RESUMO
Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.
Assuntos
Condroitina Sulfatases , Mucopolissacaridoses , Mucopolissacaridose I , Mucopolissacaridose VI , Condroitina Sulfatases/genética , Variações do Número de Cópias de DNA , Humanos , Irã (Geográfico)/epidemiologia , Mucopolissacaridoses/diagnóstico , Mucopolissacaridoses/genética , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/genética , Mucopolissacaridose VI/genéticaRESUMO
Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.
Assuntos
Obstrução das Vias Respiratórias/terapia , Pneumopatias Obstrutivas/terapia , Mucopolissacaridose I/terapia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Obstrução das Vias Respiratórias/complicações , Obstrução das Vias Respiratórias/epidemiologia , Obstrução das Vias Respiratórias/patologia , Monóxido de Carbono/metabolismo , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Pneumopatias Obstrutivas/complicações , Pneumopatias Obstrutivas/epidemiologia , Pneumopatias Obstrutivas/patologia , Masculino , Pessoa de Meia-Idade , Mucopolissacaridose I/complicações , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/patologia , Adulto JovemRESUMO
Mucopolysaccharidosis type I (MPS I)/Hurler syndrome newborn screening was added to the recommended uniform screening panel (RUSP) in 2016. As states have added screening for MPS I, programs have reported increased rates of false positives. Reasons for false positive screens include carrier status, true false positive, late-onset/attenuated forms, and in about half of cases, pseudodeficiency alleles. These alleles have DNA variants that can cause falsely decreased enzyme activity on biochemical enzyme studies and have increased frequency in individuals of African American and African descent. We describe the District of Columbia (DC) experience with MPS I screening from December 2017 to February 2019. In the context of a review of the literature on newborn screening and family experiences and this DC-based experience, we offer potential solutions to address preliminary concerns regarding this screening. The impact of overrepresentation of screen positives in a minority group and unintentional creation of health disparities and community wariness regarding medical genetics evaluations must be considered to improve the newborn screen programs nationally and internationally.
Assuntos
Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/epidemiologia , Triagem Neonatal , Negro ou Afro-Americano/genética , Alelos , Teste em Amostras de Sangue Seco , Etnicidade/genética , Feminino , Humanos , Recém-Nascido , Masculino , Mucopolissacaridose I/genética , Mucopolissacaridose I/patologiaRESUMO
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
Several studies have been published on the frequency of the mucopolysaccharidoses (MPS) in different countries. The objective of the present study was to estimate the birth prevalence (BP) of MPS in Brazil. MPS diagnosis registered at MPS-Brazil Network and in Instituto Vidas Raras were reviewed. BP was estimated by (a) the number of registered patients born between 1994 and 2015 was divided by the number of live births (LBs), and (b) a sample of 1,000 healthy individuals was tested for the most frequent variant in IDUA gene in MPS I (p.Trp402Ter) to estimate the frequency of heterozygosity and homozygosity. (a) The BP based on total number of LBs was (cases per 100,000 LBs): MPS overall: 1.25; MPS I: 0.24; MPS II: 0.37; MPS III: 0.21; MPS IV: 0.14; MPS VI: 0.28; MPS VII: 0.02. (b) The overall frequency of p.Trp402Ter was 0.002. Considering the frequency of heterozygotes for the p.Trp402Ter IDUA variant in the RS state, the frequency of this variant among MPS I patients and the relative frequency of the different MPSs, we estimated the birth prevalence of MPS in total and of each MPS type, as follows: MPS overall: 4.62; MPS I: 0.95; MPS II: 1.32; MPS III: 0.56; MPS IV: 0.57; MPS VI: 1.02; MPS VII: 0.05. This study provided original data about BP and relative frequency of the MPS types, in Brazil, based on the frequency of the commonest IDUA pathogenic variant and in the records of two large patient databases.
