Age-associated clinical characteristics and ATP7B mutation landscape in pediatric Wilson's disease: a study from...

Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism caused by pathogenic variants in ATP7B. However, the regional mutational spectrum, genotype-phenotype correlations, and biochemical trajectories in pediatric populations from Southwest China remain incompletely defined.

In total, 170 pediatric patients with WD were enrolled. The clinical data, imaging findings, and biochemical parameters were obtained. Age-stratified analyses were also conducted. ATP7B variants were analyzed in 81 patients using whole-gene sequencing. Genotype-phenotype associations were evaluated using logistic regression.

Hepatic presentation was predominant (84.12%), with neurological and mixed phenotypes more common in older patients. The incidence of Kayser-Fleischer rings, hepatic steatosis, cirrhosis, and abnormal brain magnetic resonance imaging (MRI) findings increased with age at diagnosis (all p < 0.01). Protein-truncating variants were significantly associated with neurological involvement (odds ratio [OR] = 4.058, p = 0.01), and male sex was an independent predictor (OR = 5.342, p = 0.006). The p. Pro992Leu variant was associated with hepatic fibrosis and steatosis (both p = 0.001). Liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma-glutamyltransferase [GGT]) decreased with increasing age at onset, whereas total cholesterol and low-density lipoprotein [LDL] cholesterol levels increased. 76 ATP7B variants were identified, with exon 8 being the primary hotspot. The most frequent alleles were c.2333G>T, c.2975C>T, and c.2310C>G. Co-occurrence analysis identified c.2975C>T as the central allele, with extensive allelic heterogeneity observed.

This study aimed to investigate age-related differences in clinical and biochemical features at disease onset in pediatric WD, with complementary analyses of genetic variation. It delineates age of onset-dependent phenotypic progression and a highly heterogeneous ATP7B mutational landscape in pediatric WD. Intronic variants and rare insertions further expand the mutation spectrum.