RESUMO
Fabry disease is a lysosomal storage disorder caused by a significant decrease in the activity or absence of the enzyme α-galactosidase A. The diagnostics of Fabry disease during newborn screening are reasonable, due to the availability of enzyme replacement therapy. This paper presents an electrochemical method using complementary metal-oxide semiconductor (CMOS)-compatible ion-sensitive field effect transistors (ISFETs) with hafnium oxide-sensitive surfaces for the detection of α-galactosidase A activity in dried blood spot extracts. The capability of ISFETs to detect the reaction catalyzed by α-galactosidase A was demonstrated. The buffer composition was optimized to provide suitable conditions for both enzyme and ISFET performance. The use of ISFET structures as sensor elements allowed for the label-free detection of enzymatic reactions with melibiose, a natural substrate of α-galactosidase A, instead of a synthetic fluorogenic one. ISFET chips were packaged with printed circuit boards and microfluidic reaction chambers to enable long-term signal measurement using a custom device. The packaged sensors were demonstrated to discriminate between normal and inhibited GLA activity in dried blood spots extracts. The described method offers a promising solution for increasing the widespread distribution of newborn screening of Fabry disease.
Assuntos
Técnicas Biossensoriais , Teste em Amostras de Sangue Seco , Doença de Fabry , Transistores Eletrônicos , alfa-Galactosidase , alfa-Galactosidase/sangue , Teste em Amostras de Sangue Seco/métodos , Humanos , Doença de Fabry/sangue , Doença de Fabry/diagnóstico , Técnicas Biossensoriais/métodos , Técnicas Biossensoriais/instrumentação , Recém-Nascido , Triagem Neonatal/métodosRESUMO
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.
Assuntos
Doença de Fabry , Glicolipídeos , Esfingolipídeos , alfa-Galactosidase , Humanos , Doença de Fabry/diagnóstico , Doença de Fabry/sangue , Doença de Fabry/genética , alfa-Galactosidase/genética , alfa-Galactosidase/sangue , Feminino , Masculino , Esfingolipídeos/sangue , Glicolipídeos/sangue , Adulto , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Adolescente , Adulto Jovem , Idoso , CriançaRESUMO
BACKGROUND AND AIMS: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by disease-associated variants in the alpha-galactosidase A gene (GLA). FD is a known cause of stroke in younger patients. There are limited data on prevalence of FD and stroke risk in unselected stroke patients. METHODS: A prospective nationwide study including 35 (78%) of all 45 stroke centers and all consecutive stroke patients admitted during three months. Clinical data were collected in the RES-Q database. FD was diagnosed using dried blood spots in a stepwise manner: in males-enzymatic activity, globotriaosylsphingosine (lyso-Gb3) quantification, if positive followed by GLA gene sequencing; and in females GLA sequencing followed by lyso-Gb3. RESULTS: 986 consecutive patients (54% men, mean age 70 years) were included. Observed stroke type was ischemic 79%, transient ischemic attack (TIA) 14%, intracerebral hemorrhage (ICH) 7%, subarachnoid hemorrhage 1% and cerebral venous thrombosis 0.1%. Two (0.2%, 95% CI 0.02-0.7) patients had a pathogenic variant associated with the classical FD phenotype (c.1235_1236delCT and p.G325S). Another fourteen (1.4%, 95% CI 0.08-2.4) patients had a variant of GLA gene considered benign (9 with p.D313Y, one p.A143T, one p.R118C, one p.V199A, one p.R30K and one p.R38G). The index stroke in two carriers of disease-associated variant was ischemic lacunar. In 14 carriers of GLA gene variants 11 strokes were ischemic, two TIA, and one ICH. Patients with positive as compared to negative GLA gene screening were younger (mean 60±SD, min, max, vs 70±SD, min, max, P = 0.02), otherwise there were no differences in other baseline variables. CONCLUSIONS: The prevalence of FD in unselected adult patients with acute stroke is 0.2%. Both patients who had a pathogenic GLA gene variant were younger than 50 years. Our results support FD screening in patients that had a stroke event before 50 years of age.
Assuntos
Doença de Fabry/epidemiologia , Doença de Fabry/genética , Glicolipídeos/sangue , Esfingolipídeos/sangue , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , alfa-Galactosidase/genética , Idoso , República Tcheca/epidemiologia , Teste em Amostras de Sangue Seco , Doença de Fabry/sangue , Doença de Fabry/complicações , Feminino , Expressão Gênica , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Estudos Prospectivos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , alfa-Galactosidase/sangueRESUMO
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.
