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Anderson-Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene, which encodes the enzyme α-galactosidase A. The GLA gene is located on the X-chromosome, causing an X-linked pathology: due to lyonization, female patients usually manifest a variable symptomatology, ranging from asymptomatic to severe phenotypes. The confirmation of the clinical diagnosis of Fabry disease, achieved by measuring α-galactosidase A activity, which is usually the first test used, shows differences between male and female patients. This assay is reliable in male patients with causative mutations in the GLA gene, in whom the enzymatic activity is lower than normal values; on the other hand, in female Fabry patients, the enzymatic activity is extremely variable between normal and pathological values. These fluctuations are also found in female patients' blood levels of globotriaosylsphingosine (LysoGb3) for the same reason. In this paper, we present a retrospective study conducted in our laboratories on 827 Fabry patients with causative mutations in the GLA gene. Our results show that 100% of male patients had α-galactosidase A activity below the reference value, while more than 70% of female patients had normal values. It can also be observed that almost half of the female patients with pathogenic mutations in the GLA gene showed normal values of LysoGb3 in blood. Furthermore, in women, blood LysoGb3 values can vary over time, as we show in a clinical case presented in this paper. Both these tests could lead to missed diagnoses of Fabry disease in female patients, so the analysis of the GLA gene represents the main diagnostic test for Fabry disease in women to date.

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BACKGROUND: Fabry disease (FD) is a treatable X-linked lysosomal storage disorder caused by GLA gene variants leading to alpha-galactosidase A deficiency. FD is a rare cause of stroke, and it is still controversial whether in stroke patients FD should be searched from the beginning or at the end of the diagnostic workup (in cryptogenic strokes). METHODS: Fabry-Stroke Italian Registry is a prospective, multicentric screening involving 33 stroke units. FD was sought by measuring α-galactosidase A activity (males) and by genetic tests (males with reduced enzyme activity and females) in patients aged 18-60 years hospitalized for TIA, ischemic stroke, or intracerebral hemorrhage. We diagnosed FD in patients with 1) already known pathogenic GLA variants; 2) novel GLA variants if additional clinical, laboratory, or family-derived criteria were present. RESULTS: Out of 1906 patients, we found a GLA variant in 15 (0.79%; 95%CI 0.44-1.29) with a certain FD diagnosis in 3 (0.16%; 95%CI 0.03-0.46) patients, none of whom had hemorrhage. We identified 1 novel pathogenic GLA variant. Ischemic stroke etiologies in carriers of GLA variants were: cardioaortic embolism (33%), small artery occlusion (27%), other causes (20%), and undetermined (20%). Mild severity, recurrence, previous TIA, acroparesthesias, hearing loss, and small artery occlusion were predictors of GLA variant. CONCLUSION: In this large multicenter cohort the frequency of FD and GLA variants was consistent with previous reports. Limiting the screening for GLA variants to patients with cryptogenic stroke may miss up to 80% of diagnoses. Some easily recognizable clinical features could help select patients for FD screening.

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We aimed to analyze the clinical data of 10 patients (6 male and 4 female) with Fabry disease (FD). The mean age of the patients was (28.80±9.27) years. Seven patients had classical FD and three had delayed onset FD. Among the 10 patients, six had skin involvement and cutaneous angiokeratoma; five had hypohidrosis or anhidrosis; nine had intermittent neuralgia; and three had supraorbital ridge protrusion, forehead bulge, and lip thickening. Five patients had proteinuria, including one with chronic kidney disease stage 3 and one with chronic kidney disease stage 5. Cardiac involvement occurred in three patients, two had myocardial hypertrophy and one had valvular insufficiency. The activity of galactosidase decreased in seven patients (2.80-1.55 μmol·L -1·h -1). Plasma deacetyl-GL-3 was elevated in all 10 patients(3.12-120.00 ng/ml). Three patients underwent renal biopsy, wherein two cases of focal segmental glomerulosclerosis and one of mesangial proliferative glomerulonephritis was found. A large number of myeloid and zebra bodies were found in the podocytes in three patients, including a small number of myeloid and zebra bodies in the renal tubular epithelial cells in one patient with occasional zebra bodies in the renal interstitium. Nine patients had GLA gene mutations. One patient was c.102T>A, a de novo mutation. Four patients were treated with agalsidase α injection (0.2 mg/kg, intravenous infusion every 2 weeks), and their prognosis was good. FD has various clinical manifestations and multi-system involvement, which requires multidisciplinary cooperation. Detection of galactosidase activity, plasma globotriaosylsphingosine, and GLA gene mutation can help for accurate diagnosis.

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Background: The cause of chronic kidney disease (CKD) remains unknown in ∼20% of patients with kidney failure. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, with a diagnostic yield of 12%-56%. Here, we report the use of MPS to establish a genetic diagnosis in a 24-year-old index patient who presented with hypertension, nephrotic-range proteinuria and kidney failure of unknown origin. Additionally, we describe a second family with the same mutation presenting with early-onset CKD. Results: In Family 1, MPS identified a known pathogenic variant in GLA (p.Ile319Thr), and plasma globotriaosylsphingosine and α-galactosidase A activity were compatible with the diagnosis of Fabry disease (FD). Segregation analysis identified three other family members carrying the same pathogenic variant who had mild or absent kidney phenotypes. One family member was offered enzyme therapy. While FD could not be established with certainty as the cause of kidney failure in the index patient, no alternative explanation was found. In Family 2, the index patient had severe glomerulosclerosis and a kidney biopsy compatible with FD at the age of 30 years, along with cardiac involvement and a history of acroparesthesia since childhood, in keeping with a more classical Fabry phenotype. Conclusion: These findings highlight the large phenotypic heterogeneity associated with GLA mutations in FD and underline several important implications of MPS in the work-up of patients with unexplained kidney failure.

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PURPOSE: In this prospective study we aimed to determine the rate of Fabry Disease (FD) in patients with left ventricular hypertrophy (LVH), and to evaluate the clinical presentations of patients with FD in a comprehensive manner. In addition, we aimed to raise awareness about this issue by allowing early diagnosis and treatment of FD. METHODS: Our study was planned as national, multicenter, observational. Totally 22 different centers participated in this study. A total of 886 patients diagnosed with LVH by echocardiography (ECHO) were included in the study. Demographic data, biochemical parameters, electrocardiography (ECG) findings, ECHO findings, treatments and clinical findings of the patients were recorded. Dry blood samples were sent from male patients with suspected FD. The α-Gal A enzyme level was checked and genetic testing was performed in patients with low enzyme levels. Female patients suspected of FD were genetically tested with the GLA Gene Mutation Analysis. RESULTS: FD was suspected in a total of 143 (16.13%) patients included in the study. The α-Gal-A enzyme level was found to be low in 43 (4.85%) patients whom enzyme testing was requested. GLA gene mutation analysis was positive in 14 (1.58%) patients. Male gender, E/e' mean ,and severe hypertrophy are important risk factor for FD. CONCLUSION: In daily cardiology practice, FD should be kept in mind not only in adult patients with unexplained LVH but also in the entire LVH population. Dry blood test (DBS) should be considered in high-risk patients, and mutation analysis should be considered in required patients.

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Fabry Disease (FD) is a rare lysosomal storage disorder caused by mutations in the GLA gene on the X chromosome, leading to a deficiency in α-galactosidase A (AGAL) enzyme activity. This leads to the accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in vital organs such as the kidneys, heart, and nervous system. While FD was initially considered predominantly affecting males, recent studies have uncovered that heterozygous Fabry women, carrying a single mutated GLA gene, can manifest a wide array of clinical symptoms, challenging the notion of asymptomatic carriers. The mechanisms underlying the diverse clinical manifestations in females remain not fully understood due to X-chromosome inactivation (XCI). XCI also known as "lyonization", involves the random inactivation of one of the two X chromosomes. This process is considered a potential factor influencing phenotypic variation. This review delves into the complex landscape of FD in women, discussing its genetic basis, the available biomarkers, clinical manifestations, and the potential impact of XCI on disease severity. Additionally, it highlights the challenges faced by heterozygous Fabry women, both in terms of their disease burden and interactions with healthcare professionals. Current treatment options, including enzyme replacement therapy, are discussed, along with the need for healthcare providers to be well-informed about FD in women, ultimately contributing to improved patient care and quality of life.

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[This corrects the article DOI: 10.3389/fped.2022.908657.].

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Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers.

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The deficiency or absence of the lysosomal hydrolase α-Galactosidase A results in Fabry disease (FD), a rare and underdiagnosed X-linked disorder. The symptoms caused by FD have a direct relation with the variant present in the gene coding α-Galactosidase A (GLA) and enzyme residual activity, and it can vary drastically between men and women of the same family. Here, we present four novel variants found in patients with suspicion of FD. The patients were screened for FD by enzymatic activity and/or DNA sequencing, which showed four novel GLA missense variants. To confirm the potential pathogenicity of these variants, we employed site-directed mutagenesis. GLA wild-type and mutant plasmids were transfected into mammalian cells; RNA and proteins were extracted for expression and enzymatic activity analysis. The patients presented the variants p.Ile133Asn, p.Lys140Thr, p.Lys168Gln and p.Pro323Thr in the GLA. In vitro analysis showed pathogenic potential of three variants and one tolerated variant. The variants p.Ile133Asn and p.Lys168Gln showed no residual activity and, therefore, leading to classical phenotype, and the variant p.Lys140Thr, which presented 22% of residual activity, was considered a mild variant leading to non-classical phenotype. The variant p.Pro323Thr presented 66.7% of residual activity and alone, it is not enough to cause FD.

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Inherited renal diseases represent 20% of the causes of end-stage renal diseases. Fabry disease, an X-linked lysosomal storage disorder, results from α-galactosidase A deficient or absent activity followed by globotriaosylceramide (Gb3) accumulation and multiorgan involvement. In Fabry disease, kidney involvement starts early, during intrauterine life by the Gb3 deposition. Even if chronic kidney disease (CKD) is discovered later in adult life in Fabry disease patients, a decline in glomerular filtration rate (GFR) can occur during adolescence. The first clinical sign of kidney involvement is represented by albuminuria. So, early and close monitoring of kidneys function is required: albuminuria and proteinuria, urinary albumin-to-creatinine ratio, serum creatinine, or cystatin C to estimate GFR, while urinary sediment with phase-contrast microscopy under polarized light may be useful in those cases where leucocyte α-Gal A activity and GLA genotyping are not available. Children with Fabry disease and kidney involvement should receive enzyme replacement therapy and nephroprotective drugs (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) to prevent or slow the progressive loss of kidney functions. Early diagnosis of Fabry disease is important as enzyme replacement therapy reduces symptoms, improves clinical features and biochemical markers, and the quality of life. More importantly, early treatment could slow or stop progressive organ damage in later life.

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BACKGROUND: Fabry disease (FD, OMIM #301500) is an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A (α-GalA), encoded by the GLA gene. Among more than 1100 reported GLA mutations, few were deep intronic mutations which have been linked to classic and cardiac variants of FD. METHODS AND RESULTS: We report a novel hemizygous deep intronic GLA mutation (IVS4+1326C>T) in a 33-year-old Chinese man with a mild α-GalA deficiency phenotype involving isolated proteinuria and predominant globotriaosylceramide deposits in podocytes. IVS4+1326C>T, which appears to be the first deep intronic GLA mutation associated with renal variant of FD, was identified by Sanger sequencing the entire GLA genomic DNA sequence of the patient's peripheral mononuclear blood lymphocytes (PBMCs). Further sequencing of cDNA from PBMCs of the patient revealed a minor full-length GLA transcript accounting for about 25% of total GLA transcript, along with two major aberrantly spliced GLA transcripts encoding mutant forms of α-GalA with little enzyme activity characterized by in vitro α-GalA overexpression system in the HEK293T cells. Thus, the combined clinical phenotype, genetic analysis and functional studies verified the pathogenicity of IVS4+1326C>T. CONCLUSIONS: The identification of IVS4+1326C>T establishes a link between deep intronic GLA mutation and the renal variant of FD, which extends the mutation spectrum in GLA gene and justifies further study of how IVS4+1326C>T and potentially other deep intronic GLA mutations contribute to Fabry podocytopathy through aberrant splicing. Future studies should also assess the true incidence of IVS4+1326C>T in patients with different variants of FD, which may improve early genetic diagnosis to allow timely treatment that can prevent disease progression and improve survival.

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Objective:To summarize the characteristics of neuralgia in Fabry disease and explore the effects of genders and alpha-galactosidase A (GLA) gene mutation types on neuralgia.Methods:Questionnaires and Brief Pain Inventory evaluations were conducted on the recruited patients diagnosed as Fabry disease in Department of Neurology, Peking University First Hospital from January 2001 to April 2020. The characteristics of the neuralgia were summarized, and the portrait of neuralgia between male and female patients, and the patient groups carrying truncated mutations and non-truncated mutations of GLA gene was compared.Results:A total of 93 patients with Fabry disease were enrolled. The incidence of neuralgia was 91.4% (85/93),and the average onset age of pain was 9 years. The average remission age was 20 years with the remission incidence of 22.8% (18/79). Pain attack on extremities [96.5%(82/85)] was the most common form. The neuralgia relieving rate of male patients [17.5%(11/63)] was lower than that of females (7/16, χ2=5.01, P=0.025).Brief Pain Inventory scores showed that the degree of most severe pain attack within 24 hours of male patients (4.16±3.20) was higher than that of females (2.07±2.02, t=3.03, P=0.004),and the impact of pain on daily life [male 4 (7) vs female 0 (4), Z=-2.33, P=0.020], walking ability [male 5 (8) vs female 0 (2), Z=-2.87, P=0.004], daily work [male 5 (8) vs female 0 (2), Z=-3.10, P=0.002], relationship [male 2 (6) vs female 0 (3), Z=-2.67, P=0.008] and interests [male 4 (8) vs female 0 (3), Z=-2.81, P=0.005] of male patients was also higher than female patients. The truncated mutation group [1 (2)] only showed higher score on the current pain level than the non-truncated mutation group [0(0), Z=-2.89, P=0.003]. Conclusions:The neuralgia in Chinese patients with Fabry disease showed high incidence and early onset. Male patients presented more severe pain than female which led to a greater impact on life, while the type of GLA gene mutation had less impact on neuralgia.

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Fabry Disease (FD) is a rare X-linked recessive disease caused by mutations in the GLA gene that lead to a decrease or lack of activity of the enzyme alpha galactosyl A. This lysosomal storage disorder results in progressive damage and dysfunction of several organs and, depending on the type of mutation and gender of the patient, and it may have different manifestations. As FD is a multisystem disease with a progressive character and varying severity, the diagnosis can be challenging, especially when it comes to non-classical forms. As this is a hereditary disease, its diagnosis impacts not only the patient but also his family, making an accurate and timely diagnosis even more important. We present the case of a 59-years-old man diagnosed with non-classical FD, with previous neurological and psychiatric complaints, who was admitted to the Emergency Department (ED) with a generalized tonic-clonic seizure that required orotracheal intubation for airway protection and transferred to an Intensive Care Unit (ICU).

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AIMS: Fabry disease (FD) is an X-linked genetic disease caused by mutations in the GLA gene that leads to deficient activity of lysosomal enzymes, accumulation of globotriaosylceramide in multi-organ systems, and variant clinical manifestations. We aimed to detail the clinical and genetic spectrum of FD in Chinese families. METHODS AND RESULTS: Five male probands with unexplained left ventricular hypertrophy and their family members were investigated. Genetic screening was available in 11 subjects of the 5 families, 10 of whom proved to be carriers of either GLA gene mutation, including 3 previous reported missense mutations (c.128G > A, c.811G > A, c.950T > C), 1 novel missense mutation (c.37G > C), and 1 novel deletion mutation (c.1241delT). A total of 17 patients were definitely or possibly diagnosed of FD, given their clinical manifestations and hereditary nature of FD. Echocardiography demonstrated normal cardiac structure and function in six female patients. Electrocardiographic pre-excitation occurred in 80% (4/5) of men and 16.7% (1/6) of women. Six patients (6/14, 42.9%) had chronic kidney disease with decreased renal function and all were male (6/7, 85.7%). Six patients presented with acroparesthesia, hypohidrosis, or both. Three female patients and two male patients experienced sudden death, and one male patient with the mutation (c.128G > A) died of progressive heart failure, between 41 and 66 years of age. CONCLUSIONS: We reported five unrelated families of FD with different GLA mutations. Clinical manifestations were highly heterogeneous between male and female patients even within the same family. Female patients showed relatively low risks of structural heart disease and renal insufficiency. However, the long-term outcomes might be adverse in both sexes. Our study underlines the importance of molecular screening of the GLA gene for early identification and clinical decision making in patients with FD.

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Fabry disease (FD) is a rare X-linked disorder of glycosphingolipid metabolism caused by pathogenic variants within the alpha-galactosidase A (GLA) gene, often leading to neurological manifestations including stroke. Multiple screening programs seeking GLA variants among stroke survivors lacked detailed phenotype description, making the interpretation of the detected variant's pathogenicity difficult. Here, we describe detailed clinical characteristics of GLA variant carriers identified by a nationwide stroke screening program in the Czech Republic. A total of 23 individuals with 8 different GLA variants were included in the study. A comprehensive diagnostic workup was performed by a team of FD specialists. The investigation led to the suggestion of phenotype reclassification for the G325S mutation from late-onset to classical. A novel variant R30K was found and was classified as a variant of unknown significance (VUS). The typical manifestation in our FD patients was a stroke occurring in the posterior circulation with an accompanying pathological finding in the cerebrospinal fluid. Moreover, we confirmed that cornea verticillata is typically associated with classical variants. Our findings underline the importance of detailed phenotype description and data sharing in the correct identification of pathogenicity of gene variants detected by high-risk-population screening programs.

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Fabry disease (FD) is a progressive multisystemic lysosomal storage disease. Early diagnosis by newborn screening (NBS) may allow for timely treatment, thus preventing future irreversible organ damage. We present the results of 5.5 years of NBS for FD by α-galactosidase A activity and globotriaosylsphingosine (lyso-Gb3) assays in dried blood spot through a multiplexed MS/MS assay. Furthermore, we report our experience with long-term follow-up of positive subjects. We screened more than 170,000 newborns and 22 males were confirmed to have a GLA gene variant, with an incidence of 1:7879 newborns. All patients were diagnosed with a variant previously associated with the later-onset phenotype of FD or carried an unclassified variant (four patients) or the likely benign p.Ala143Thr variant. All were asymptomatic at the last visit. Although lyso-Gb3 is not considered a reliable second tier test for newborn screening, it can simplify the screening algorithm when its levels are elevated at birth. After birth, plasma lyso-Gb3 is a useful marker for non-invasive monitoring of all positive patients. Our study is the largest reported to date in Europe, and presents data from long-term NBS for FD that reveals the current incidence of FD in northeastern Italy. Our follow-up data describe the early disease course and the trend of plasma lyso-Gb3 during early childhood.

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Fabry disease (FD) is an X-linked, rare inherited lysosomal storage disease caused by α-galactosidase A gene variants resulting in deficient or undetectable α-galactosidase A enzyme activity. Progressive accumulation of pathogenic globotriaosylceramide and its deacylated form globotriaosylsphingosine in multiple cell types and organs is proposed as main pathophysiology of FD, with elicited pro-inflammatory cascade as alternative key pathological process. The clinical manifestations may present with either early onset and multisystemic involvement (cutaneous, neurological, nephrological and the cardiovascular system) with a progressive disease nature in classic phenotype, or present with a later-onset course with predominant cardiac involvement (non-classical or cardiac variant; e.g. IVS4+919G>A in Taiwan) from missense variants. In either form, cardiac involvement is featured by progressive cardiac hypertrophy, myocardial fibrosis, various arrhythmias, and heart failure known as Fabry cardiomyopathy with potential risk of sudden cardiac death. Several plasma biomarkers and advances in imaging modalities along with novel parameters, cardiac magnetic resonance (CMR: native T1/T2 mapping) for myocardial tissue characterization or echocardiographic deformations, have shown promising performance in differentiating from other etiologies of cardiomyopathy and are presumed to be helpful in assessing the extent of cardiac involvement of FD and in guiding or monitoring subsequent treatment. Early recognition from extra-cardiac red flag signs either in classic form or red flags from cardiac manifestations in cardiac variants, and awareness from multispecialty team work remains the cornerstone for timely managements and beneficial responses from therapeutic interventions (e.g. oral chaperone therapy or enzyme replacement therapy) prior to irreversible organ damage. We aim to summarize contemporary knowledge based on literature review and the gap or future perspectives in clinical practice of FD-related cardiomyopathy in an attempt to form a current expert consensus in Taiwan.

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Fabry disease (FD) (Anderson-Fabry disease, OMIM 301500) is a genetic disorder caused by a pathogenic variant in the GLA gene on chromosome Xq22 that produces a deficiency in the lysosomal enzyme alpha-galactosidase A. It is transmitted as an X-linked trait, although de novo mutations have been described. The objective of this report is to describe the clinical characteristics of a patient with FD who is a carrier of a mutation not previously studied, in order to provide information on the genotype-phenotype correlation in this pathology. 38-year-old patient who consulted Neurology for positional vertigo. He also reported acroparesthesia, anhidrosis, heat intolerance and episodes of abdominal pain, with postprandial discomfort from 10 years of age. Physical examination showed horizonto-rotatory nystagmus in both looks, the rest of the neurological evaluation did not present abnormalities. The presence of umbilical and thighs angiokeratomas was identified. Determination of Alpha-Galactosidase in blood was requested: 0.34 µmol/l/h (2.10-10.51 µmol/l/h). Genetic analysis detected a deletion of a guanine at position 448, in exon 3 of the GLA gene (c.448delG). This mutation was considered to be pathogenic, confirming the diagnosis of FD, although it is not described in the data bases. Genetic counseling and a family pedifree study were performed without finding relatives with this variant of the GLA gene or a family history of FD, which suggests a de novo mutation.

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Fabry disease (FD) is an important underlying condition in young cryptogenic stroke patients and has also been implicated in cerebral small vessel disease. However, the contributions of causative GLA mutations in patients with intracerebral hemorrhage (ICH) remain unclear. In this study, GLA sequences were analyzed in a Chinese ICH cohort comprising 373 patients with computed tomography-confirmed ICH and 563 in-house controls and East Asians from public databases. Only one previously reported mutation, p. Ala15Val, responsible for Fabry disease was identified in a female patient with nonlobar ICH. Therefore, this definitive GLA mutation accounted for 0.27% (1/373) of Chinese patients with ICH. Another functional variant, rs2071225 (c.-10C>T), was present at minor allele frequency (MAF) of 9.1%, indicating no association with ICH, despite a trend of an association for male patients with lobar ICH. In conclusion, our results indicate that the GLA mutation is an uncommon genetic etiology of ICH in China.

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