RESUMEN
BACKGROUND: The necessity of early treatment for lysosomal storage diseases (LSDs) has triggered the development of newborn screening for LSDs in recent years. Here we report the first 70,000 newborns screened for Mucopolysaccharidosis (MPS) type 4A (Morquio syndrome) and other LSDs by an 8-plex assay including the original 4-plex LSD screening tandem mass spectrometry (MS/MS) assay for Pompe disease, Fabry disease, Gaucher disease, and MPS I disease. METHODS: The additional reaction for MPS II, MPS 3B, MPS 4A, and MPS 6 enzymes was performed separately from the 4-plex reaction. The two reactions were quenched and extracted, then combined before carrying out a single 2-min UPLC-MS/MS analysis. RESULTS: From Mar. 2018 to Apr. 2019, 73,743 newborns were screened with the 8-plex LSD screening assay. The 8-plex assay revealed a better analytical precision than the previous 4-plex assay possibly because the 8-plex was carried out using UPLC-MS/MS. Six newborns were found to have low MPS-4A enzyme (N-acetylgalactosamine-6-sulfatase) activity and biallelic GALNS pathogenic mutations in trans; these patients are presumably affected with MPS4A, making an incidence of one in 12,291 (95% confident interval (CI): 5633-26,817). One mutation, c.857C > T (p.T286 M) of the GALNS gene, accounted 5 of the 12 mutated alleles. These newborns had immature vertebral bodies at 1 month of age, and one case was treated with elosulfase alfa 2 mg/kg/week starting from 4 months of age. Among other MPSs screened, one case of MPS I, 3 cases of MPS II, and 3 cases of MPS 3B were detected. One case of mucolipidosis type III was also diagnosed. In conjunction with another 9 patients of Pompe disease, Gaucher disease, and classical Fabry disease, making an incidence of LSDs as one in 3206 newborns (95% CI: 2137 - 4811). The one with infantile-onset Pompe disease and the one with Gaucher disease were treated since the age of 8 days and 41 days respectively. CONCLUSIONS: Routine newborn screening of MPS 4A and other LSDs were made possible by the 8-plex LSD screening assay. However, detailed phenotype prediction and the time to start treatment will need further elucidation.
Asunto(s)
Condroitinsulfatasas , Enfermedades por Almacenamiento Lisosomal , Mucopolisacaridosis IV , Cromatografía Liquida , Humanos , Recién Nacido , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Enfermedades por Almacenamiento Lisosomal/genética , Mucopolisacaridosis IV/diagnóstico , Mucopolisacaridosis IV/genética , Tamizaje Neonatal , Espectrometría de Masas en TándemRESUMEN
Terrestrial species, especially non-vagile ones (those unable to fly or swim), cannot cross oceans without exploiting other animals or floating objects. However, the colonisation history of flightless Pachyrhynchus weevils, inferred from genetic data, reveals their ability to travel long distances to colonise remote islands. Here, we used captive-bred Pachyrhynchus jitanasaius to analyse (i) the physiological tolerance of weevils (egg, larva and adult stages) to different levels of salinity; (ii) the survival rate of larvae in a simulated ocean environment in the laboratory; and (iii) the survival rate of larvae in a field experiment in the ocean using fruit of the fish poison tree floating on the Kuroshio current in the Pacific Ocean. We found that the survival rate of larvae in seawater was lower than in fresh water, although if the larvae survived 7â days of immersion in seawater, some emerged as adults in the subsequent rearing process. No adults survived for more than 2â days, regardless of salinity level. After floating separately for 6â days in salt water in the laboratory and in the Kuroshio current, two of 18 larvae survived in the fruit. This study provides the first empirical evidence that P. jitanasaius larvae can survive 'rafting' on ocean currents and that the eggs and larvae of these weevils have the highest probability of crossing the oceanic barrier. This ability may facilitate over-the-sea dispersal of these flightless insects and further shape their distribution and speciation pattern in the Western Pacific islands.
Asunto(s)
Distribución Animal , Longevidad , Salinidad , Gorgojos/fisiología , Animales , Vuelo Animal , Frutas , Larva/crecimiento & desarrollo , Larva/fisiología , Óvulo/crecimiento & desarrollo , Óvulo/fisiología , Océano Pacífico , Distribución Aleatoria , Movimientos del Agua , Gorgojos/crecimiento & desarrolloAsunto(s)
Quimiocinas CC/sangre , Enfermedad de Gaucher/sangre , Enfermedad de Niemann-Pick Tipo A/sangre , Enfermedad de Niemann-Pick Tipo B/sangre , Biomarcadores/sangre , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/fisiopatología , Enfermedad de Gaucher/terapia , Hexosaminidasas/sangre , Hexosaminidasas/deficiencia , Humanos , Enfermedad de Niemann-Pick Tipo A/fisiopatología , Enfermedad de Niemann-Pick Tipo A/terapia , Enfermedad de Niemann-Pick Tipo B/fisiopatología , Enfermedad de Niemann-Pick Tipo B/terapia , Esplenectomía , Factores de TiempoRESUMEN
Fabry disease (alpha-galactosidase A (alpha-Gal A, GLA) deficiency) is a panethnic inborn error of glycosphingolipid metabolism. Because optimal therapeutic outcomes depend on early intervention, a pilot program was designed to assess newborn screening for this disease in 171,977 consecutive Taiwanese newborns by measuring their dry blood spot (DBS) alpha-Gal A activities and beta-galactosidase/alpha-Gal A ratios. Of the 90,288 male screenees, 638 (0.7%) had DBS alpha-Gal A activity <30% of normal mean and/or activity ratios >10. A second DBS assay reduced these to 91 (0.1%). Of these, 11 (including twins) had <5% (Group-A), 64 had 5-30% (Group-B), and 11 had >30% (Group-C) of mean normal leukocyte alpha-Gal A activity. All 11 Group-A, 61 Group-B, and 1 Group-C males had GLA gene mutations. Surprisingly, 86% had the later-onset cryptic splice mutation c.936+919G>A (also called IVS4+919G>A). In contrast, screening 81,689 females detected two heterozygotes. The novel mutations were expressed in vitro, predicting their classical or later-onset phenotypes. Newborn screening identified a surprisingly high frequency of Taiwanese males with Fabry disease (approximately 1 in 1,250), 86% having the IVS4+919G>A mutation previously found in later-onset cardiac phenotype patients. Further studies of the IVS4 later-onset phenotype will determine its natural history and optimal timing for therapeutic intervention.
Asunto(s)
Enfermedad de Fabry/diagnóstico , Tamizaje Neonatal , alfa-Galactosidasa/genética , Edad de Inicio , Secuencia de Aminoácidos , Enfermedad de Fabry/epidemiología , Enfermedad de Fabry/genética , Femenino , Humanos , Incidencia , Recién Nacido , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Homología de Secuencia de Aminoácido , Taiwán/epidemiología , alfa-Galactosidasa/químicaRESUMEN
GTP cyclohydrolase I (GCH, EC 3.5.4.16) regulates the level of tetrahydrobiopterin and in turn the activities of nitric oxide synthase and aromatic amino acid hydroxylases. Type II GCH mRNA, an alternatively spliced species abundant in blood cells, encodes a truncated and nonfunctional protein. When we stimulate peripheral blood mononuclear cells by PHA, the transcription of full-length GCH mRNA increased, but that of type II mRNA decreased transiently. We further demonstrated that the type II cDNA exerted a dominant-negative effect on the wild-type cDNA, similar to the effect of some GCH mutants. Therefore, type II mRNA may regulate GCH and then contribute to the regulation of NO production by BH4-dependent iNOS in mononuclear cells. Selection of the splicing sites may be coupled with transcriptional activation of the GCH gene.
Asunto(s)
GTP Ciclohidrolasa/biosíntesis , Regulación Enzimológica de la Expresión Génica , Leucocitos Mononucleares/enzimología , Empalme Alternativo , Western Blotting , Línea Celular , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , GTP Ciclohidrolasa/química , GTP Ciclohidrolasa/genética , Genes Dominantes , Humanos , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Plásmidos/metabolismo , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Transcripción Genética , Transfección , Células Tumorales CultivadasRESUMEN
BACKGROUND AND PURPOSE: Ornithine transcarbamylase (OTC) deficiency is the most common inherited urea cycle disorder. It is an X-linked semidominant disease with variable severity affecting both males and females. The characteristics and course have not been assessed in Taiwanese. This study analyzed the phenotype and genotype of OTC deficiency in Taiwanese. METHODS: During the period from January 1993 to December 2001 inclusive, 8 patients had the diagnosis of OTC deficiency by the criteria of hyperammonemia, hypocitrullinemia, and orotic aciduria. All 10 exons of the OTC gene were analyzed for mutations. RESULTS: Among the 8 cases, 3 belonged to the early-onset group (initial symptoms before or equal to age 28 days) and 5 belonged to the late-onset group (median onset age, 18 months; range, 8 months to 52 years). One case in the former group, and 4 cases in the latter group survived (mean survival, 8.2 years; range, 3 to 16 years). The average time between initial symptoms and diagnosis was 60 months in the late-onset group. Analysis of the OTC genes detected 5 different mutations in 5 patients, including 3 novel mutations: 42delT, 652G>A, and 791C>A. IQ tests, conducted in 3 patients, revealed low scores (mean, 53; range, 40 to 72). CONCLUSIONS: Both early-onset and late-onset cases of OTC deficiency were identified in Taiwanese. The diagnosis was delayed in these patients, and their outcomes were poor. All mutations detected were different and most of them have not been reported in other populations, which may explain the variability of phenotypes in Taiwanese patients.