Assuntos
Iduronidase/genética , Mucopolissacaridoses/genética , Brasil/epidemiologia , Feminino , Humanos , Iduronidase/sangue , Nascido Vivo , Masculino , Mucopolissacaridoses/sangue , Mucopolissacaridoses/epidemiologia , Mucopolissacaridoses/patologia , Mucopolissacaridose I/sangue , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/genética , Mucopolissacaridose II/sangue , Mucopolissacaridose II/epidemiologia , Mucopolissacaridose II/genética , Mucopolissacaridose III/sangue , Mucopolissacaridose III/epidemiologia , Mucopolissacaridose III/genética , Mucopolissacaridose VI/sangue , Mucopolissacaridose VI/epidemiologia , Mucopolissacaridose VI/genética , Mutação/genéticaRESUMO
OBJECTIVE: To evaluate the initial cutoff values, rates of screen positives, and genotypes for the large-scale newborn screening program for multiple mucopolysaccharidoses (MPS) in Taiwan. STUDY DESIGN: More than 100 000 dried blood spots were collected consecutively as part of the national Taiwan newborn screening programs. Enzyme activities were measured by tandem mass spectrometry from dried blood spot punches. Genotypes were obtained when a second newborn screening specimen again had a decreased enzyme activity. Additional clinical evaluation was then initiated based on enzyme activity and/or genotype. RESULTS: Molecular genetic analysis for cases with low enzyme activity revealed 5 newborns with pathogenic alpha-L-iduronidase mutations, 3 newborns with pathogenic iduronate-2-sulfatase mutations, and 1 newborn was a carrier of an arylsulfatase B mutation. Several variants of unknown pathogenic significance were also identified, most likely causing pseudodeficiency. CONCLUSIONS: The highly robust tandem mass spectrometry-based enzyme assays for MPS-I, MPS-II, and MPS-VI allow for high-throughput newborn screening for these lysosomal storage disorders. Optimized cutoff values combined with second tier testing could largely eliminate false-positive results. Accordingly, newborn screening for these lysosomal storage disorders is possible.
Assuntos
Mucopolissacaridose II/diagnóstico , Mucopolissacaridose IV/diagnóstico , Mucopolissacaridose I/diagnóstico , Triagem Neonatal/métodos , Espectrometria de Massas em Tandem/métodos , Teste em Amostras de Sangue Seco/métodos , Testes Genéticos/métodos , Humanos , Recém-Nascido , Morbidade/tendências , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/genética , Mucopolissacaridose II/epidemiologia , Mucopolissacaridose II/genética , Mucopolissacaridose IV/epidemiologia , Mucopolissacaridose IV/genética , Reprodutibilidade dos Testes , Estudos Retrospectivos , Taiwan/epidemiologiaRESUMO
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Iduronidase/genética , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/genética , Mutação , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética/métodos , Genótipo , Saúde Global , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mucopolissacaridose I/epidemiologia , Fenótipo , Sistema de Registros , Índice de Gravidade de Doença , Adulto JovemRESUMO
Mucopolysaccharidosis Type I (MPS I), caused by deficiency of α-L-iduronidase results in progressive, multisystemic disease with a broad phenotypic spectrum including patients with severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) disease. Disordered growth is common with either phenotype. The study objectives were to construct sex- and age-specific estimated length/height and head circumference growth curves for untreated individuals with severe and attenuated disease and compare them with clinical reference standards. Untreated individuals in the MPS I Registry with at least one observation for length/height and/or head circumference and assigned phenotype as of May 2017 were included. Median growth for 463 untreated individuals with severe disease deviated from reference growth curves by ~6 months of age and fell below the third percentile by 4 years of age. Median head circumference was above reference curves from 3 to 4 months through 3 years of age. Among 207 individuals with untreated attenuated disease, median height fell below the third percentile by 9 years of age with divergence from reference curves by 2 years of age. MPS I-specific growth curves will be useful in evaluation of long-term outcomes of therapeutics interventions and will provide a foundation for understanding the pathogenesis of skeletal disease in MPS I.
