RESUMO
INTRODUCTION: Lysosomal storage disorders and peroxisomal disorders are rare diseases caused by the accumulation of substrates of the metabolic pathway within lysosomes and peroxisomes, respectively. Owing to the rarity of these diseases, the prevalence of lysosomal storage disorders and peroxisomal disorders in Japan is unknown. Therefore, we conducted a nationwide survey to estimate the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. METHODS: A nationwide survey was conducted following the "Manual of nationwide epidemiological survey for understanding patient number and clinical epidemiology of rare diseases (3rd version)". A questionnaire asking for detailed information, such as disease phenotypes and medical history, was created and sent to 504 institutions with doctors who have experience in treating patients with lysosomal storage disorders and peroxisomal disorders. Result A total of 303 completed questionnaires were collected from 504 institutions (response rate: 60.1%). The number of patients was estimated by calculating the rate/frequency of overlap. The estimated number of patients was 1658 (±264.8) for Fabry disease, 72 (±11.3) for mucopolysaccharidosis I, 275 (±49.9) for mucopolysaccharidosis II, 211 (±31.3) for Gaucher disease, 124 (±25.8) for Pompe disease, 83 (±44.3) for metachromatic leukodystrophy, 57 (±9.4) for Niemann-Pick type C, and 262 (±42.3) for adrenoleukodystrophy. In addition the birth prevalence was calculated using the estimated number of patients and birth year data for each disease, and was 1.25 for Fabry disease, 0.09 for mucopolysaccharidosis I, 0.38 for mucopolysaccharidosis II, 0.19 for Gaucher disease, 0.14 for Pompe disease, 0.16 for metachromatic leukodystrophy, 0.16 for Niemann-Pick type C, and 0.20 for adrenoleukodystrophy. DISCUSSION: Among the diseases analyzed, the disease with the highest prevalence was Fabry disease, followed by mucopolysaccharidosis II, adrenoleukodystrophy, Gaucher disease and metachromatic leukodystrophy. In particular, the high prevalence of mucopolysaccharidosis II and Gaucher disease type II was a feature characteristic of Japan. CONCLUSION: We estimated the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. The details of the age at diagnosis and treatment methods for each disease were clarified, and will be useful for the early diagnosis of these patients and to provide appropriate treatments. Furthermore, our results suggest that supportive care and the development of an environment that can provide optimal medical care is important in the future.
Assuntos
Monitoramento Epidemiológico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/epidemiologia , Transtornos Peroxissômicos/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Doenças por Armazenamento dos Lisossomos/classificação , Doenças por Armazenamento dos Lisossomos/terapia , Masculino , Pessoa de Meia-Idade , Triagem Neonatal , Transtornos Peroxissômicos/sangue , Transtornos Peroxissômicos/diagnóstico , Prevalência , Inquéritos e Questionários , Adulto JovemRESUMO
Mucopolysaccharidoses (MPS) are a subtype of lysosomal storage disorders (LSDs) characterized by the deficiency of the enzyme involved in the breakdown of glycosaminoglycans (GAGs). Mucopolysaccharidosis type I (MPS I, Hurler Syndrome) was endorsed by the U.S. Secretary of the Department of Health and Human Services for universal newborn screening (NBS) in February 2016. Its endorsement exemplifies the need to enhance the accuracy of diagnostic testing for disorders that are considered for NBS. The progression of MPS disorders typically incudes irreversible CNS involvement, severe bone dysplasia, and cardiac and respiratory issues. Patients with MPS have a significantly decreased quality of life if untreated and require timely diagnosis and management for optimal outcomes. NBS provides the opportunity to diagnose and initiate treatment plans for MPS patients as early as possible. Most newborns with MPS are asymptomatic at birth; therefore, it is crucial to have biomarkers that can be identified in the newborn. At present, there are tiered methods and different instrumentation available for this purpose. The screening of quick, cost-effective, sensitive, and specific biomarkers in patients with MPS at birth is important. Rapid newborn diagnosis enables treatments to maximize therapeutic efficacy and to introduce immune tolerance during the neonatal period. Currently, newborn screening for MPS I and II has been implemented and/or in pilot testing in several countries. In this review article, historical aspects of NBS for MPS and the prospect of newborn screening for MPS are described, including the potential tiers of screening.
Assuntos
Doenças por Armazenamento dos Lisossomos/diagnóstico , Mucopolissacaridoses/diagnóstico , Mucopolissacaridose I/diagnóstico , Triagem Neonatal , Glicosaminoglicanos , Humanos , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/patologia , Mucopolissacaridoses/epidemiologia , Mucopolissacaridoses/genética , Mucopolissacaridoses/patologia , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/genética , Mucopolissacaridose I/patologia , Qualidade de Vida , Espectrometria de Massas em TandemRESUMO
AIMS: As of 2016, there were five patients with Pompe in Slovenia (two infantile, one childhood and two adult onset) with a prevalence of 1:400 000; however, the prevalence of late-onset Pompe disease (LOPD) in some other countries means this ratio could be an underestimate. Since an LOPD muscle biopsy could be unspecific or even normal, the purpose of this study is to assess the prevalence of LOPD in patients with non-diagnostic muscle biopsies. METHODS: Six hundred biopsies were recorded at the Neuromuscular Tissue Bank of the University of Ljubljana for the period 2004-2014. All adult patients with non-diagnostic muscle biopsies were invited to the National Slovenian Neuromuscular Centre for dried blood spot testing for LOPD. RESULTS: A total of 90 patients (56% of those invited) responded. No patient with LOPD was found. A total of 49 patients (54%) had fixed muscle weakness, 31 (34%) had mild symptoms and no weakness and 10 (11%) had asymptomatic hyperCKemia. Ventilatory insufficiency associated with proximal muscle weakness was found in two patients (2%). No patients exhibited vacuolar myopathy, globular accumulations of glycogen or regions of increased acid phosphatase activity within the sarcoplasm. CONCLUSIONS: The study results do not support the hypothesis that LOPD is underestimated in Slovenian patients with non-diagnostic muscle biopsies; this could be consistent with the fact that LOPD is of low prevalence in Slovenia, as is the case in the populations of Finland, French-speaking Belgium, west Sweden and west Denmark.
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Doença de Depósito de Glicogênio Tipo II/diagnóstico , Transtornos de Início Tardio/diagnóstico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças Musculares/diagnóstico , Adulto , Idoso , Biópsia , Feminino , Doença de Depósito de Glicogênio Tipo II/enzimologia , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Transtornos de Início Tardio/patologia , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/patologia , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Doenças Musculares/epidemiologia , Doenças Musculares/patologia , Prevalência , Estudos Prospectivos , Eslovênia/epidemiologia , Adulto JovemRESUMO
Lysosomal storage diseases (LSDs) are a group of over 70 diseases that are characterized by lysosomal dysfunction, most of which are inherited as autosomal recessive traits. These disorders are individually rare but collectively affect 1 in 5,000 live births. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most LSDs have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. LSD-associated genes encode different lysosomal proteins, including lysosomal enzymes and lysosomal membrane proteins. The lysosome is the key cellular hub for macromolecule catabolism, recycling and signalling, and defects that impair any of these functions cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, 'storage') or impair the transport of molecules, which can result in cellular damage. Consequently, the cellular pathogenesis of these diseases is complex and is currently incompletely understood. Several LSDs can be treated with approved, disease-specific therapies that are mostly based on enzyme replacement. However, small-molecule therapies, including substrate reduction and chaperone therapies, have also been developed and are approved for some LSDs, whereas gene therapy and genome editing are at advanced preclinical stages and, for a few disorders, have already progressed to the clinic.
