to the deficit of alpha-galactosidase A, a lysosomal enzyme. The enzyme deficiency is responsible for an accumulation of neutral glycosphingolipids in the organism with a consequent disease of overload that is responsible for pain, dermatological, renal, cardiac, gastro-intestinal, cochlear and neurological manifestations. Fabry disease starts during childhood but the diagnosis is often made too late. An early diagnosis is nevertheless essential in order to commence a treatment before the occurrence of morbid cardio or cerebro-vascular accidents, or the development of end-stage chronic renal failure. Some phenotypic variants of Fabry disease are probably under-diagnosed among patients with so-called idiopathic hypertrophic cardiomyopathy on haemodialysis. Treatment by substitution of the enzyme with a recombinant alpha-galactosidase has been recently validated in breakthrough controlled clinical trials. Substitutive enzyme treatment represents a major therapeutic development. At the same time, it raises numerous questions such as the ideal age for initiation of treatment, the dose and the optimal frequency of enzyme administration, the reversibility of certain histopathological lesions and the determination of the best markers for the assessment and follow-up of the efficacy of treatment. Monitoring of the plasma levels of the enzyme substrate and the antibody titre seem to be essential. The documentation of short-term clinical benefits could require the use of sophisticated investigation methods such as the study of the myocardial function by tissue Doppler imaging.

Lysosomal storage disorders (LSDs) are monogenic inborn errors of metabolism. Various groups have been delineated according to the affected pathway and the accumulated substrate, and new entities are still being identified. They are severe disorders with a heterogeneous clinical spectrum encompassing visceral, skeletal and neurologic involvement, and high morbidity and mortality. Most of the genes encoding the lysosomal enzymes have been cloned, and animal models have been obtained for almost each disease. In the last decades, LSDs have been models for the development of molecular and cellular therapies for inherited metabolic diseases. Studies in preclinical in vitro systems and animal models have allowed the successful development of bone marrow transplantation, substrate deprivation, enzyme replacement therapy and gene transfer methods as therapeutic options for several LSDs. The aim of this paper is to review the biology of acid hydrolases and lysosomal membrane proteins, to describe the systematic classification of LSDs and the most recently identified entities, and to briefly review novel therapeutic approaches for two lipidoses: Gaucher disease and Fabry disease.

Fabry disease (FD, OMIM 301500) is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the accumulation of neutral glycosphingolipids throughout the body, particularly within endothelial cells. Resulting narrowing and tortuosity of small blood vessels lead to tissue ischaemia and infarction. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity (acroparesthesia, angiokeratoma, autonomic dysfunction, cardiomyopathy and deafness), and mortality from early onset strokes, heart attack and renal failure in adulthood. Demonstration of alpha-galactosidase A deficiency in leukocytes or plasma is the definitive method for the diagnosis of affected hemizygous males. Most heterozygotes present with a cardiac, renal or neurological symptomatology, although to a lesser extent than what is observed in hemizygotes. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. Molecular testing of possible carriers is therefore mandatory for accurate genetic counselling. The GLA gene has been cloned and more than 200 mutations have been identified. Medical management is symptomatic and consists of partial pain relief with analgesic drugs (gabapentin, carbamazepine), whereas renal transplantation or dialysis is available for patients experiencing end-stage renal failure. However, the ability to produce high doses of alpha-galactosidase A in vitro has opened the way to clinical studies and enzyme replacement therapy has recently been validated as a therapeutic agent for FD patients in clinical trials. Long term safety and efficacy of replacement therapy are currently being investigated.

Fabry disease (FD, OMIM 301500) is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the accumulation of neutral glycosphingolipids throughout the body, particularly within endothelial cells. Resulting narrowing and tortuosity of small blood vessels with endothelial dysfunction lead to tissue ischaemia and infarction. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity and mortality from early onset strokes, cardiomyopathy and renal failure in adulthood. Medical management is symptomatic and consists of partial pain relief with analgesic drugs (gabapentin, carbamazepine), antihypertensive drugs, whereas renal transplantation or dialysis is available for patients experiencing end-stage renal failure. However, the ability to produce high doses of alpha-galactosidase A in vitro has opened the way to preclinical studies in the mouse model, and to the development of the first clinical trials in patients with Fabry disease. Enzyme replacement therapy has recently been validated as a therapeutic agent for Fabry disease patients. Long term safety and efficacy of replacement therapy are currently being investigated. Substrate deprivation and gene therapy may also prove future alternative therapeutic options.

Introduction: This review presents the clinical and genetic aspects of Fabry disease, along with recent advances in research., Current Knowledge and Key Points: Fabry disease is an X-linked inborn error of metabolism due to a deficient activity of the lysosomal enzyme alpha-galactosidase A. The enzymatic defect leads to the systemic accumulation of neutral glycosphingolipids in plasma and tissues. Clinical manifestations in affected hemizygous males are primarily due to progressive disease of small vessels, including angiokeratoma, autonomic dysfunction, and lifelong debilitating pain. Renal failure and vasculopathy of the heart and brain lead to early demise in adulthood. Demonstration of alpha-galactosidase A deficiency in leukocytes or plasma is the definitive method for the diagnosis of affected hemizygous males. Most female carriers are clinically symptomatic, they may present isolated acroparesthesia, cardiac symptoms, or the characteristic benign corneal dystrophy. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. A reliable molecular test for detection of heterozygosity is therefore highly desirable for accurate genetic counselling. The GLA gene has been mapped to chromosome Xq22, and cloned. Several studies have shown the molecular heterogeneity of the disease. Currently, no standard treatment exists for Fabry disease. Symptomatic treatment is provided as appropriate. In addition, renal transplantation or dialysis is available for patients experiencing end-stage renal failure., Future Prospects and Projects: The ability to produce high doses of recombinant alpha-galactosidase A in vitro has opened the way to preclinical studies in the mouse model and led to the development of the first clinical trials with enzyme replacement therapy in patients with Fabry disease.