Assuntos
Teste em Amostras de Sangue Seco/métodos , Doença de Fabry/sangue , Doença de Fabry/diagnóstico , Triagem Neonatal/métodos , alfa-Galactosidase/sangue , Teste em Amostras de Sangue Seco/tendências , Doença de Fabry/epidemiologia , Feminino , Seguimentos , Glicolipídeos/sangue , Humanos , Recém-Nascido , Itália/epidemiologia , Masculino , Triagem Neonatal/tendências , Esfingolipídeos/sangue , Fatores de TempoRESUMO
Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients enrolled from 1 January to 31 December 2016 for evaluating the potential of plasma globotriaosylsphingosine and GLA activity as a combined screening marker. We screened 5691 patients (3439 males) referred from 237 Japanese specialty clinics based on clinical findings suggestive of Fabry disease using plasma globotriaosylsphingosine and GLA activity as primary screening markers, and GLA variant status as a secondary screening marker. Of the 14 males who tested positive in the globotriaosylsphingosine screen (≥2.0 ng/mL), 11 with low GLA activity (<4.0 nmol/h/mL) displayed GLA variants (four classic, seven late-onset) and one with normal GLA activity and no pathogenic variant displayed lamellar bodies in affected organs, indicating late-onset biopsy-proven Fabry disease. Of the 19 females who tested positive in the globotriaosylsphingosine screen, eight with low GLA activity displayed GLA variants (six classic, two late-onset) and five with normal GLA activity displayed a GLA variant (one classic) and no pathogenic variant (four late-onset biopsy-proven). The combination of plasma globotriaosylsphingosine and GLA activity can be a primary screening biomarker for classic, late-onset, and late-onset biopsy-proven Fabry disease probands.
Assuntos
Biomarcadores/sangue , Doença de Fabry/sangue , Glicolipídeos/sangue , Programas de Rastreamento/métodos , Esfingolipídeos/sangue , alfa-Galactosidase/sangue , Adolescente , Adulto , Idoso , Povo Asiático , Criança , Estudos de Coortes , Doença de Fabry/diagnóstico , Doença de Fabry/etnologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , alfa-Galactosidase/metabolismoRESUMO
Male patients with Fabry disease (FD) are at high risk for the formation of antibodies to recombinant α-galactosidase A (AGAL), used for enzyme replacement therapy. Due to the rapid disease progression, the identification of patients at risk is highly warranted. However, currently suitable references and standardized protocols for anti-drug antibodies (ADA) determination do not exist. Here we generate a comprehensive patient-derived antibody mixture as a reference, allowing ELISA-based quantification of antibody titers from individual blood samples. Serum samples of 22 male patients with FD and ADAs against AGAL were pooled and purified by immune adsorption. ADA-affinities against agalsidase-α, agalsidase-ß and Moss-AGAL were measured by quartz crystal microbalance with dissipation monitoring (QCM-D). AGAL-specific immune adsorption generated a polyclonal ADA mixture showing a concentration-dependent binding and inhibition of AGAL. Titers in raw sera and from purified total IgGs (r2 = 0.9063 and r2 = 0.8952, both p < 0.0001) correlated with the individual inhibitory capacities of ADAs. QCM-D measurements demonstrated comparable affinities of the reference antibody for agalsidase-α, agalsidase-ß and Moss-AGAL (KD: 1.94 ± 0.11 µM, 2.46 ± 0.21 µM, and 1.33 ± 0.09 µM, respectively). The reference antibody allows the ELISA-based ADA titer determination and quantification of absolute concentrations. Furthermore, ADAs from patients with FD have comparable affinities to agalsidase-α, agalsidase-ß and Moss-AGAL.
Assuntos
Anticorpos Neutralizantes/imunologia , Terapia de Reposição de Enzimas , Ensaio de Imunoadsorção Enzimática , Doença de Fabry/imunologia , alfa-Galactosidase/imunologia , alfa-N-Acetilgalactosaminidase/imunologia , Anticorpos Neutralizantes/biossíntese , Afinidade de Anticorpos , Relação Dose-Resposta Imunológica , Doença de Fabry/sangue , Doença de Fabry/tratamento farmacológico , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Masculino , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Padrões de Referência , alfa-Galactosidase/sangue , alfa-Galactosidase/uso terapêutico , alfa-N-Acetilgalactosaminidase/sangue , alfa-N-Acetilgalactosaminidase/uso terapêuticoRESUMO
Fabry disease (FD) is an X-linked lysosomal storage disorder. Deficiency of the lysosomal enzyme alpha-galactosidase (GLA) leads to accumulation of potentially toxic globotriaosylceramide (Gb3) on a multisystem level. Cardiac and cerebrovascular abnormalities as well as progressive renal failure are severe, life-threatening long-term complications. The complete pathophysiology of chronic kidney disease (CKD) in FD and the role of tubular involvement for its progression are unclear. We established human renal tubular epithelial cell lines from the urine of male FD patients and male controls. The renal tubular system is rich in mitochondria and involved in transport processes at high-energy costs. Our studies revealed fragmented mitochondria with disrupted cristae structure in FD patient cells. Oxidative stress levels were elevated and oxidative phosphorylation was upregulated in FD pointing at enhanced energetic needs. Mitochondrial homeostasis and energy metabolism revealed major changes as evidenced by differences in mitochondrial number, energy production and fuel consumption. The changes were accompanied by activation of the autophagy machinery in FD. Sirtuin1, an important sensor of (renal) metabolic stress and modifier of different defense pathways, was highly expressed in FD. Our data show that lysosomal FD impairs mitochondrial function and results in severe disturbance of mitochondrial energy metabolism in renal cells. This insight on a tissue-specific level points to new therapeutic targets which might enhance treatment efficacy.
Assuntos
Doença de Fabry/complicações , Insuficiência Renal Crônica/etiologia , Adolescente , Células Epiteliais/metabolismo , Doença de Fabry/genética , Humanos , Lisossomos/metabolismo , Masculino , Mitocôndrias/patologia , Estresse Oxidativo/genética , Sistema de Registros , Insuficiência Renal Crônica/genética , Triexosilceramidas/sangue , Adulto Jovem , alfa-Galactosidase/sangueRESUMO
OBJECTIVES: Fabry disease (FD) is a rare disease associated with sphingolipid accumulation. Sphingolipids are components of plasma membranes that are important in podocyte function and accumulate in various glomerular diseases such as focal segmental glomerulosclerosis (FSGS). Both FD and FSGS can cause podocyte damage and are classified as podocytopathies. In this respect, FD and FSGS share the same pathophysiologic pathways. Previous screening studies have shown that a significant proportion of end-stage renal disease (ESRD) patients receiving hemodialysis (HD) have unsuspected FD, and the prevalence of low alpha-galactosidase A (αGLA) enzyme activity in these patients is higher than that in the normal population. We aimed to compare αGLA enzyme activity in patients with biopsy-proven FSGS and ESRD receiving HD. METHODS: The records of 232 patients [62 FSGS (F/M: 33/29); 170 HD (M/F: 93/79)] were evaluated retrospectively. The screening was performed based on the αGLA enzyme activity on a dried blood spot, with the confirmation of plasma LysoGb3 levels, and the known GLA mutations were tested in patients with low enzyme activities. The two groups were compared using these parameters. RESULTS: The mean level of αGLA enzyme activity was found to be lower in FSGS patients than in the HD group (2.88±1.2 µmol/L/h versus 3.79±1.9 µmol/L/h, p<0.001). There was no significant relationship between the two groups with regard to the plasma LysoGb3 levels (2.2±1.22 ng/ml versus 1.7±0.66 ng/ml, p: 0.4). In the analysis of GLA mutations, a D313Y mutation [C(937G>T) in exon p] was found in one patient from the FSGS group. CONCLUSIONS: We found that αGAL activity in patients with FSGS is lower than that in patients undergoing HD. The low enzyme activity in patients with FSGS may be explained by considering the similar pathogenesis of FSGS and FD, which may also lead to sphingolipid deposition and podocyte injury.
Assuntos
Falência Renal Crônica/terapia , alfa-Galactosidase/sangue , Feminino , Glomerulosclerose Segmentar e Focal/sangue , Glomerulosclerose Segmentar e Focal/epidemiologia , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Prevalência , Estudos RetrospectivosRESUMO
A patient with diffuse angiokeratomas of the lower abdomen and genital region was diagnosed with Fabry disease on the basis of genetic testing. Fabry disease is an X-linked lysosomal storage disease that can affect several organ systems including the heart or kidneys, resulting in reduced median survival. Pathogenetically, Fabry disease leads to a deficiency of the lysosomal enzyme αgalactosidase A (α-GAL A). Treatment options include lifelong enzyme replacement therapy or chaperone therapy.
Assuntos
Terapia de Reposição de Enzimas , Doença de Fabry/diagnóstico , Doença de Fabry/terapia , Abdome , Adulto , Angioceratoma/patologia , Doença de Fabry/genética , Genitália , Glicoesfingolipídeos/sangue , Humanos , Masculino , Neoplasias Cutâneas/patologia , alfa-Galactosidase/sangueRESUMO
BACKGROUND: Fabry disease (FD) is a rare, lysosomal storage disorder caused by the absence or deficiency of the enzyme alpha-galactosidase A (α-Gal A) that leads to the abnormal accumulation of the lipid globotriaosylceramide (GB3) in a variety of cell types and tissues throughout the body. FD has an x-linked inheritance pattern. Previously thought to be only carriers, females can also experience FD symptomatology. Symptoms vary in type and severity from patient to patient and tend to increase in severity with age. FD symptoms are non-specific and may be shared with those of other diseases. Misdiagnoses and diagnostic delays are common, often resulting in progressive, irreversible tissue damage. The estimated prevalence of FD in the general population is 1:40,000 to 1:117,000 individuals. However, it is estimated that the prevalence of FD in the dialysis population is 0.12 to 0.7%. Little is known about the prevalence of FD in the broader Chronic Kidney Disease (CKD) population. METHODS: This is an epidemiological study of the prevalence of FD in CKD patents identified from the public renal speciality practices in Queensland, Australia. A cascade approach to screening is being employed with dried blood spot testing for blood levels of alpha-galactosidase A (Alpha-Gal), with follow-up testing for patients with abnormal results by plasma levels of globotriaosylsphingosine (Lyso-GB3) for females and non-definitive cases in males. A diagnosis of FD is confirmed through genetic testing of the GLA gene in cases suspected of having FD based upon Alpha-Gal and Lyso-GB3 testing. DISCUSSION: Expected outcomes of this study include more information about the prevalence of FD at all stages of CKD, including for both males and females. The study may also provide information about common characteristics of FD to assist with diagnosis and optimal management/treatment. Screening is also available for family members of diagnosed patients, with potential for early diagnosis of FD and intervention for those individuals. TRIAL REGISTRATION: Queensland Health Database of Research Activity (DORA, https://dora.health.qld.gov.au) pj09946 (Registered 3rd July 2017).
Assuntos
Doença de Fabry/epidemiologia , Insuficiência Renal Crônica/etiologia , Adulto , Protocolos Clínicos , Diagnóstico Tardio , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Feminino , Glicolipídeos/sangue , Humanos , Masculino , Prevalência , Estudos Prospectivos , Queensland/epidemiologia , Diálise Renal , Insuficiência Renal Crônica/genética , Esfingolipídeos/sangue , alfa-Galactosidase/sangueRESUMO
Fabry disease (FD [MIM:301500]) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene. Deficient activity of its product, lysosomal enzyme α-galactosidase A (α-Gal A), leads to excessive accumulation of glycosphingolipids in cells of multiple organs. The establishing of the diagnosis is challenge in female patients because of milder clinical manifestation and normal α-Gal A activity. The globotriaosylsphingosine (lysoGb3) is described as a more sensitive diagnostic biomarker for females with pathogenic mutation in the GLA gene. Thus, the aim of this study is to improve the biochemical diagnostic efficiency for FD in females. Here we report the α-Gal A/lysoGb3 ratio as the novel biochemical criteria for diagnosis of female patients with FD, using dried blood spots (DBS) as test samples. It showed 100% sensitivity in distinguishing our group of 35 female patients from control (n = 140). Whereas measurement of α-Gal A and lysoGb3 alone showed 8.6% and 74.4% respectively. A new approach of using the ratio of α-Gal A activity to lysoGb3 concentration in DBS may provide a more accurate screening tool for identification of FD females.
Assuntos
Teste em Amostras de Sangue Seco , Doença de Fabry/sangue , Glicolipídeos/sangue , Esfingolipídeos/sangue , alfa-Galactosidase/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Criança , Doença de Fabry/diagnóstico , Feminino , Genótipo , Glicolipídeos/genética , Humanos , Pessoa de Meia-Idade , Esfingolipídeos/genética , Adulto Jovem , alfa-Galactosidase/genéticaRESUMO
Fabry disease (FD) is a lysosomal storage disease, treatable by enzyme replacement therapy (ERT) that substitutes deficient α-galactosidase A (AGAL). The formation of neutralising anti-drug antibodies (ADA) inhibiting AGAL activity during infusion is associated with disease progression in affected male patients. In this study we analysed if ADAs also inhibit endothelial enzyme uptake as well as intracellular enzyme activity. Therefore, fluorescence-labelled AGAL in combination with ADA-positive sera from FD patients (n = 8) was used to analyse enzyme uptake in endothelial and FD-specific cells. Furthermore, immune adsorption and a comprehensive ADA epitope mapping were performed. Pre-incubation of AGAL with ADAs significantly inhibited intracellular enzyme activity, which was rescued by immune adsorption (both P < .01). ADAs from some patients also inhibited enzyme uptake. ADA epitope mapping identified an epitope at position 121 to 140 aa potentially responsible for uptake inhibition for these patients. Further analyses revealed the presence of stable AGAL/ADA-immune complexes at pH 4.5 and decreased intracellular enzyme activity in endothelial cells (P < .001). Finally, the pre-incubation of AGAL with ADAs resulted in a reduced depletion of intracellular globotriaosylceramide in patient-derived AGAL-deficient cells, demonstrating a direct negative impact of ADAs on intracellular clearance. Neutralising ADAs may not only inhibit infused AGAL activity, but according to their epitopes can also inhibit endothelial AGAL uptake. Indeed, internalised AGAL/ADA-complexes may not dissociate, underlining the importance of novel therapeutic approaches for ADA reduction and prevention to increase therapy efficiency in affected patients.
Assuntos
Anticorpos Neutralizantes/imunologia , Terapia de Reposição de Enzimas , Doença de Fabry/imunologia , alfa-Galactosidase/imunologia , Adulto , Anticorpos Neutralizantes/biossíntese , Ensaio de Imunoadsorção Enzimática , Doença de Fabry/sangue , Doença de Fabry/tratamento farmacológico , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , alfa-Galactosidase/sangue , alfa-Galactosidase/uso terapêuticoRESUMO
BACKGROUND: Sporadic Parkinson's disease (PD) patients have lower α-galactosidase A (α-GAL A) enzymatic activity and Fabry disease (FD) patients potentially carry an increased risk of PD. OBJECTIVE: Determination of PD prevalence in FD and clinical, biochemical and vascular neuroimaging description of FD pedigrees with concomitant PD. METHODS: Clinical screening for PD in 229 FD patients belonging to 31 families, harbouring GLA gene mutation p.F113L, and subsequent pedigree analysis. Gender-stratified comparison of FD+/PD+ patients with their family members with FD but without PD (FD+/PD-) regarding Mainz scores, plasma & leukocytes α-GAL A enzymatic activity, urinary Gb3 and plasma Lyso-Gb3, vascular brain neuroimaging. RESULTS: Prevalence of PD in FD was 1.3% (3/229) (3% in patients aged ≥50 years). Three FD patients, one female (73 years old) (P1) and two males (60 and 65 years old) (P2 and P3), three different pedigrees, presented akinetic-rigid PD, with weak response to levodopa (16% - 36%), and dopaminergic deficiency on 18F-DOPA PET. No pathogenic mutations were found in a PD gene panel. FD+/PD+ patients had worse clinical severity of FD (above upper 75% IQR in Mainz scores), and cortico-subcortical white matter/small vessel lesions. P3 patient was under enzyme therapy, started 1 year before PD diagnosis. P2-P3 patients had higher leucocyte α-GAL A activity (2,2-3 vs.1,0 (median)(nmol/h/mg)). CONCLUSION: We have shown a high prevalence of PD in a late-onset phenotype of FD, presenting high cerebrovascular burden and weak response to levodopa. Further studies will untangle how much of this PD phenotype is due to Gb3 deposition versus cerebrovascular lesions in the nigro-striatal network.
Assuntos
Encéfalo/diagnóstico por imagem , Doença de Fabry , Glicolipídeos/metabolismo , Leucócitos/enzimologia , Doença de Parkinson , Esfingolipídeos/metabolismo , alfa-Galactosidase/metabolismo , Adulto , Idoso , Estudos de Coortes , Comorbidade , Doença de Fabry/diagnóstico por imagem , Doença de Fabry/enzimologia , Doença de Fabry/epidemiologia , Doença de Fabry/fisiopatologia , Feminino , Glicolipídeos/sangue , Glicolipídeos/urina , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/enzimologia , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia , Linhagem , Fenótipo , Prevalência , Esfingolipídeos/sangue , Esfingolipídeos/urina , alfa-Galactosidase/sangue , alfa-Galactosidase/genéticaRESUMO
OBJECTIVES: Fabry disease (FD) is a rare disease associated with sphingolipid accumulation. Sphingolipids are components of plasma membranes that are important in podocyte function and accumulate in various glomerular diseases such as focal segmental glomerulosclerosis (FSGS). Both FD and FSGS can cause podocyte damage and are classified as podocytopathies. In this respect, FD and FSGS share the same pathophysiologic pathways. Previous screening studies have shown that a significant proportion of end-stage renal disease (ESRD) patients receiving hemodialysis (HD) have unsuspected FD, and the prevalence of low alpha-galactosidase A (αGLA) enzyme activity in these patients is higher than that in the normal population. We aimed to compare αGLA enzyme activity in patients with biopsy-proven FSGS and ESRD receiving HD. METHODS: The records of 232 patients [62 FSGS (F/M: 33/29); 170 HD (M/F: 93/79)] were evaluated retrospectively. The screening was performed based on the αGLA enzyme activity on a dried blood spot, with the confirmation of plasma LysoGb3 levels, and the known GLA mutations were tested in patients with low enzyme activities. The two groups were compared using these parameters. RESULTS: The mean level of αGLA enzyme activity was found to be lower in FSGS patients than in the HD group (2.88±1.2 μmol/L/h versus 3.79±1.9 μmol/L/h, p<0.001). There was no significant relationship between the two groups with regard to the plasma LysoGb3 levels (2.2±1.22 ng/ml versus 1.7±0.66 ng/ml, p: 0.4). In the analysis of GLA mutations, a D313Y mutation [C(937G>T) in exon p] was found in one patient from the FSGS group. CONCLUSIONS: We found that αGAL activity in patients with FSGS is lower than that in patients undergoing HD. The low enzyme activity in patients with FSGS may be explained by considering the similar pathogenesis of FSGS and FD, which may also lead to sphingolipid deposition and podocyte injury.
Assuntos
Humanos , Masculino , Feminino , alfa-Galactosidase/sangue , Falência Renal Crônica/terapia , Glomerulosclerose Segmentar e Focal/sangue , Glomerulosclerose Segmentar e Focal/epidemiologia , Prevalência , Estudos Retrospectivos , Falência Renal Crônica/epidemiologiaRESUMO
BACKGROUND: Although previous studies have suggested a certain prevalence of Fabry disease (FD) in left ventricular hypertrophy (LVH) patients, the screening of FD is difficult because of its wide-ranging clinical phenotypes. We aimed to clarify the utility of combined measurement of plasma globotriaosylsphingosine (lyso-Gb3) concentration and α-galactosidase A activity (α-GAL) as a primary screening of FD in unexplained LVH patients.MethodsâandâResults:Between 2014 and 2016, both lyso-Gb3 and α-GAL were measured in 277 consecutive patients (male 215, female 62, age 25-79 years) with left ventricular wall thickness >12 mm on echocardiogram: 5 patients (1.8%) screened positive (2 (0.7%) showed high lyso-Gb3 and 4 (1.4%) had low α-GAL levels). Finally, 2 patients (0.7%) were diagnosed with clinically significant FD. In 1 case, a female heterozygote with normal α-GAL levels had genetic variants of unknown significance and was diagnosed as FD by endomyocardial biopsy. The other case was a male chronic renal failure patient requiring hemodialysis, and he had a p.R112H mutation. In both cases there were high lyso-Gb3 levels. CONCLUSIONS: The serum lyso-Gb3 level can be relevant for clinically significant FD, and combined measurement of lyso-Gb3 and α-GAL can provide better screening of FD in unexplained LVH patients.