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Doenças por Armazenamento dos Lisossomos/genética , Doença de Fabry/epidemiologia , Doença de Fabry/genética , Doença de Gaucher/epidemiologia , Doença de Gaucher/genética , Doença de Depósito de Glicogênio Tipo II/epidemiologia , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Leucodistrofia Metacromática/epidemiologia , Leucodistrofia Metacromática/genética , Doenças por Armazenamento dos Lisossomos/epidemiologia , Proteínas/análiseRESUMO
BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of α-galactosidase A and the resulting accumulation of the glycosphingolipid globotriaosylceramide (Gb3) and its derivatives, including globotriaosylsphingosine (Lyso-Gb3). Increased cellular and plasma levels of Gb3 and Lyso-Gb3 affect multiple organs, with specific clinical consequences for the kidneys, heart and brain. There is growing evidence that alterations in glycosphingolipids may have an oncogenic role and this prompted a review of cases of cancer and benign lesions in a large single centre cohort of Fabry patients. We also explored whether there is a difference in the risk of cancer in Fabry patients compared to the general population. RESULTS: Our results suggest that Fabry patients may have a marginally reduced rate of all cancer (incidence rate ratio 0.61, 95% confidence interval 0.37 to 0.99) but possibly increased rates of melanoma, urological malignancies and meningiomas. CONCLUSION: Greater knowledge and awareness of cancer in patients with Fabry disease may help identify at-risk individuals and elucidate cancer mechanisms in this rare inherited disease, which may potentially be relevant to the wider cancer population.
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Doença de Fabry/epidemiologia , Neoplasias/epidemiologia , Adulto , Intervalos de Confiança , Doença de Fabry/complicações , Feminino , Humanos , Incidência , Doenças por Armazenamento dos Lisossomos/complicações , Doenças por Armazenamento dos Lisossomos/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Inquéritos e QuestionáriosRESUMO
Patients with lysosomal storage diseases (LSDs) suffer from physical and mental disabilities, which together with poor access to professional care may lead to impaired oral health. This cross-sectional case-control study characterized the status of oral health in patients with LSDs in Poland. Thirty-six children and young adults with various forms of LSDs were examined. The data were compared with those from age- and sex-matched healthy controls. Exemplary cases were presented to highlight typical problems in oral care associated with LSDs. When possible, saliva was collected and analyzed for total protein, inflammatory mediators, and antioxidant status. Generally, patients with LSDs had significantly higher prevalence of caries, inferior gingival status, and inadequate oral hygiene. The severity of oral health impairment in mucopolysaccaridoses, the most common LSD in Poland, was similar to that seen in patients with mannosidoses or Pompe disease. Saliva could be collected only from few less handicapped patients. In MPS, it did not appear to differ significantly from the controls, but in patients with Pompe disease it contained lower concentrations of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1), but higher levels of tumor necrosis factor receptors 1 and 2 (TNF-R1, TNF-R2) and myeloperoxidase (MPO). In conclusion, Polish patients with LSDs have an inadequate level of oral hygiene and substantially deteriorated oral health.
Assuntos
Cárie Dentária/etiologia , Nível de Saúde , Doenças por Armazenamento dos Lisossomos/complicações , Doenças por Armazenamento dos Lisossomos/epidemiologia , Saúde Bucal , Saliva/química , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Higiene Bucal , Polônia/epidemiologia , Prevalência , Adulto JovemAssuntos
Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/patologia , Lisossomos/enzimologia , Lisossomos/patologia , Transplante de Medula Óssea , Doença de Gaucher/epidemiologia , Humanos , Doenças por Armazenamento dos Lisossomos/enzimologia , Doenças por Armazenamento dos Lisossomos/terapiaRESUMO
Lysosomal storage diseases (LSDs) are an individually rare but collectively common group of hereditary, progressive, multi-systemic disorders. Recent technological advances have brought newborn screening (NBS) for LSDs to attention in the United States. However, many LSD symptoms present in later childhood or adulthood, with a wide spectrum of severity. Because late-onset symptoms stray from the traditional NBS model, healthcare providers have expressed concerns about potential harm to patients and/or their families. In this study, 47 individuals with Fabry disease (FD), 22 with Gaucher disease (GD), and 22 with late-onset Pompe disease (LOPD) were surveyed regarding how their life might have been impacted by NBS. Of the 91 participants, none had symptoms at birth and 42 (46.7%) were symptom-free until adulthood. Over half (52.8%) were diagnosed ≥5years from symptom onset; of these, significantly more had FD (60%) or LOPD (63.6%) than GD (23.8%). However, length of diagnostic odyssey was not significantly correlated with opinion on NBS. Most participants either strongly agreed (45%) or agreed (33.3%) with NBS for their condition, with no significant differences between diseases. Opinions on NBS were correlated with participants' opinions on whether NBS would have resulted in better current health, but uncorrelated with disease severity or current life satisfaction. Significantly more participants with FD (42.6%) and LOPD (63.6%) than GD (13.6%) felt they would have greater life satisfaction had they been diagnosed as a newborn (p=0.007). Almost half (41%) of participants would have made different life decisions, including lifestyle, financial, and reproductive decisions. Regarding potential harm, participants were most concerned about insurability and least concerned about removal of children's autonomy. In conclusion, NBS is highly approved of among individuals with LSDs themselves, as it would significantly eliminate diagnostic odysseys and potentially alter life planning.
Assuntos
Doença de Fabry/epidemiologia , Doença de Gaucher/epidemiologia , Doença de Depósito de Glicogênio Tipo II/epidemiologia , Doenças por Armazenamento dos Lisossomos/epidemiologia , Triagem Neonatal/psicologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Doença de Fabry/patologia , Doença de Fabry/psicologia , Feminino , Doença de Gaucher/patologia , Doença de Gaucher/psicologia , Doença de Depósito de Glicogênio Tipo II/patologia , Doença de Depósito de Glicogênio Tipo II/psicologia , Humanos , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/patologia , Doenças por Armazenamento dos Lisossomos/psicologia , Masculino , Pessoa de Meia-Idade , Triagem Neonatal/ética , Pacientes/psicologiaRESUMO
OBJECTIVE: To describe the spectrum, relative prevalence and molecular background of lysosomal storage disorders in Egypt. METHODS: The authors evaluated the selective screening program for the diagnosis of lysosomal storage disorders in Egyptian children presenting to the inherited metabolic disease unit at Cairo University Children's Hospital, the largest tertiary care pediatric hospital in Egypt, over a six-year period (April 2008 through April 2014). During this period, 1,065 suspected children were assessed clinically, biochemically and some genetically. RESULTS: Two hundred and eleven children (aged 44 ± 32 mo; 56 % boys, 82 % with consanguineous parents) were confirmed with 21 different lysosomal disorders. The diagnostic gap ranged between 2 mo and 14 y (average 25 mo). Mucopolysaccharidoses were the most common group of diseases diagnosed (44.5 %), while Maroteaux-Lamy, Gaucher and nephropathic cystinosis were the most commonly detected syndromes (17.1, 14.7 and 13.7 %, respectively). Eighty mutant alleles and 17 pathogenic mutations were detected in 48 genetically assessed confirmed patients (30 Gaucher, 16 cystinosis and two Niemann-Pick type C patients). CONCLUSIONS: This report is the first to describe relative frequency and spectrum of clinical and molecular data in a large cohort of Egyptian lysosomal patients. The crude estimate denotes that over 80 % of Egyptian lysosomal patients do not have access to optimal diagnosis. Upgrading diagnostic and genetic services for lysosomal storage disorders in Egypt is absolutely necessary.
Assuntos
Doenças por Armazenamento dos Lisossomos , Criança , Pré-Escolar , Estudos de Coortes , Consanguinidade , Egito/epidemiologia , Feminino , Humanos , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/genética , Masculino , PrevalênciaRESUMO
BACKGROUND: The interest in neonatal screening for lysosomal storage disorders has increased substantially because of newly developed enzyme replacement therapies, the need for early diagnosis, and technical advances. We tested for Gaucher's disease, Pompe's disease, Fabry's disease, and Niemann-Pick disease types A and B in an anonymous prospective nationwide screening study that included genetic mutation analysis to assess the practicality and appropriateness of including these disorders in neonatal screening panels. METHODS: Specimens from dried blood spots of 34,736 newborn babies were collected consecutively from January, 2010 to July, 2010, as part of the national routine Austrian newborn screening programme. Anonymised samples were analysed for enzyme activities of acid ß-glucocerebrosidase, α-galactosidase, α-glucosidase, and acid sphingomyelinase by electrospray ionisation tandem mass spectrometry. Genetic mutation analyses were done in samples with suspected enzyme deficiency. FINDINGS: All 34,736 samples were analysed successfully by the multiplex screening assay. Low enzyme activities were detected in 38 babies. Mutation analysis confirmed lysosomal storage disorders in 15 of them. The most frequent mutations were found for Fabry's disease (1 per 3859 births), followed by Pompe's disease (1 per 8684), and Gaucher's disease (1 per 17,368). The positive predictive values were 32% (95% CI 16-52), 80% (28-99), and 50% (7-93), respectively. Mutational analysis detected predominantly missense mutations associated with a late-onset phenotype. INTERPRETATION: The combined overall proportion of infants carrying a mutation for lysosomal storage disorders was higher than expected. Neonatal screening for lysosomal storage disorders is likely to raise challenges for primary health-care providers. Furthermore, the high frequency of late-onset mutations makes lysosomal storage disorders a broad health problem beyond childhood. FUNDING: Austrian Ministry of Health, Family, and Women.
Assuntos
Doenças por Armazenamento dos Lisossomos/diagnóstico , Triagem Neonatal , Áustria/epidemiologia , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Feminino , Doença de Gaucher/diagnóstico , Doença de Gaucher/genética , Glucosilceramidase/sangue , Glucosilceramidase/genética , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Incidência , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/genética , Masculino , Mutação , Doenças de Niemann-Pick/diagnóstico , Doenças de Niemann-Pick/genética , Esfingomielina Fosfodiesterase/sangue , Esfingomielina Fosfodiesterase/genética , alfa-Galactosidase/sangue , alfa-Galactosidase/genética , alfa-Glucosidases/sangue , alfa-Glucosidases/genéticaRESUMO
BACKGROUND: Lysosomal protein profiling is being developed as a high throughput method to screen populations for lysosomal storage disorders (LSD). DESIGN: 1415 blood spots from patients referred to a metabolic clinic for LSD were screened using a single multiplex assay for 14 proteins in a dried blood spot. RESULTS: All patients with Pompe disease, metachromatic leukodystrophy, and mucopolysaccharidosis (MPS) type I, IIIA, IIIB and VI were identified by reduced lysosomal protein. Five samples were identified as possible pseudo-arylsulfatase A deficiency; four were confirmed. One multiple sulfatase deficiency patient was identified with multiple reduced sulfatase proteins. There were 10 MPS II patients identified with reduced iduronate 2-sulfatase, and one MPS II patient with iduronate 2-sulfatase in the unaffected range. For Fabry disease, 10 male patients were identified with reduced α-galactosidase and 2/6 female Fabry heterozygotes returned α-galactosidase concentrations in the male Fabry range. All 10 mucolipidosis II/III patients were identified with multiple raised proteins. For 79 blood spots with chitotriosidase >3.4mg/l, a follow-up one-plex chitotriosidase assay enabled identification of all nine Gaucher patients. CONCLUSION: This study demonstrates the sensitivity and specificity of this technology to accurately identify 99% of LSD patients, with the exception of one MPS II false negative.
Assuntos
Hexosaminidases/genética , Iduronato Sulfatase/genética , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/genética , Proteínas/genética , alfa-Galactosidase/genética , Austrália , Criança , Ensaios Enzimáticos Clínicos , Feminino , Heterogeneidade Genética , Glicosaminoglicanos/metabolismo , Hexosaminidases/sangue , Ensaios de Triagem em Larga Escala , Humanos , Iduronato Sulfatase/sangue , Imunoquímica , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/sangue , Doenças por Armazenamento dos Lisossomos/epidemiologia , Masculino , Programas de Rastreamento , Mutação , Proteínas/análise , Sensibilidade e Especificidade , alfa-Galactosidase/sangueRESUMO
Lysosomal storage diseases (LSD) are caused by monogenic mutations in genes coding for multiple aberrant proteins involved in the catabolism of complex lipids, glycosaminoglycans, oligosaccharides, or nucleic acids. The pathophysiology of the LSD is due to abnormal accumulation of non-hydrolyzed substrate in the lysosomes, affecting the architecture and function of cells, tissues and organs. Due to their genic and allelic heterogeneity the LSD present a wide clinical spectrum in severity of symptoms, evolution and age of onset. The therapeutic strategy has two goals: 1) Palliative management of symptoms (splenectomy, surgery to improve or restore joints or bones, drugs for CNS symptoms, etc.), and 2) The correction of activity of the mutant protein, the former has two approaches: A) Replacing deficient protein (bone marrow transplantation, hematopoietic stem cells or umbilical cord blood cells; replacement with recombinant enzyme and gene therapy) and B) Activate or enhanced the functionality of the mutant enzyme with therapeutic small molecules. Neither of the known treatments is able to address all aspects of these multisystemic disorders, nor cure the patients. Currently, the combination of corrective therapy (CT) with paliative therapy (PT) is the most promising strategy to solve most of the multisystem manifestations. The multidisciplinary medical care is fundamental for diagnosis, treatment and control of disease. Nanotechnology opens a promising new era in the treatment of LSD. Finally, the LSD that has CT must be included in newborn screening programs in order to implement timely treatment and prevent irreversible damage.
Assuntos
Doenças por Armazenamento dos Lisossomos/terapia , Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Terapia Combinada , Gerenciamento Clínico , Terapia de Reposição de Enzimas , Terapia Genética , Humanos , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/dietoterapia , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/genética , Chaperonas Moleculares/uso terapêutico , Triagem Neonatal , Cuidados Paliativos , Equipe de Assistência ao Paciente , Terminação Traducional da Cadeia Peptídica/efeitos dos fármacos , Dobramento de Proteína/efeitos dos fármacos , Proteínas Recombinantes/uso terapêutico , Esplenectomia , Transplante de Células-TroncoRESUMO
Two surveys were carried out to establish the status of enzyme replacement therapy (ERT) for lysosomal storage diseases in Italy. The first was a national survey covering the regional reference centres (RRCs) for these diseases; replies disclosed that 57.7% of patients are on ERT, administered almost exclusively in hospital settings (local hospital 60.7%, RRC 34.8%, home 2.6%); Italian health service procedures do not support ERT at home. The second survey was a regional survey in Lombardy, involving 48 patients (six of whom were on ERT at home). According to 40% of the patients, hospital-based ERT is disruptive, causing loss of days at school/work, stress and family issues. The patients on home therapy did not have these problems. However, 93% of patients receiving ERT in hospital perceived the advantages of greater safety, closer monitoring and more support from health professionals and experts. A total of 55% were willing to receive ERT at home, but 33% were against it. This may be the result of a lack of experience with ERT at home in Italy, or because of different opinions between family members and physicians. As international experience shows that ERT at home saves healthcare resources and improves quality of life, the issue should be raised with Italian healthcare policy makers, who should ensure nursing support for home-based ERT.
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Terapia de Reposição de Enzimas/estatística & dados numéricos , Terapia por Infusões no Domicílio/estatística & dados numéricos , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Absenteísmo , Adulto , Atitude Frente a Saúde , Criança , Terapia de Reposição de Enzimas/efeitos adversos , Terapia de Reposição de Enzimas/enfermagem , Pesquisas sobre Atenção à Saúde , Terapia por Infusões no Domicílio/efeitos adversos , Terapia por Infusões no Domicílio/enfermagem , Hospitalização/estatística & dados numéricos , Humanos , Itália/epidemiologia , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/genética , Programas Nacionais de Saúde/organização & administração , Avaliação das Necessidades , Padrões de Prática Médica/organização & administração , Gestão da SegurançaAssuntos
Técnicas de Diagnóstico Oftalmológico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Microscopia/métodos , Técnicas de Diagnóstico Oftalmológico/instrumentação , Doença de Fabry/sangue , Doença de Fabry/diagnóstico , Alemanha/epidemiologia , Humanos , Doenças por Armazenamento dos Lisossomos/sangue , Doenças por Armazenamento dos Lisossomos/epidemiologia , Programas de Rastreamento , Mucopolissacaridose I/sangue , Mucopolissacaridose I/diagnóstico , EspanhaRESUMO
Anderson-Fabry disease is a rare lysosomal storage disorder. It results from a deficiency of the lysosomal alpha-galactosidase A and leads to progressive accumulation of globotriaosylceramide in the endothelium and tissue cells of various organs. Some of the typical clinical findings such as tiredness, dry skin, myalgia and arthralgia as well as vague gastrointestinal complaints are also symptoms of hypothyroidism. Therefore, we studied the thyroid function in patients with Anderson-Fabry disease. Thyroid function was studied in 11 patients (6 female, 5 male) with Anderson-Fabry disease by measuring thyroid-stimulating hormone (TSH) and free thyroxine serum levels. Nine patients had chronic kidney disease with stage 1 and two with stage 5. Subclinical hypothyroidism (normal serum free thyroxine concentrations along with elevated serum TSH levels) was found in 4 of 11 patients (36.4%). Subclinical hypothyroidism was observed in both male and female patients as well as in patients with stage 1 and stage 5 kidney disease. Subclinical hypothyroidism is a common finding in patients with Anderson-Fabry disease, showing an excess prevalence as compared to the normal population. The high frequency seems to be relevant regarding the potential consequences of a hypothyroid state.
Assuntos
Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Hipotireoidismo/diagnóstico , Adulto , Doença de Fabry/epidemiologia , Feminino , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/complicações , Hipotireoidismo/epidemiologia , Nefropatias/complicações , Doenças por Armazenamento dos Lisossomos/complicações , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Testes de Função Tireóidea , Glândula Tireoide/patologia , Tireotropina/sangue , Tiroxina/sangueRESUMO
The AGA gene is mutated in patients with aspartylglucosaminuria (AGU), a lysosomal storage disease enriched in the Finnish population. The disease mechanism of AGU and the biochemistry and cell biology of the lysosomal aspartylglucosaminidase (AGA) enzyme are well characterized. Here, we have investigated a novel AGU mutation found in a Finnish patient. The mutation was detected as a compound heterozygote with the Finnish major mutation in the other allele. The novel point mutation, c.44T>G, causes the L15R amino acid substitution in the signal sequence of the AGA enzyme. The mutated AGA enzyme was here analyzed by over expression in BHK and COS-1 cells. The L15R AGA protein was only faintly detectable by immunofluorescence analysis and observed in the endoplasmic reticulum. Metabolic labeling and immunoprecipitation revealed only a small amount of AGA polypeptides but the specific activity of the mutant enzyme was surprisingly high, 37% of the wild type. The amino acid substitution probably affects translocation of AGA polypeptides by altering a critical hydrophobic core structure of the signal sequence. It appears that the small amounts of active enzyme are not able to reach the lysosomes thus explaining the development of AGU disease in the patient.
Assuntos
Substituição de Aminoácidos , Aspartilglucosilaminase/genética , Doenças por Armazenamento dos Lisossomos/genética , Lisossomos/enzimologia , Mutação de Sentido Incorreto , Mutação Puntual , Transporte Proteico/genética , Sequência de Aminoácidos , Animais , Aspartilglucosaminúria , Aspartilglucosilaminase/fisiologia , Células COS/enzimologia , Linhagem Celular/enzimologia , Chlorocebus aethiops , Cricetinae , Análise Mutacional de DNA , Retículo Endoplasmático/enzimologia , Finlândia/epidemiologia , Heterozigoto , Humanos , Interações Hidrofóbicas e Hidrofílicas , Doenças por Armazenamento dos Lisossomos/enzimologia , Doenças por Armazenamento dos Lisossomos/epidemiologia , Masculino , Mesocricetus , Dados de Sequência Molecular , Sinais Direcionadores de Proteínas/genética , Proteínas Recombinantes de Fusão/metabolismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
Lysosomal free sialic acid-storage diseases include the allelic disorders Salla disease (SD) and infantile sialic acid-storage disease (ISSD). The defective gene, SLC17A5, coding for the lysosomal free sialic acid transporter was recently isolated by positional cloning. In the present study, we have identified a large number of mutations in SLC17A5 in patients presenting with either Salla disease or the ISSD phenotype. We also report for the first time the exon-intron boundaries of SLC17A5. All Finnish patients with SD (n=80) had a missense mutation changing a highly conserved arginine to cysteine (R39C); 91% of them were homozygotes for this old founder mutation. The compound-heterozygote patients, with the founder mutation in only one allele, presented with a more severe phenotype than did the homozygote patients. The same R39C mutation was also found both in most of the Swedish patients with SD and in a heterozygous form in five patients from central Europe who presented with an unusually severe (intermediate) SD phenotype. Ten different mutations, including deletions, insertions, and missense and nonsense mutations, were identified in patients with the most severe ISSD phenotype, most of whom were compound heterozygotes. Our results indicate some genotype-phenotype correlation in free sialic acid-storage diseases, suggesting that the phenotype associated with the homozygote R39C mutation is milder than that associated with other mutations.
Assuntos
Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/metabolismo , Proteínas de Membrana Transportadoras/genética , Mutação/genética , Ácido N-Acetilneuramínico/metabolismo , Transportadores de Ânions Orgânicos , Simportadores , Idade de Início , Alelos , Substituição de Aminoácidos/genética , Sequência de Bases , Análise Mutacional de DNA , Éxons/genética , Finlândia/epidemiologia , Efeito Fundador , Frequência do Gene/genética , Testes Genéticos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Íntrons/genética , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/fisiopatologia , Proteínas de Membrana Transportadoras/química , Fenótipo , Reação em Cadeia da Polimerase , Conformação Proteica , RNA Mensageiro/análise , RNA Mensageiro/genética , Suécia/epidemiologiaRESUMO
Hermansky-Pudlak syndrome (HPS) is an often-fatal autosomal recessive disease in which albinism, bleeding, and lysosomal storage result from defects of diverse cytoplasmic organelles: melanosomes, platelet dense bodies, and lysosomes. HPS is the most common single-gene disorder in Puerto Rico, with an incidence of 1 in 1,800. We have identified the HPS gene by positional cloning, and found homozygous frameshifts in this gene in Puerto Rican, Swiss, Irish and Japanese HPS patients. The HPS polypeptide is a novel transmembrane protein that is likely to be a component of multiple cytoplasmic organelles and that is apparently crucial for their normal development and function. The different clinical phenotypes associated with the different HPS frameshifts we observed suggests that differentially truncated HPS polypeptides may have somewhat different consequences for subcellular function.