RESUMO
Wilson disease is an infrequent autosomal recessive disorder caused by mutations in the ATP7B gene (13q14.3) producing pathologic phenotypes due to copper accumulation in critical tissues. The aim of the research was to probe Wilson disease genetic epidemiology in Venezuela, through the identification in diagnosed index cases, of ATP7B locus mutations, their geographic distribution, frequency, in-phase haplotypes and probable ethnic ancestry. During the last three decades 33 independent Wilson disease families from the country at large were ascertained and diagnosed through severely reduced ceruloplasmin activity, higher urinary copper excretion, and specific clinical signs. Molecular studies of the ATP7B gene were accomplished in 26 of the families. Disease prevalence was estimated as 1:94,000 families between 1985 and 2013, showing geographic aggregation in the state of Zulia with 1:27,000 families in it. DNA analysis in 26 families revealed 13 different mutations. The c.3402delC was the most frequent one (26.9%), presenting two independent in-phase haplotypes, both of likely European descent; which is followed by the not previously reported p.G691V (9.6%) and by the frequent European H1069Q (7.7%). Known mutations c.51 + 4A > T, c.1285 + 5G > T, M645R, T788I, V845SfsX28, T977M, L1088X, T1220M, R1319X and a novel P767L showed frequencies between 5.8 and 1.9%. Despite the ample mutation heterogeneity for Wilson disease in the country, the findings provide a diagnostic algorithm to ease mutation assessment in new patients; the predominant c.3402delC displayed wide geographic distribution and two genetic origins.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Transporte de Cátions/genética , Degeneração Hepatolenticular/genética , Adolescente , Adulto , Criança , Cobre/urina , ATPases Transportadoras de Cobre , Feminino , Frequência do Gene , Degeneração Hepatolenticular/epidemiologia , Degeneração Hepatolenticular/urina , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Prevalência , Venezuela/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Urinary copper excretion higher than 100 µg/24 h is useful for diagnosing Wilson's disease. d-Penicillamine challenge test may produce higher levels than 1400 µg/24 h, allowing for better diagnostic accuracy. This study investigated whether heterozygotes reach this value and compared copper serum levels, ceruloplasmin, and urinary copper excretion before and after administering d-penicillamine to the parents of Wilson's disease patients. METHODS: Fifty parents of adult patients were enrolled to obtain copper serum levels and ceruloplasmin along with 24-h urinary copper excretion before and after administering 1g d-penicillamine. RESULTS: Serum ceruloplasmin and copper levels were significantly lower in fathers than in mothers (mean 21.8×27.8 mg%; 71.4×88.0 µg%; p ≤ 0.001). The mean of basal 24-h urinary copper excretion was higher in fathers (26.2×18.7 µg/24 h, p=0.01), but did not differ between the genders after d-penicillamine (521.7×525.3, range 31.6-1085.1 µg/24h, p=0.8). CONCLUSIONS: The mean values of serum copper, ceruloplasmin, and basal urinary copper excretion were different between males and females. The current diagnostic threshold of 24-h urinary copper excretion after d-penicillamine was not reached by heterozygotes. The increased urinary copper excretion after d-penicillamine challenge was much higher than fivefold the upper limit of normal urinary copper excretion in the majority of heterozygotes and should not be taken into account when diagnosing Wilson's disease.
Assuntos
Cobre/urina , Degeneração Hepatolenticular/genética , Degeneração Hepatolenticular/urina , Ceruloplasmina/metabolismo , Quelantes , Cobre/sangue , Feminino , Degeneração Hepatolenticular/diagnóstico , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Penicilamina , Fatores SexuaisRESUMO
We conducted a mass-screening method to detect presymptomatic Wilson's disease in children by measuring urinary holoceruloplasmin. Two cases of Wilson's disease were found by testing urine samples from 48,819 children. The diagnosis was confirmed by clinical laboratory tests and the detection of a mutated ATP 7B gene.