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Fabry (or Anderson‐Fabry) is a rare pan‐ethnic disease affecting males and females. Fabry is an X‐linked lysosomal storage disease, affecting glycosphingolipid metabolism, that is caused by mutations of the GLA gene that codes for α‐galactosidase A. Fabry disease (FD) can be classified into a severe, classical phenotype, most often seen in men with no residual enzyme activity, that usually appear before 18 years and a usually milder, nonclassical (later‐onset) phenotype that usually appear above 18 years. Affected patients show multifactorial complications, including renal failure, cardiovascular problems, and neuropathy. In this review, we briefly report the clinical trials so far performed with the available therapies, and then we focus on the in vitro and the in vivo experimental models of the disease, to highlight the relevance in improving the existing therapeutics and understand the mechanism of this rare disorder. Current available in vivo and in vitro models can assist in better comprehension of the pathogenesis and underlying mechanisms of FD, thus the existing therapeutic approaches can be optimized, and new options can be developed., Schematic representation of the pathogenic mechanism that occurs in Fabry disease.

The purpose of this study was to examine the applicability of the use of samples in dried blood spot (DBS) for the definitive diagnosis of Fabry disease (FD) in males and females and to compare the diagnostic role of α-galactosidase A activity (α-Gal A), levels of lyso-Gb3 and sequencing of the GLA gene in screening patients with suspected FD. Measurement of α-Gal A activity in suspected FD patients in DBS was made followed by lyso-Gb3 determination and GLA gene sequencing. Of the 2381 subjects analyzed, FD was confirmed in 24 patients. Thirteen different variants were considered like pathogenic, five of which had not been previously described (c.143A > G; c.455A > C; c.487G > T; c.554delA; c.1045_1046insA). None of the patients with normal enzyme activity had FD confirmation. The DBS measurement of α-Gal A was more sensitive than lyso-Gb3 levels in both men and women. Definitive diagnosis of FD from a single DBS is possible, allowing samples to be easily sent from anywhere to the reference laboratory.

Fabry disease (FD), a rare X‐linked disease, can be treated with bi‐monthly infusion of enzyme replacement therapy (ERT) to replace deficient α‐galactosidase A (AGAL‐A). ERT reduces symptoms, improves quality of life (QoL), and improves clinical signs and biochemical markers. ERT initiation in childhood could slow or stop progressive organ damage. Preventative treatment of FD from childhood is thought to avoid organ damage in later life, prompting a French expert working group to collaborate and produce recommendations for treating and monitoring children with FD. Organ involvement should be assessed by age 5 for asymptomatic boys (age 12‐15 for asymptomatic girls), and immediately for children diagnosed via symptoms. The renal, cardiac, nervous and gastrointestinal systems should be assessed, as well as bone, skin, eyes, hearing, and QoL. The plasma biomarker globotriaosylsphingosine is also useful. ERT should be considered for symptomatic boys and girls with neuropathic pain, pathological albuminuria (≥3 mg/mmol creatinine), severe GI involvement and abdominal pain or cardiac involvement. ERT should be considered for asymptomatic boys from the age of 7. Organ involvement should be treated as needed. Early diagnosis and management of FD represents a promising strategy to reduce organ damage, morbidity and premature mortality in adulthood.

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A which causes accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. Gastrointestinal symptoms are due to intestinal dysmotility as well as impaired autonomic function, vasculopathy and myopathy. Since 2001, enzyme replacement therapy has been a mainstay in treatment of gastrointestinal symptoms of Fabry disease (FD), resulting in reduced gastrointestinal symptoms. Here, we report on four patients with Fabry disease (FD) who manifested early gastrointestinal involvement.

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 describe the results of the multidisciplinary evaluation in patients with Fabry disease and the same genetic mutation and their outcomes using different approved enzyme replacement therapy (ERT). We measured baseline data and serial results of neuropathic pain assessment and renal, cardiac and cerebrovascular functioning. Pain scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa-treated patients after 1 year with posterior increase. During the agalsidase beta shortage, two male patients were switched to agalsidasa alfa, after 1 year both cases presented an increase in scale values. Renal evolution showed a tendency toward a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain magnetic resonance imaging (MRI) showed increase of white matter lesions in four patients. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. Following the reported recommendations on reintroduction of agalsidase beta after the enzyme shortage, we decided to switch all patients to agalsidase beta.

Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A 50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory.

Fabry disease (FD) is an X-linked disease in which mutations of the GLA gene result in a deficiency of the enzyme α-galactosidase A and subsequent progressive, intralysosomal deposition of undegraded glycosphingolipid products, primarily globotriaosylceramide, in multiple organs. Progressive nephropathy is one of the main features of FD and is marked by an insidious development, with an overall rate of progression of chronic kidney disease (CKD) very similar to diabetic nephropathy. Untreated patients usually develop end stage renal disease in their 50s. The decline in renal function in FD is adversely affected by male gender, advanced CKD, hypertension and, in particular, severe proteinuria. Enzyme replacement therapy (ERT) has been shown to slow the progression of Fabry nephropathy. The current consensus is that ERT should be started in all men and women with signs of renal involvement.

Fabry disease (FD) is a multisystem lysosomal storage disorder caused by mutations in the GLA gene. The clinical significance of the mutation p.D313Y is still under debate. Retrospective chart analysis of clinical (neurological, cardiac, renal, and ophthalmological), genetic, and biochemical (lyso-globotriaosylsphingosine, lyso-Gb3; enzyme activity) data was performed in all our patients carrying the p.D313Y mutation. Fourteen patients from 5 families (10 female, 4 male; age range 10-51) were included. Symptoms and organ manifestations compatible with FD could be identified in 10 patients. Cerebrovascular events occurred in 4 females. Seven patients reported pain or acroparaesthesia. Cornea verticillata was found in 1 patient, mild retinal vascular tortuosity in 5 patients. Lyso-Gb3 was elevated in 2 females with cerebrovascular involvement. Classical cardiac, renal or skin manifestations could not be identified. The mutation p.D313Y in the GLA gene may lead to organ manifestations and elevation of the Fabry-specific biomarker lyso-Gb3. Neurological symptoms (stroke and pain) and ocular manifestations seem to be the leading findings. Annual routine visits are recommended for patients carrying the p.D313Y mutation. Enzyme replacement therapy might be considered in symptomatic patients.

Fabry disease (FD) is an X-linked lysosomal storage disorder (LSD) caused by the deficiency of the enzyme α-galactosidase. It exhibits a wide clinical spectrum that may lead to a delayed or even missed diagnosis and the real incidence can be underestimated. We report the cases of two unrelated Italian families in whom FD was incidentally diagnosed in two females. In both families, the risk for other lysosomal disorders was known from other members affected by fucosidosis or mucopolysaccharidosis I Hurler/Scheie. Some subjects were simultaneously heterozygous for Fabry and the other lysosomal deficiency. Our study shows that the risk for more than one LSDs can occur in a family pedigree. The diagnosis of Fabry in female probands represents a diagnostic challenge, as symptoms and signs can be variably present because of the random X-chromosome inactivation.

Fabry disease is a rare, multiorgan disease. The most serious complications involve the kidney, brain and heart. This study aims to assess the effect of enzyme replacement therapy (ERT) using agalsidase-beta in children with Fabry disease. We carried out a nationwide, descriptive and observational retrospective cohort study of 10 children (9-16 years at baseline), who underwent regular systematic investigations for 1-8 years after initiation of ERT with agalsidase-beta (Fabryzyme®, Genzyme). Ophthalmological, echocardiographic abnormalities and hypohidrosis were found at baseline and during the follow-up period. Serious kidney, heart or brain involvement had not developed at the last follow-up examination. For the majority of the patients improvements were found concerning headache, acroparaesthesias and gastrointestinal pain during the follow-up period. The level of energy and physical activity also increased. Treatment with agalsidase-beta was associated with a reduction of neuropathic and abdominal pain and headache. Although all aspects of the Fabry pain phenotype cannot be treated with ERT, the observed effects were clinically significant in the lives of the majority of Fabry children and together with the absence of serious Fabry manifestations at last follow-up, we argue that early initiation of ERT may be considered.

Fabry disease (FD) is an underdiagnosed pathology due to its symptomatology that overlaps with various systemic and rheumatic disorders, including familial Mediterranean fever (FMF). We examined the Mediterranean fever (MEFV) and α-galactosidase A (GLA) genes, whose mutations are responsible for FMF and FD, respectively, in 42 unrelated patients diagnosed with FMF, which revealed significant ambiguity regarding some of the symptoms which are also present in FD. The objective of this study was to determine the spectrum of mutations present in these genes, in order to identify cases of mistaken diagnosis of FMF and/or missed diagnosis of FD. Ten out of 42 patients had one mutation in homozygosis or two different mutations in heterozygosis in the MEFV gene; 20/42 had a single heterozygous mutation, and 12/42 did not have genetic alterations in MEFV. The analysis of the GLA gene conducted on all the samples revealed that three subjects, and some members of their families, had two different exonic mutations associated with FD. Family studies allowed us to identify eight other cases of FD, bringing the total undiagnosed subjects to 11/53. Analyzing the MEFV and GLA genes in patients with clinical diagnoses of FMF proved to be fundamentally important for the reduction of diagnostic errors.

The Fabry Outcome Survey (FOS) was established to extend the knowledge of the natural history of Fabry disease and to assess the effects of enzyme replacement therapy (ERT) with agalsidase alfa. As of March 2009, 64 boys and 34 girls with Fabry disease had enrolled in the FOS and been treated with agalsidase alfa for at least 6 months. The prevalence of symptoms tended to be reduced after 12 and 24 months of ERT in patients who experienced symptoms at baseline. In the entire population, non-significant decreases in the prevalence of gastrointestinal problems in boys and pain crises in girls were observed after 12-24 months. Kidney function and left ventricular mass indexed to height remained stable. Fifty-eight treatment-related adverse events were reported in 23 patients (21 boys and 2 girls), including 55 infusion reactions. Anti-agalsidase alfa IgG antibodies were found in two boys. No IgE antibodies were reported. This study represents the largest observational study of paediatric Fabry disease patients treated with ERT and indicates continued safety of long-term ERT in children. Continued long-term follow-up is recommended to determine early initiation of ERT, which could potentially slow or prevent the progression of serious morbidities of Fabry disease.

A new variant form of Fabry disease with hypertrophic cardiomyopathy of late onset is reported. Two unrelated male hemizygotes of this disease first presented with signs and symptoms of cardiomyopathy after 50 years of age. Cultured lymphoblastoid cells showed significantly higher residual alpha-galactosidase A activities than in the patients with classical phenotypic expressions.

Both Fabry disease and Duchenne muscular dystrophy were confirmed by gene analysis in a Japanese boy. He developed muscle weakness at 4 years of age. A muscle biopsy revealed lamellar inclusion bodies in vascular endothelial cells in addition to myopathic changes with negative dystrophin staining. The myopathic symptoms progressed, and he died of pneumonia at 24 years of age. No clinical manifestations of Fabry disease were observed except for hypohidrosis and angiokeratoma. However, glycolipid accumulation was found in biopsied renal tissue. Molecular analysis demonstrated two gene mutations; a novel single-base deletion in exon 3 of the alpha-galactosidase gene, and a dystrophin gene deletion extending from exon 46 to exon 50. His mother was confirmed to be heterozygous for both gene deletions.

A patient with severe deficiency of beta-galactosidase, who developed skin lesions of angiokeratoma corporis diffusum between the 3rd and 10th month of life, is described. The activity of other lysosomal enzymes, including alpha-neuraminidase, was normal. The first signs of the disease were noticed during the first month of life. By 3 months coarseness of the face and psychomotor retardation were present. In addition to angiokeratoma, he had large mongolian spots and several scattered slate-blue spots of pigmentation over his body. With the exception of the skin lesions, the other clinical signs and the course of the psychomotor deterioration were within the clinical picture of GM1 gangliosidosis, Type 1. Angiokeratoma, a manifestation of several lysosomal disorders, may appear in GM1 gangliosidosis during the first year of life.

Thromboembolism, increased platelet aggregation and high plasma concentration of beta-thromboglobulin were observed frequently in hemizygotes and heterozygotes of Fabry's disease. The administration of vitamin E and ticlopidine could improve the increased platelet aggregation in this disease. The platelet activation, probably induced by vascular endothelial damages, would accelerate atherosclerotic and thromboembolic vascular changes. Antiplatelet therapy will be effective for the prevention of these vascular complications in this disease.

An immunofluorometric method was developed for the semiquantitative determination of trihexosylceramide in cultured fibroblasts from Fabry disease patients, using a laser scanning confocal imaging system. The accumulated glycolipid was detected as granular inclusions in the cells. Heterozygote identification was achieved both by counting of immunoreactive cells and by measuring the relative fluorescence intensity with a digital imaging system.

In a pregnancy at risk for Fabry's disease, a prenatal diagnosis could be established 11 days after amniocentesis in the 15th week of pregnancy. This was possible by microchemical analysis of the αgalactosidase activity in isolated groups of 100–200 freeze-dried, cultured amniotic fluid cells. The results of this microassay were confirmed by (micro)biochemical analysis in cell homogenates from replicate cultures performed in two independent laboratories. Some problems in prenatal diagnosis of heterozygotes are discussed, as well as the possibilities of microchemical techniques for the more rapid prenatal diagnosis of other lysosomal storage diseases.

Apparent deficiency of alpha-galactosidase A was observed in a 51-year-old, clinically healthy male, with no clinical symptoms of Fabry disease, and without excess urinary excretion of ceramide trihexoside. The deficiency, which was similar to that found in Fabry disease patients, could be demonstrated using both synthetic and natural substrates. This pseudodeficiency was transmitted in his family by classical X-linked inheritance. His wife showed enzyme activity in the normal range, two daughters were heterozygotes for this mutation as demonstrated by hair root assay, and three sons showed normal alpha-galactosidase activity. Kinetic studies in cultured skin fibroblasts indicated a five-fold increase in the apparent Km and a greater heat stability of the residual alpha-galactosidase activity when compared to controls. These data indicate that the residual enzyme activity in this mutation behaves similarly to that observed in Fabry disease patients but does not cause any clinical abnormalities.

Cardiovascular manifestations of Fabry's disease were studied clinically in 10 hemizygous males and 13 heterozygous females. Mitral valve prolapse was found in 5 of 9 hemizygotes and in 5 of 13 heterozygotes examined by echocardiography. Ordinary medical examinations revealed cardiomyopathy in some asymptomatic females, and the diagnosis of the Fabry heterozygote was established by demonstration of specific inclusion bodies in the biopsied myocardium and low alpha-galactosidase activity in leukocytes. Renovascular hypertension of juvenile onset and thromboembolism were also found in 7 patients. It was concluded that Fabry's disease should always be considered in cases of mitral valve prolapse, cardiomyopathy, renovascular hypertension and thrombosis of unknown etiology, and that the Fabry patients should be followed carefully for the early detection of cardiovascular involvements in this disease.

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A which causes accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. Gastrointestinal symptoms are due to intestinal dysmotility as well as impaired autonomic function, vasculopathy and myopathy. Since 2001, enzyme replacement therapy has been a mainstay in treatment of gastrointestinal symptoms of Fabry disease (FD), resulting in reduced gastrointestinal symptoms. Here, we report on four patients with Fabry disease (FD) who manifested early gastrointestinal involvement.

We describe the results of the multidisciplinary evaluation in patients with Fabry disease and the same genetic mutation and their outcomes using different approved enzyme replacement therapy (ERT). We measured baseline data and serial results of neuropathic pain assessment and renal, cardiac and cerebrovascular functioning. Pain scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa-treated patients after 1 year with posterior increase. During the agalsidase beta shortage, two male patients were switched to agalsidasa alfa, after 1 year both cases presented an increase in scale values. Renal evolution showed a tendency toward a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain magnetic resonance imaging (MRI) showed increase of white matter lesions in four patients. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. Following the reported recommendations on reintroduction of agalsidase beta after the enzyme shortage, we decided to switch all patients to agalsidase beta.

Fabry disease is an X-linked lysosomal disorder caused by the deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). In males, the laboratory diagnosis is based on the demonstration of decreased levels of alpha-Gal A activity, while in females, the disease is diagnosed by the identification of a mutation in alpha-Gal A gene. Fabry disease in Argentina is underdiagnosed. To date, no comprehensive screening study of Fabry disease in our country has been reported. The present study aimed at developing a targeted screening for the detection of Fabry patients from Argentina based on the set of typical signs and symptoms. We received 121 blood samples from probable Fabry patients for enzymatic and genetic assay. We diagnosed six Fabry patients from six unrelated families, representing a yield of detection of 4.96%. The mutations detected in five of the families analysed were missense mutations: p.Leu243Trp, p.Asp155His, p.Leu415Pro, p.Cys94Tyr and p.Leu191Pro. After the detection of a Fabry patient, his/her relatives were also screened. In the course of these family studies, other 64 Fabry patients, 29 males and 35 females, were detected. To our knowledge, this is the first comprehensive screening of Fabry disease in Argentina. We detected 70 patients in a period of 2.5 years. The development of targeted protocols and the constitution of interdisciplinary groups for the identification of patients with Fabry disease are recommended to obtain a higher yield in the process.

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.

Fabry's disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase that results in an accumulation of neutral glycosphingolipids throughout the body, including the cardiovascular system. Fabry cardiomyopathy, characterized by progressive severe concentric left ventricular (LV) hypertrophy, is very frequent and is the most important cause of death in affected patients. Enzyme replacement therapy (ERT) allows a specific treatment for this disease, however, there are very few data on the effectiveness of therapy on cardiac involvement. Nine patients with Fabry cardiac disease were studied on basal condition and after 6 and 12 months of treatment with algasidase beta (Fabrazyme). A complete clinical, electrocardiographic and echocardiographic evaluation was performed in all patients. Interpretable Doppler recordings of transmitral flow and pulmonary flow velocity curves were also acquired. At baseline, the patients with Fabry's disease had increased LV septum and posterior wall thickness, normal LV fractional shortening, LV ejection fraction, normal Doppler parameters of mitral inflow but a duration of pulmonary vein flow velocity wave exceeding that of the mitral wave at atrial systole. ERT did not affect heart rate and arterial pressure. LV internal diameters did not change, there was a slight but not significant decrease in the LV posterior wall thickening and a progressive decrease in the interventricular septum thickening (p < 0.025) and in LV mass (p < 0.001) The difference in duration between pulmonary vein flow velocity wave and mitral wave at atrial systole significantly decreased (p < 0.001). These results suggest that ERT in patients with Fabry cardiomyopathy is able to reduce the LV mass and ameliorate the LV stiffness.

Fabry disease is an X-linked disorder caused by a deficiency of the lysosomal alpha-galactosidase A [EC 3.2.1.22]. The molecular diagnosis of Fabry disease is important for genotype/phenotype correlation, pre-natal or early diagnosis, and detection of carrier status. Although more than 200 genotypes of the alpha-galactosidase A gene have been identified, mutation data on the Chinese population is sparse. We recently identified two unrelated Chinese families with Fabry disease. Mutation analysis was performed by polymerase chain reaction (PCR) sequencing of the seven exons and adjacent introns of the alpha-galactosidase A gene. Two novel mutations were identified: in family I, a C-to-A transversion resulted in an early termination at amino acid 222 (Y222X), while in family II, an A-to-G transition resulted in a substitution of alanine for threonine at amino acid 410 (T410A). Carrier status was identified in all four females in the two families. The genotype Y222X is associated with classic Fabry disease, with unexpectedly rapid deterioration of visual acuity, while T410A is associated with a milder Fabry disease, with ventricular hypertrophy and neuropathic pain.