Assuntos
Gráficos de Crescimento , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/genética , Fenótipo , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/terapia , Vigilância da População , Sistema de RegistrosRESUMO
Mucopolysaccharidosis type I (MPS I) is a rare disorder caused by deleterious sequence variants in the α-L-iduronidase (IDUA) gene. More than 200 pathogenic variants have been described so far, but their frequencies have not yet been analyzed on a worldwide scale. To address this, we analyzed the genotypes of MPS I patients from 35 published studies papers. The most common pathogenic variant observed was p.Trp402Ter. With frequencies of up to 63%, it was the major allele in most European countries, America and Australia. The variant p.Gln70Ter was also frequent; it was found mainly in Northern and Eastern Europe. The most frequent variant in North African countries was p.Pro533Arg; in Morocco, it represented more than 90% of mutant alleles. Variants observed in East Asians were not found in Western populations, including c.1190-1G>A, p.Ala79Val, p.Leu346Arg and c.613_617dupTGCTC. Conversely, p.Trp402Ter and p.Pro533Arg were not found in patients from East Asia. In conclusion, the most common pathogenic IDUA variant in MPS I patients are p.Trp402Ter, p.Gln70Ter and p.Pro533Arg. Knowledge about the genetic background of MPS I for each population is essential when developing new genotype-targeted therapies, as well as to enable faster genetic analysis and improve patient management.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Iduronidase/genética , Alelos , Substituição de Aminoácidos , Frequência do Gene , Genótipo , Saúde Global , Humanos , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/genética , FenótipoRESUMO
Mucopolysaccharidosis Type I (MPS I) is a lysosomal storage disorder with varying degrees of phenotypic severity caused by mutations in IDUA. Over 200 disease-causing variants in IDUA have been reported. We describe the profile of disease-causing variants in 291 individuals with MPS I for whom IDUA sequencing was performed, focusing on the UK subset of the cohort. A total of 63 variants were identified, of which 20 were novel, and the functional significance of the novel variants is explored. The severe form of MPS I is treated with hematopoietic stem cell transplantation, known to have improved outcomes with earlier age at treatment. Developing genotype-phenotype relationships would therefore have considerable clinical utility, especially in the light of the development of newborn screening programs for MPS I. Associations between genotype and phenotype are examined in this cohort, particularly in the context of the profile of variants identified in UK individuals. Relevant associations can be made for the majority of UK individuals based on the presence of nonsense or truncating variants as well as other associations described in this report.
Assuntos
Estudos de Associação Genética , Iduronidase/genética , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/genética , Mutação , Alelos , Ativação Enzimática , Genótipo , Humanos , Iduronidase/metabolismo , Mucopolissacaridose I/epidemiologia , Fenótipo , Análise de Sequência de DNA , Índice de Gravidade de Doença , Reino Unido/epidemiologiaRESUMO
The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively. A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS is also reported to be higher in these countries. Birth prevalence of MPS II in Switzerland and other European countries is comparatively lower. The birth prevalence of MPS III and IV in Switzerland is higher than in Japan but comparable to that in most other European countries. Moreover, the birth prevalence of MPS VI and VII was very low in both, Switzerland and Japan. Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of MPS, as seen for other rare genetic diseases. Methods for identification of MPS patients are not uniform across all countries, and consequently, if patients are not identified, recorded prevalence rates will be aberrantly low.
