Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Eur J Hum Genet ; 24(1): 66-72, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25804398

RESUMEN

Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.


Asunto(s)
Alcaptonuria/genética , Enfermedades Óseas Metabólicas/genética , Huesos/enzimología , Homogentisato 1,2-Dioxigenasa/genética , Mutación Missense , Polimorfismo de Nucleótido Simple , Alcaptonuria/diagnóstico , Alcaptonuria/enzimología , Alcaptonuria/patología , Secuencia de Bases , Enfermedades Óseas Metabólicas/diagnóstico , Enfermedades Óseas Metabólicas/enzimología , Enfermedades Óseas Metabólicas/patología , Huesos/patología , Dominio Catalítico , Bases de Datos Genéticas , Exones , Femenino , Expresión Génica , Heterogeneidad Genética , Homogentisato 1,2-Dioxigenasa/química , Humanos , Intrones , Italia , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Fenotipo , Estructura Secundaria de Proteína , Análisis de Secuencia de ADN
2.
Ann Rheum Dis ; 75(2): 362-7, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25475116

RESUMEN

BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. METHODS: Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. FINDINGS: A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. CONCLUSIONS: In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.


Asunto(s)
Alcaptonuria/tratamiento farmacológico , Ciclohexanonas/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Ácido Homogentísico/orina , Nitrobenzoatos/administración & dosificación , Adulto , Alcaptonuria/sangre , Alcaptonuria/orina , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Ácido Homogentísico/sangre , Humanos , Masculino , Persona de Mediana Edad , Proyectos de Investigación , Tirosina/sangre
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA