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Objective: The study objective was to evaluate the safety and clinical and echocardiographic outcomes of a new surgical technique in adult patients diagnosed with a giant left atrium. Methods: We analyzed a cohort of patients who underwent left atrium reduction surgery between January 2016 and June 2020 performed by a specialized surgical team in 2 national reference centers in Lima, Peru. We assessed the major adverse valvular-related events and the New York Heart Association functional class as primary clinical outcomes. Also, our primary echocardiographic endings were the diameter, area, and volume of the left atrium. We assessed these variables at 3 time periods: baseline (t0), perioperative period (t1), and extended follow-up (t2: 12 ± 3.4 months). We carried out descriptive and bivariate exploratory statistical analysis for dependent measures. Results: We included 17 patients, 70.6% of whom were women. Rheumatic mitral valve disease (76.5%) was the main etiology. We performed 14 (82.4%) mitral valve replacements and 3 repairs. Major adverse valvular-related events occurred in 1 patient (5.9%) (hemorrhagic stroke) at t1. A significant reduction in the size of the left atrium was observed: diameter (77 mm vs 48 mm, P < .001), area (75 cm2 vs 31 cm2, P < .001), and volume (332 cm3 vs 90 cm3, P < .001). Compared with t0 and t1, these echocardiographic findings remained without significant changes during t2. Conclusions: Our surgical left atrium reduction technique was associated with improved clinical functionality and reduced left atrium measures in patients with a giant left atrium undergoing mitral valve surgery.
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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.
Assuntos
Doença de Fabry , Animais , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Feminino , Humanos , Masculino , Mamíferos/metabolismo , Mutação , Mutação de Sentido Incorreto , Fenótipo , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismoRESUMO
BACKGROUND: Fabry disease (FD) is a rare, X-linked, multisystemic lysosomal storage disorder (LSD) that results from a deficiency in the hydrolase alpha-galactosidase A (âº-GalA). During childhood, classic FD symptomatology is rare. The majority of children may show non-specific symptoms, including in the musculoskeletal system. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients is unknown. OBJECTIVE: This study aimed to identify the frequency of FD in a JIA cohort, characterizing early clinical symptoms, enzyme titers, and GLA genotyping. METHODS: Children with JIA followed in a tertiary Children Hospital cohort were selected. Clinical, laboratory and familiar information were recorded. Molecular genetic testing to detect GLA gene mutations was performed in girls and enzymatic analysis in boys. RESULTS: In 89 patients (56.2% female, age at disease onset: 8.93 ± 4.35 years), one male (1.12%) patient presented pathogenic mutation in GLA gene, c.1244 T > C p.L415P, one female patient had a variant of uncertain significance c.38C > T (p.Ala13Val). Three additional (3.4%) patients had the enzymatic activity of alpha-galactosidase slightly decreased. We observed the presence of intronic variants in 44.44% of patients in our cohort: c.1000-22C > T; c.370-81_-77del; c.640-16A > G; c.10C > T; c.548-125C > G and c.-12G > A. These variants and their combination were associated with clinical symptoms in our cohort. CONCLUSIONS: The incidence of FD in our cohort was 1.12%. Intronic variants were associated with symptoms previously described in the literature. Screening for FD in JIA may be a reasonable strategy for those with an atypical pattern of pain.
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Artrite Juvenil/complicações , Doença de Fabry/complicações , Doença de Fabry/epidemiologia , Criança , Pré-Escolar , Doença de Fabry/genética , Feminino , Humanos , Masculino , MutaçãoRESUMO
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 a rare X-linked glycosphingolipidosis caused by mutations in GLA, a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel GLA variant located in the 5' splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms.
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Encéfalo/metabolismo , Doença de Fabry/genética , Mutação , alfa-Galactosidase/genética , Adolescente , Doença de Fabry/enzimologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem , alfa-Galactosidase/metabolismoRESUMO
OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal disease caused by variants of the GLA gene; the formation of defective alpha-galactosidase A contributes to the accumulation of substrates in several organs. Chronic inflammation is thought to contribute to organ damage in FD patients. METHODS: In total, 36 classic FD patients (15 men/21 women) and 25 healthy controls (20 men/8 women) were assessed. The Mainz Severity Score Index (MSSI) was established after conducting interviews with the patients and chart review. Serum IL-6, IL-1β, and TNF-α levels were evaluated in both groups. RESULTS: The mean age (years) for FD patients was 43.1±15.4 and that for the controls was 47.4±12.2 (p>0.05). Twenty-two patients (59.5%) were treated with enzyme replacement therapy (ERT). Serum IL-6 and TNF-α levels were significantly higher in FD patients than in the controls. Patients treated with ERT had higher serum IL-6 and TNF-α levels than those not treated with ERT. There was no difference in the serum IL-1β levels between patients treated with ERT and those who were not. The MSSI scores in the patients were correlated with serum levels of IL-6 (r=0.60, p<0.001) and TNF-α (r=0.45, p<0.001). CONCLUSION: FD was associated with elevated serum levels of IL-6 and TNF-α in this cohort. The FD patients treated with ERT, particularly, women, exhibited higher levels of serum IL-6 and TNF-α than those not treated with ERT; the serum IL-6 and TNF-α levels were correlated with the MSSI scores reflecting greater disease burden.
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Humanos , Masculino , Feminino , Fator de Necrose Tumoral alfa , Doença de Fabry/tratamento farmacológico , Interleucina-6 , Efeitos Psicossociais da Doença , alfa-GalactosidaseRESUMO
There is little evidence that current control strategies for canine leishmaniosis (CanL), the veterinary disease caused by L. infantum infection, are having a positive impact. This is of critical importance because dogs are a primary reservoir for L. infantum and a significant source of parasite transmission to humans. Drugs intended primarily for human use are prohibited for the treatment of CanL because of concerns over the propagation of resistant parasites. Although allopurinol effectively decreases parasite burden in CanL the treatment needs to be maintained for life. We hypothesized that during the allopurinol-induced parasite reduction dogs may become capable of developing a more robust immune response that may permit more effective control of parasites. To test this, we investigated the clinical and parasitological impact of short-term treatment with allopurinol, either alone or in combination with a defined subunit vaccine, on dogs naturally infected with L. infantum. A total of 28 dogs were distributed as follows: untreated; oral allopurinol alone (20 mg/kg, once each day for 90 days); or allopurinol with immunization with the Leish-F2 antigen formulated with the Toll-like receptor (TLR) 4 agonist Second generation Lipid Adjuvant (SLA) in stable emulsion (SE; SLA-SE). Dogs that did not receive treatment had a progressive decline in their clinical condition and an increase in their infection levels, while treatment with allopurinol alone alleviated the clinical symptoms of CanL but did not generate sustained reduction in parasites. Concomitant immunization with Leish-F2 + SLA-SE, however, improved clinical condition while also providing long-term clearance of L. infantum from lymphoid tissues and systemic organs. These results have important implications for both the management of CanL and for limiting L. infantum transmission to humans.
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BACKGROUND: Fabry disease (FD) is an X-linked lysosomal disorder due to mutations in the GLA gene resulting in defective enzyme alpha-galactosidase A. FD patients are frequently misdiagnosed, commonly for rheumatic diseases. Determining pathogenicity of a mutation depends of in silico predictions but mostly on available clinical information and interpretation may change in light of evolving knowledge. Similar signs and symptoms in carriers of GLA gene genetic variants of unknown significance or of benign variants may hamper diagnosis. This study reviews rheumatic and immune-mediated manifestations in a cohort of Brazilian FD patients with classic mutations and also in subjects with GLA gene A143T and R118C mutations. Misdiagnoses, time to correct diagnosis or determination of GLA gene status, time to treatment initiation and reasons for treatment prescription in A143T and R118C subjects are reviewed. METHODS: Genotype confirmed classic FD patients (n = 37) and subjects with GLA gene mutations A143T and R118C (n = 19) were referred for assessment. Subjects with R118C and A143T mutations had been previously identified during screening procedures at hemodialysis units. All patients were interviewed and examined by a rheumatologist with previous knowledge of disease and/or mutation status. A structured tool developed by the authors was used to cover all aspects of FD and of common rheumatic conditions. All available laboratory and imaging data were reviewed. RESULTS: Thirty-seven consecutive FD patients were interviewed - 16 male / 21 female (mean age: 43.1 years) and 19 consecutive subjects with GLA gene mutations R118C and A143T were evaluated - 8 male / 11 female (mean age: 39.6 years); 15 [R118C] / 4 [A143T]. Misdiagnosis in FD patients occurred in 11 males (68.8%) and 13 females (61.9%) of which 10 males and 9 females were previously diagnosed with one or more rheumatic conditions, most frequently rheumatic fever or "rheumatism" (unspecified rheumatic disorder). Median time for diagnosis after symptom onset was 16 years (range, 0-52 years). Twenty-two patients were treated with enzyme replacement therapy (ERT) - 13 male and 9 female. Median time to ERT initiation after FD diagnosis was 0.5 years (range, 0-15 years). Rheumatic manifestations occurred in 68.4% of R118C and A143T subjects. Two subjects had been prescribed ERT because of renal disease [R118C] and neuropsychiatric symptoms [A143T]. CONCLUSION: Misdiagnoses occurred in 64.8% of FD patients, most frequently for rheumatic conditions. Median time for correct diagnosis was 16 years. Rheumatic manifestations are also frequent in subjects with GLA gene R118C and A143T mutations. These results reinforce the need to raise awareness and increase knowledge about Fabry disease among physicians, notably rheumatologists, who definitely have a role in identifying patients and determining disease burden. Decision to start treatment should consider expert opinion and follow local guidelines.
Assuntos
Doença de Fabry/diagnóstico , alfa-Galactosidase/genética , Adolescente , Adulto , Idoso , Brasil , Criança , Pré-Escolar , Diagnóstico Tardio/estatística & dados numéricos , Erros de Diagnóstico , Terapia de Reposição de Enzimas/estatística & dados numéricos , Doença de Fabry/complicações , Doença de Fabry/genética , Doença de Fabry/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/etiologia , Febre Reumática/diagnóstico , Fatores de Tempo , Tempo para o Tratamento , Adulto JovemRESUMO
BACKGROUND: Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms. RESULTS: We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls. CONCLUSION: The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease.
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Teste em Amostras de Sangue Seco/métodos , Doença de Fabry/genética , alfa-Galactosidase/genética , Genótipo , Haplótipos/genética , Humanos , Masculino , Mutação/genéticaRESUMO
Abstract Background: Fabry disease (FD) is an X-linked lysosomal disorder due to mutations in the GLA gene resulting in defective enzyme alpha-galactosidase A. FD patients are frequently misdiagnosed, commonly for rheumatic diseases. Determining pathogenicity of a mutation depends of in silico predictions but mostly on available clinical information and interpretation may change in light of evolving knowledge. Similar signs and symptoms in carriers of GLA gene genetic variants of unknown significance or of benign variants may hamper diagnosis. This study reviews rheumatic and immune-mediated manifestations in a cohort of Brazilian FD patients with classic mutations and also in subjects with GLA gene A143T and R118C mutations. Misdiagnoses, time to correct diagnosis or determination of GLA gene status, time to treatment initiation and reasons for treatment prescription in A143T and R118C subjects are reviewed. Methods: Genotype confirmed classic FD patients (n = 37) and subjects with GLA gene mutations A143T and R118C (n = 19) were referred for assessment. Subjects with R118C and A143T mutations had been previously identified during screening procedures at hemodialysis units. All patients were interviewed and examined by a rheumatologist with previous knowledge of disease and/or mutation status. A structured tool developed by the authors was used to cover all aspects of FD and of common rheumatic conditions. All available laboratory and imaging data were reviewed. Results: Thirty-seven consecutive FD patients were interviewed - 16 male / 21 female (mean age: 43.1 years) and 19 consecutive subjects with GLA gene mutations R118C and A143T were evaluated - 8 male / 11 female (mean age: 39.6 years); 15 [R118C] / 4 [A143T]. Misdiagnosis in FD patients occurred in 11 males (68.8%) and 13 females (61.9%) of which 10 males and 9 females were previously diagnosed with one or more rheumatic conditions, most frequently rheumatic fever or "rheumatism" (unspecified rheumatic disorder). Median time for diagnosis after symptom onset was 16 years (range, 0-52 years). Twenty-two patients were treated with enzyme replacement therapy (ERT) - 13 male and 9 female. Median time to ERT initiation after FD diagnosis was 0.5 years (range, 0-15 years). Rheumatic manifestations occurred in 68.4% of R118C and A143T subjects. Two subjects had been prescribed ERT because of renal disease [R118C] and neuropsychiatric symptoms [A143T]. Conclusion: Misdiagnoses occurred in 64.8% of FD patients, most frequently for rheumatic conditions. Median time for correct diagnosis was 16 years. Rheumatic manifestations are also frequent in subjects with GLA gene R118C and A143T mutations. These results reinforce the need to raise awareness and increase knowledge about Fabry disease among physicians, notably rheumatologists, who definitely have a role in identifying patients and determining disease burden. Decision to start treatment should consider expert opinion and follow local guidelines.(AU)