Assuntos
Mucopolissacaridoses/epidemiologia , Coleta de Dados , Europa (Continente)/epidemiologia , Alemanha/epidemiologia , Glicosaminoglicanos/urina , Humanos , Incidência , Japão/epidemiologia , Mucopolissacaridoses/classificação , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose II/epidemiologia , Mucopolissacaridose III/epidemiologia , Mucopolissacaridose VI/epidemiologia , Países Baixos/epidemiologia , Prevalência , Estudos RetrospectivosRESUMO
Mucopolysaccharidosis type I-Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation (HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I/terapia , Adolescente , Adulto , Criança , Desenvolvimento Infantil , Pré-Escolar , Cognição , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/fisiopatologia , Mucopolissacaridose I/psicologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Mucopolissacaridose I/terapia , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/mortalidade , Agonistas Mieloablativos/efeitos adversos , Estudos Retrospectivos , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/métodos , Condicionamento Pré-Transplante/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: In this study, we aimed to describe the natural history of mucopolysaccharidosis I. METHODS: Data from 1,046 patients who enrolled in the MPS I Registry as of August 2013 were available for descriptive analysis. Only data from untreated patients and data prior to treatment for patients who received treatment were considered. Age at symptom onset, diagnosis, and treatment initiation were examined by geographic region and phenotype (from most to least severe: Hurler, Hurler-Scheie, and Scheie). For each symptom, frequency and age at onset were examined. RESULTS: Natural history data were available for 987 patients. Most patients were from Europe (45.5%), followed by North America (34.8%), Latin America (17.3%), and Asia Pacific (2.4%). Phenotype distribution was 60.9% for Hurler, 23.0% for Hurler-Scheie, and 12.9% for Scheie (3.2% undetermined) syndromes. Median age at symptom onset for Hurler, Hurler-Scheie, and Scheie syndromes was 6 months, 1.5 years, and 5.3 years, respectively; median age at treatment initiation was 1.5 years, 8.0 years, and 16.9 years, respectively. Coarse facial features and corneal clouding were among the most common symptoms in all three phenotypes. CONCLUSION: A delay between symptom onset and treatment exists, especially in patients with attenuated mucopolysaccharidosis I. A better understanding of disease manifestations may help facilitate prompt diagnosis and treatment and improve patient outcomes.
Assuntos
Estudos de Associação Genética , Mucopolissacaridose I/genética , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Idade de Início , Ásia/epidemiologia , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Genótipo , Humanos , Lactente , América Latina/epidemiologia , Masculino , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/terapia , América do Norte/epidemiologia , Fenótipo , PrevalênciaRESUMO
BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by the deficiency of hydrolases involved in the degradative pathway of glycosaminoglycans. In MPS, upper airway obstruction may result from multiple causative factors which may impact severely upon morbidity and mortality. METHODS: We evaluated upper airway obstructive disease and related clinical findings through home sleep study in 19 patients (11 with MPS VI, 4 with MPS I, 4 with MPS II) with MPS followed at Gazi University Pediatric Metabolic Unit. Patients underwent home-based sleep measurements, and sleep respiratory problems were asked in a detailed clinical history. Measurements of apnea, apnea-hypopnea index (AHI), hypopnea index, oxygen desaturation index, and minimal oxygen saturation were obtained through home sleep study. RESULTS: For 19 children, the disorder was normal in 1, mild (AHI=1.5-5/h) in 5, moderate (AHI=5-10/h) in 2, and severe (AHI>10/h) in 11. The prevalence of OSA was 94.7 % (18/19) in patients with MPS. Snoring, witnessed apnea, pectus carinatum, and macroglossia were the main clinical findings. Echocardiograms showed evidence of pulmonary hypertension in 13 patients. CONCLUSION: Home sleep study is a quick and accessible screening test to determine the abnormalities of breathing during sleep and enables clinicians to take necessary action for patients with severe manifestations.
Assuntos
Serviços de Assistência Domiciliar , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/epidemiologia , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose VI/diagnóstico , Mucopolissacaridose VI/epidemiologia , Polissonografia , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Adolescente , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Programas de Rastreamento , Polissonografia/instrumentação , TurquiaRESUMO
PURPOSE: Mucopolysaccharidosis (MPS) encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans in organs and tissues. Respiratory disorders occur in all MPS types. In these patients, the prevalence of obstructive sleep apnea syndrome (OSAS), which may confer additional morbidity, remains overlooked, and the results of the few existing studies are controversial. The present study aimed to characterize the prevalence of OSAS in patients with MPS types I, II, and VI in a reference center. METHODS: Forty-five patients with MPS (I, n=17; II, n=16; and VI; n=12) in the Centro de Referência em Erros Inatos do Metabolismo, who underwent full-night polysomnography, were enrolled in a retrospective study. Demographic data and clinical history were collected from medical records of the first medical consultation. RESULTS: The prevalence of OSAS in patients with MPS was 69.8%. MPS type I patients seemed to be more susceptible to OSA-induced hypoxemia, as indicated by reduced mean SpO2 levels during both NREM and rapid eye movement sleep as well as during SpO2 nadir. CONCLUSIONS: Patients with MPS displayed a high prevalence of OSAS, often with moderate to high severity. Together, our results reinforce the need for OSAS screening in all patients with MPS.
Assuntos
Mucopolissacaridose II/epidemiologia , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose VI/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Adolescente , Brasil , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose VI/diagnóstico , Polissonografia , Estudos Retrospectivos , Apneia Obstrutiva do Sono/diagnóstico , Adulto JovemRESUMO
Posterior fossa "horns" caused by internal hypertrophy of the occipitomastoid sutures are one of the more recently defined cranial abnormalities described in mucopolysaccharidoses, especially in Hurler Syndrome. However, details of this finding, including the development and natural history, are not well-understood. Two hundred eighty-six brain MR imaging studies of 61 patients with mucopolysaccharidosis I-Hurler syndrome treated at single institution between 1996 and 2015 were studied. Posterior fossa horn height was measured as the perpendicular distance from the tip of the horn to the expected curvature of the occipital inner table. Fifty-seven of the 61 patients (93.4%) had evidence of posterior fossa horns on at least one occasion. The initial average height of the right horn was 4.5 mm, and the left horn, 4.7 mm. Most of the posterior horns regressed before transplantation in our cohort, though the exact age was variable among the patients. Nearly all patients in our cohort had posterior fossa horns, and these horns regressed with age. The regression of the horns frequently started before transplantation. This trend has not been previously described, and it may suggest unknown effects of mucopolysaccharidosis on skull development.
Assuntos
Mucopolissacaridose I , Humanos , Mucopolissacaridose I/complicações , Mucopolissacaridose I/epidemiologia , Prevalência , Crânio , Encéfalo , Cabeça , Fossa Craniana Posterior/diagnóstico por imagemRESUMO
Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder characterized by the deficiency of the alpha-L-iduronidase enzyme necessary for the degradation of glycosaminoglycans (GAG) in the lysosome. Hurler syndrome is the most severe form of MPS I, manifesting as multiorgan dysfunction, cognitive delay, and death, usually within ten years if left untreated. Hematopoietic stem cell transplantation (HSCT) is the optimal treatment option, providing a permanent solution to enzyme deficiency and halting cognitive decline; however, the HSCT complications transplantation-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD) are known risk factors for bloodstream infection (BSI). BSI is a serious complication of HSCT, contributing to poor outcomes and transplantation-related morbidity. There are little data evaluating BSI after HSCT in the Hurler syndrome population. We performed a retrospective analysis of patients with Hurler syndrome who underwent HSCT at our center between 2013 and 2020 to determine the incidence of BSI within the first year post-transplantation. Patient BSI data were collected through the first year post-HSCT. Variables including patient demographics and transplantation-related characteristics were collected, including information on BSI and mortality. Twenty-five patients with a total of 28 HSCTs were included in the analysis; the majority (n = 17; 68%) were male, with a median age of 1.1 years (interquartile range, .35 to 1.44 years) at the time of transplantation. The most common graft source was cord blood (n = 15; 54%), followed by bone marrow (n = 13; 46%), with the majority from matched unrelated donors (n = 14; 52%) and mismatched unrelated donors (n = 13; 44%). Sixteen BSIs were diagnosed in 12 patients (48%). Most infections (n = 7; 43.8%) were diagnosed in the first 20 days post-transplantation, with fewer infections observed at later time points. Seven of the 9 Hurler patients diagnosed with TA-TMA (78%) also had a BSI. The incidence rate of BSIs in Hurler patients (n = 12; 48%) was higher than the rates reported in the general pediatric HSCT population at 1-year post-transplantation (15% to 35%). Given the high rate of both TA-TMA and a BSI in Hurler patients, we suspect a possible correlation between the 2. Additionally, due to the time it takes for GAG levels to normalize post-HSCT in Hurler patients, it is reasonable to suspect that the high BSI rates in these patients are linked to their Hurler diagnosis. These findings bring awareness to possible disease-related factors contributing to high BSI rates in the Hurler population post-HSCT.
Assuntos
Doenças Transmissíveis , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Sepse , Humanos , Masculino , Criança , Feminino , Mucopolissacaridose I/complicações , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/terapia , Incidência , Estudos Retrospectivos , Doenças Transmissíveis/etiologia , Sepse/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodosRESUMO
OBJECTIVE: Hurler Syndrome, (MPSIH) is an inborn error of glycosaminoglycan metabolism. Haematopoietic stem cell transplantation (HSCT) has transformed the prognosis for these children. Prior to transplant patients receive chemotherapy or chemo-radiotherapy. Regular screening for the development of endocrine sequelae is therefore essential. We present for the first time data on final adult height and endocrine complications in children with MPSIH post HSCT. DESIGN: Retrospective case note study and a prospective programme of growth and endocrine assessment. PATIENTS: 22 patients were included, mean age at last assessment 12.2 (Range 6.3-21.6) years. Mean age at HSCT was 1.3 (SD 0.6) years. Conditioning included mostly busulphan and cyclophosphamide, with 5 patients receiving total body irradiation prior to second transplant. RESULTS: Height SDS decreased over time. Final height (FH) was attained in seven patients with male FH SDS -4.3 (Range -3.8, -5.1) and female FH SDS -3.4 (Range -2.9, -5.6). Eight of 13 patients tested had evidence of high growth hormone (GH) levels, while one had GH deficiency. Adrenal and thyroid function was normal in all. 11 patients were pubertal or post pubertal. Two females had pubertal failure requiring intervention. All male patients had spontaneous, complete puberty; however three patients have reduced testicular volumes. Five out of 13 patients tested had an abnormal oral glucose tolerance test. CONCLUSION: Growth is impaired, primarily related to skeletal dysplasia, but also associated with GH resistance. Pubertal development may be compromised and abnormalities of glucose metabolism are common. We recommend a structured endocrine surveillance programme for these patients.
Assuntos
Mucopolissacaridose I/genética , Mucopolissacaridose I/metabolismo , Adolescente , Adulto , Estatura , Bussulfano/farmacologia , Criança , Ciclofosfamida/farmacologia , Sistema Endócrino , Doenças do Sistema Endócrino/complicações , Feminino , Teste de Tolerância a Glucose , Glicosaminoglicanos/metabolismo , Humanos , Masculino , Mucopolissacaridose I/epidemiologia , Estudos Retrospectivos , Condicionamento Pré-Transplante , Reino UnidoRESUMO
BACKGROUND: Mucopolysaccharidosis I (MPS I) comprises a spectrum of clinical manifestations and is divided into three phenotypes reflecting clinical severity: Hurler, Hurler-Scheie, and Scheie syndromes. There may be important variations in clinical manifestations of this genetic disease in patients residing in different regions of the world. METHODS: Using data from the MPS I Registry (as of September 2009), we evaluated patients from Latin America (n = 118) compared with patients from the rest of the world [ROW (n = 727)]. RESULTS: Phenotype distribution differed among patients in Latin America compared to ROW (Hurler 31 vs. 62%, Hurler-Scheie 36 vs. 21%, Scheie 10 vs. 11%, and unknown 22 vs. 6%). The frequency of certain symptoms, such as cardiac valve abnormalities, sleep impairment, and joint contractures, also differed between Latin America and ROW for some phenotypes. Median age at MPS I diagnosis was earlier in the ROW than Latin America for all phenotypes, and age at first treatment for Hurler and Hurler-Scheie patients was also earlier in the ROW. Hurler patients in Latin America showed a gap of 3.1 years between median ages of diagnosis and first treatment compared to only 0.5 years in the ROW. Treatment allocation in Latin America compared to ROW was as follows: enzyme replacement therapy (ERT) only, 80 vs. 45%; hematopoietic stem cell transplantation (HSCT) only, 0.9 vs. 27%; both ERT and HSCT, 0 vs. 16%; and neither treatment, 19 vs. 13%. CONCLUSION: These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices.