关键词: 肝豆状核变性, 临床表型, ATP7B, 基因突变谱, 儿童

Abstract: Objective The aim of this study was to investigate the clinical phenotypes and blood ATP7B gene mutation profile changes in children with Wilson's disease (WD). Methods 62 children with WD including hepatic phenotype in 41 cases (clinical phenotypes in 11 cases and subclinical phenotypes in 30 cases) and neuropathy in 21 cases (clinical phenotypes in 6 cases and subclinical phenotypes in 15 cases) were admitted to our hospital between January 2020 and January 2023. The blood ATP7B gene mutation profile was obtained by gene sequencing and the results were compared in ATP7B mutation data bank. 24 hour-urine copper and serum ceruloplasmin levels were assayed by flame atomic absorption spectrometry. Results The onset age, incidence of corneal K-F ring, serum alanine aminotransferase (ALT) and 24-hour urinary copper levels in children with hepatic phenotype were(6.1±2.5)yr, 17.0%, (149.6±51.3)U/L and (157.0±25.7)μg, significantly different compared to in those with neuropathy(P<0.05); the onset age, incidence of corneal K-F ring, bile acid, serum ALT and 24-hour urinary copper levels in children with clinical phenotype of liver disease were(6.8±1.9)yr, 54.5%, (158.5±23.6)μmol/L, (279.6±17.5)U/L and (196.6±62.8)μg, significantly different compared to in those with subclinical phenotype of liver diseases (P<0.05), and the incidence of corneal K-F ring, bile acid, serum ALT and 24-hour urinary copper levels in children with clinical neuropathy were 100.0%, (26.8±5.8)μmol/L, (96.7±10.1)U/L and (376.5±48.9)μg, significantly different compared to in those with subclinical neuropathy (P<0.05); as for the ATP7B gene mutation spectrum, the c.2333G>T (Arg778Leu) was found in 41 alleles, with 33.1% of allele frequency, the c.2975G>T (Pro992Leu) was found in 10 alleles, with 8.1% of allele frequency, and the C.2621C>T (Ala874Val), c.1708-5t>g (Ala874Val) and c.994G >T (Glu332stop) were found with 4.8%, 3.2% and 3.2% allelic frequencies; 34 missense mutations, 15 insertion mutations, 8 shear mutations and 5 nonsense mutations were detected in our series and there were compound heterozygosity in 45 cases, heterozygosity mutation in 7 cases and homozygous mutation in 10 cases; there was no statistical differences as respect to the mutation frequencies of the top five pathogenic mutation genes, e.g., p.Arg778Le, p.Pro992Leu, p.Ala874Val, IvS4-5: t>g and p.Glu332stop between children with liver illness and neuropathy phenotypes (P>0.05). Conclusion The common clinical phenotype of children with WD is liver involvement, and the top five pathogenic gene variants are Arg778Leu, Pro992Leu, Ala874Val, Ala874Val and Glu332stop, which might be firstly sequenced for early diagnosis, but the gene screening probably hard to predict the clinical phenotypes.

Key words: Wilson&apos, s disease, Clinical phenotypes, ATP7B, Gene mutation profile, Children