Assuntos
Doença de Fabry/sangue , Glicolipídeos/sangue , Hipertrofia Ventricular Esquerda/sangue , Esfingolipídeos/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Doença de Fabry/diagnóstico por imagem , Doença de Fabry/genética , Doença de Fabry/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Japão , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Estudos Prospectivos , Função Ventricular Esquerda , Remodelação Ventricular , Adulto Jovem , alfa-Galactosidase/sangue , alfa-Galactosidase/genéticaRESUMO
Background: Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants. Currently, more than 700 different FD-causing mutations have been identified in the human GLA gene. We identified a novel mutation in a Lithuanian family with classical manifestations of Fabry disease, revealing severe effects to the cardiovascular systems of heterozygous women. Case presentation: A 49-year-old woman underwent echocardiography due to progressive dyspnea that lasted seven years, reduced physical activity, and periodic cardiac arrhythmia. Echocardiography revealed left ventricular hypertrophy with normal diastolic function. The patient had experienced acroparesthesia in her upper limbs and abdominal pain since childhood, and in the last decade had experienced mild proteinuria without renal failure. Her renal biopsy was typical for Fabry disease. The patient's brain magnetic resonance imaging (MRI) (T2 flair) showed white matter hyperintensities lesions. DNA sequencing of the proband, her mother and one of her sons showed a novel GLA gene exon 2 mutation, c.270C>G (p.Cys90Trp). All three patients had decreased α-galactosidase A activity and specific FD manifestations. Conclusion: A novel GLA mutation, c.270C>G (p.Cys90Trp), was found in a Lithuanian family with a classical form of Fabry disease in heterozygous women with predominant cardiac involvement. However, the exact manifestation of this mutation is still unclear as it is newly reported and further research must be done.
Assuntos
Doença de Fabry/genética , alfa-Galactosidase/análise , Dispneia/etiologia , Eletrocardiografia/métodos , Doença de Fabry/epidemiologia , Feminino , Glicolipídeos/análise , Glicolipídeos/sangue , Humanos , Lituânia , Pessoa de Meia-Idade , Mutação/fisiologia , Esfingolipídeos/análise , Esfingolipídeos/sangue , alfa-Galactosidase/sangueRESUMO
BACKGROUND: Fabry disease is an X-linked recessive disorder caused by deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A). Previous studies identified many cases of Fabry disease among men with left ventricular hypertrophy (LVH). The purpose of this study was to define the frequency of Fabry disease among Korean men with LVH. METHODS: In this national prospective multicenter study, we screened Fabry disease in men with LVH on echocardiography. The criterion for LVH diagnosis was a maximum LV wall thickness 13 mm or greater. We screened 988 men with LVH for plasma α-Gal A activity. In patients with low α-Gal A activity (< 3 nmol/hr/mL), we searched for mutations in the α-galactosidase gene. RESULTS: In seven men, α-Gal A activity was low. Three had previously identified mutations; Gly328Arg, Arg301Gln, and His46Arg. Two unrelated men had the E66Q variant associated with functional polymorphism. In two patients, we did not detect GLA mutations, although α-Gal A activity was low on repeated assessment. CONCLUSION: We identified three patients (0.3%) with Fabry disease among unselected Korean men with LVH. Although the prevalence of Fabry disease was low in our study, early treatment of Fabry disease can result in a good prognosis. Therefore, in men with unexplained LVH, differential diagnosis of Fabry disease should be considered.
Assuntos
Doença de Fabry/diagnóstico , Hipertrofia Ventricular Esquerda/diagnóstico , Adulto , Idoso , Análise Mutacional de DNA , Ecocardiografia , Doença de Fabry/complicações , Doença de Fabry/epidemiologia , Genótipo , Humanos , Hipertrofia Ventricular Esquerda/complicações , Rim/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , República da Coreia/epidemiologia , Adulto Jovem , alfa-Galactosidase/sangue , alfa-Galactosidase/genéticaRESUMO
The prevalence of Fabry disease (FD) in adult patients with suspected hypertrophic cardiomyopathy (HCM) has been reported between 0.3% and 4%. Fabry disease-specific therapy necessitates early diagnosis; however, the optimal screening strategy and cost efficacy of routine α-galactosidase A (α-gal A) vs comprehensive galactosidase alpha gene (GLA) testing remain poorly understood. We identified 1192 patients who underwent routine α-gal A screening between January 1, 2011, and December 31, 2017, for suspected HCM. Cost efficacy was explored using prevalence and cost estimates. Ten patients had reduced α-gal A enzyme activity, and 5 (3 women) were ultimately diagnosed with FD (prevalence estimate, 0.42%). An alternative cardiac diagnosis was made in 3 patients with mildly reduced enzyme activity. Two women with reduced borderline enzyme levels did not undergo confirmatory testing, but FD was not suspected. The number needed to screen to diagnose 1 patient with FD in a similar cohort is estimated at 238 (5 new cases per 1192 at-risk individuals) at a cost of approximately US $24,000 per diagnosis. We identified a 0.42% prevalence of FD using routine α-gal A screening in adult patients referred to a dedicated HCM center in the United States. Compared with more comprehensive genetic testing strategies, we identified a similar prevalence of FD at a lower cost per diagnosis.
Assuntos
Doença de Fabry/diagnóstico , Programas de Rastreamento/economia , alfa-Galactosidase/sangue , Adulto , Idoso , Biomarcadores/sangue , Análise Custo-Benefício , Doença de Fabry/enzimologia , Doença de Fabry/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Prevalência , Estudos RetrospectivosRESUMO
BACKGROUND/AIMS: Fabry disease (FD), a rare x-lined genetic disorder is a cause of renal deterioration. The phenotype of FD is highly variable and nonspecific, and correct diagnosis has always been delayed. We aimed to explore the prevalence and clinical presentation of FD in this high-risk male population in a Northern Taiwan medical center. METHODS: This is the first study to survey the incidence of FD in this high-risk population through the platform of a chronic kidney disease (CKD) education program in Asia. A total of 1,012 male patients with unknown CKD causes were screened using an assay of alpha-galactosidase A activity (α-Gal A) by dried blood spots (DBS). A final GLA gene analysis was also done for those with low enzyme activity. RESULTS: We identified two new patients with classic FD and four patients with late-onset FD. One novel GLA mutation with c.413 G>A was found in one classic FD patient (index 5). The prevalence of FD is about 0.59 % (6 in 1,012) in the high-risk population group with CKD. The clinical symptoms of FD patients are nonspecific except in those with various degrees of renal failure. Those patients' correct diagnosis was delayed, taking years and even decades. Three patients received enzyme replacement therapy and one started regular hemodialysis due to persistent renal function deterioration. Another two patients were found from family screening through a new index. In addition, a false negative result occurred in one patient who was proved to have FD by his kidney pathology as determined by this screening. CONCLUSION: FD is not such as rare a disease and its prevalence is greater in this high-risk male population. Clinicians need to be aware that FD should be included in the differential diagnosis in CKD with unknown etiology.
Assuntos
Doença de Fabry/diagnóstico , Falência Renal Crônica/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Doença de Fabry/epidemiologia , Humanos , Isoenzimas/sangue , Isoenzimas/genética , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prevalência , Proteínas Recombinantes/sangue , Proteínas Recombinantes/genética , Insuficiência Renal Crônica , Taiwan , Adulto Jovem , alfa-Galactosidase/sangue , alfa-Galactosidase/genéticaRESUMO
BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in GLA, which encodes the enzyme α-galactosidase A (α-Gal A). Although the prevalence of Fabry disease in patients with stroke has been reported to range from 0% to 4%, few cohort studies have examined Japanese stroke patients. We aimed to clarify the prevalence of Fabry disease and the frequency of GLA mutations among patients with young-onset stroke in Japan. METHODS: From April 2015 to December 2016, we enrolled patients with young-onset (≤60 years old) ischemic stroke or intracerebral hemorrhage. We measured α-Gal A activity and the concentration of globotriaosylsphingosine in plasma. Genetic evaluations were performed in patients with low α-Gal A activity or high concentrations of globotriaosylsphingosine. RESULTS: Overall, 516 patients (median age of onset, 52 years old; 120 women) were consecutively enrolled in this study. Five patients (4 men and 1 woman) had low α-Gal A activity, and no patients were detected with the screen for plasma globotriaosylsphingosine levels. The genetic analysis did not identify a causative mutation responsible for classic Fabry disease in any of the patients, but 2 patients (.4%) carried the p.E66Q in GLA. CONCLUSIONS: No patient with Fabry disease was detected in our young-onset stroke cohort.