RESUMO
Fabry disease (FD) is a genetic disease, with X-chromosome linked inheritance, due to variants in the GLA gene that encodes the α-galactosidase A (α-GAL) enzyme. The purpose of the present study was to create a consensus aiming to standardize the recommendations regarding the renal involvement of FD with guidelines on the diagnosis, screening, and treatment of pediatric patients. This consensus is an initiative of the Rare Diseases Committee (Comdora) of the Brazilian Society of Nephrology (SBN). Randomized controlled clinical studies and studies with real-life data added to the authors' experience were considered for this review. The result of this consensus was to help manage patient and physician expectations regarding treatment outcomes. Thus, this consensus document recommends the investigation of the pediatric family members of an index case, as well as cases with suggestive clinical signs. From the diagnosis, assess all possible FD impairments and grade through scales. From an extensive review of the literature including pediatric protocols and particularly evaluating pediatric cases from general studies, it can be concluded that the benefits of early treatment are great, especially in terms of neuropathic pain and renal impairment parameters and outweigh the possible adverse effects that were mainly manifested by infusion reactions.
Assuntos
Doença de Fabry , Nefrologia , Brasil , Criança , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Doença de Fabry/terapia , Humanos , Doenças Raras , alfa-Galactosidase/genética , alfa-Galactosidase/uso terapêuticoRESUMO
Fabry disease (FD) is an X-linked inherited disorder caused by mutations in the GLA gene encoding enzyme alpha-galactosidase A (α-Gal A). The purpose of this study was to produce a consensus statement to standardize the recommendations concerning kidney involvement in FD and provide advice on the diagnosis, screening, and treatment of adult and pediatric patients. This consensus document was organized from an initiative led by the Committee for Rare Diseases (Comdora) of the Brazilian Society of Nephrology (SBN). The review considered randomized clinical trials, real-world data studies, and the expertise of its authors. The purpose of this consensus statement is to help manage patient and physician expectations concerning the outcomes of treatment. Our recommendations must be interpreted within the context of available evidence. The decisions pertaining to each individual case must be made with the involvement of patients and their families and take into account not only the potential cost of treatment, but also concurrent conditions and personal preferences. The Comdora intends to update these recommendations regularly so as to reflect recent literature evidence, real-world data, and appreciate the professional experience of those involved. This consensus document establishes clear criteria for the diagnosis of FD and for when to start or stop specific therapies or adjuvant measures, to thus advise the medical community and standardize clinical practice.
Assuntos
Doença de Fabry , Nefrologia , Adulto , Brasil , Criança , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Doença de Fabry/terapia , Humanos , Doenças Raras/diagnóstico , Doenças Raras/terapia , alfa-Galactosidase/genética , alfa-Galactosidase/uso terapêuticoRESUMO
Fabry disease (FD), like COVID-19, can affect multiple organs, including the lungs. Patients with FD are expected to develop severe COVID-19, due to involvement of not only the lungs but also the kidneys and the presence of other comorbidities. We present 2 cases of mild COVID-19 in patients with FD who were infected with the COVID-19 virus. Although it is unknown whether the X chromosome mutation in patients with FD affects the development of severe COVID-19, it is suggested that it may play a protective role against COVID-19 infection. Based on these cases, we suggest that FD is not a risk factor for severe COVID-19.
Assuntos
COVID-19/etiologia , Doença de Fabry/etiologia , COVID-19/diagnóstico por imagem , COVID-19/terapia , Teste para COVID-19 , Terapia de Reposição de Enzimas , Doença de Fabry/genética , Doença de Fabry/terapia , Feminino , Humanos , Rim/patologia , Pessoa de Meia-IdadeRESUMO
Abstract There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.
Resumo As doenças renais genéticas raras compreendem mais de 150 desordens. Elas podem ser classificadas segundo achados diagnósticos como (i) distúrbios do crescimento e estrutura, (ii) doenças glomerulares, (iii) tubulares e (iv) metabólicas. Nos últimos anos, houve uma mudança de paradigma nesse campo. Os testes moleculares tornaram-se mais acessíveis, nossa compreensão sobre os mecanismos fisiopatológicos subjacentes a essas doenças evoluiu e novas estratégias terapêuticas foram propostas. Portanto, o papel do nefrologista mudou progressivamente de mero espectador a participante ativo, parte de uma equipe multidisciplinar, no diagnóstico e tratamento desses distúrbios. O presente artigo oferece um panorama geral dos recentes avanços a respeito dos distúrbios renais hereditários raros, discutindo aspectos genéticos, manifestações clínicas e abordagens diagnósticas e terapêuticas de alguns desses distúrbios, mais especificamente a glomeruloesclerose segmentar e focal familiar, complexo da esclerose tuberosa, nefropatia de Fabry e doença relacionada ao MYH9.
Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adulto , Doenças Genéticas Inatas/genética , Rim/fisiopatologia , Nefropatias/congênito , Nefropatias/diagnóstico , Trombocitopenia/congênito , Trombocitopenia/diagnóstico , Trombocitopenia/terapia , Esclerose Tuberosa/terapia , Testes Genéticos/métodos , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Doença de Fabry/terapia , Comunicação Interdisciplinar , Taxa de Filtração Glomerular/fisiologia , Perda Auditiva Neurossensorial/diagnóstico , Doenças Genéticas Inatas/diagnóstico , Túbulos Renais/patologia , Doenças Metabólicas/patologia , Nefrologia/normasRESUMO
There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.
Assuntos
Doenças Genéticas Inatas/genética , Nefropatias/congênito , Nefropatias/diagnóstico , Rim/fisiopatologia , Adulto , Criança , Pré-Escolar , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Doença de Fabry/terapia , Feminino , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/métodos , Taxa de Filtração Glomerular/fisiologia , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/terapia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/terapia , Humanos , Lactente , Comunicação Interdisciplinar , Nefropatias/fisiopatologia , Nefropatias/terapia , Glomérulos Renais/patologia , Túbulos Renais/patologia , Masculino , Doenças Metabólicas/patologia , Nefrologia/normas , Trombocitopenia/congênito , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapiaRESUMO
Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between 1:8,454 and 1:117,000 among males and is probably underdiagnosed. Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The onset of symptoms occurs during childhood, with acroparesthesia, heat intolerance, and gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and neuropathic pain. Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency. The latter being the main cause of death in FD. The gold standard for diagnosis is the genetic analysis in search of mutation, in addition to family history. In homozygous patients, the enzyme activity can also be used. Once the diagnosis is confirmed, the patient and their family should receive genetic counseling. The treatment, in turn, currently focuses mainly on replacing the enzyme that is absent or deficient by means of enzyme replacement therapy, with the purpose of avoiding or removing deposits of Gb3. Chaperones can also be used for the treatment of some cases. It is considered that the specific treatment should be initiated as soon as a diagnosis is obtained, which can change the prognosis of the disease.
Assuntos
Terapia de Reposição de Enzimas , Doença de Fabry/patologia , Rim/patologia , Insuficiência Renal Crônica/patologia , Doença de Fabry/complicações , Doença de Fabry/genética , Doença de Fabry/terapia , Feminino , Humanos , Masculino , Insuficiência Renal Crônica/etiologia , TriexosilceramidasRESUMO
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
SUMMARY Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between 1:8,454 and 1:117,000 among males and is probably underdiagnosed. Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The onset of symptoms occurs during childhood, with acroparesthesia, heat intolerance, and gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and neuropathic pain. Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency. The latter being the main cause of death in FD. The gold standard for diagnosis is the genetic analysis in search of mutation, in addition to family history. In homozygous patients, the enzyme activity can also be used. Once the diagnosis is confirmed, the patient and their family should receive genetic counseling. The treatment, in turn, currently focuses mainly on replacing the enzyme that is absent or deficient by means of enzyme replacement therapy, with the purpose of avoiding or removing deposits of Gb3. Chaperones can also be used for the treatment of some cases. It is considered that the specific treatment should be initiated as soon as a diagnosis is obtained, which can change the prognosis of the disease.
Assuntos
Humanos , Masculino , Feminino , Doença de Fabry/patologia , Insuficiência Renal Crônica/patologia , Terapia de Reposição de Enzimas , Rim/patologia , Triexosilceramidas , Doença de Fabry/complicações , Doença de Fabry/genética , Doença de Fabry/terapia , Insuficiência Renal Crônica/etiologiaRESUMO
Since ERT for several LSDs treatment has emerged at the beginning of the 1980s with Orphan Drug approval, patients' expectancy and life quality have been improved. Most LSDs treatment are based on the replaced of mutated or deficient protein with the natural or recombinant protein.One of the main ERT drawback is the high drug prices. Therefore, different strategies trying to optimize the global ERT biotherapeutic production have been proposed. LVs, a gene delivery tool, can be proposed as an alternative method to generate stable cell lines in manufacturing of recombinant proteins. Since LVs have been used in human gene therapy, clinical trials, safety testing assays and procedures have been developed. Moreover, one of the main advantages of LVs strategy to obtain manufacturing cell line is the short period required as well as the high protein levels achieved.In this chapter, we will focus on LVs as a recombinant protein production platform and we will present a case study that employs LVs to express in a manufacturing cell line, alpha-Galactosidase A (rhαGAL), which is used as ERT for Fabry disease treatment.