Intrafamilial phenotypic variability of the Wilson–Konovalov disease in pediatric patients

Introduction. The Wilson–Konovalov disease (WKD) is a rare genetic disorder characterized by polymorphism of clinical manifestations and a progressive course with the development of irreversible and life-threatening conditions. The study of WKD phenotypes is complicated by the number of potential factors that play a role in its formation, their possible combination.

To identify the significance of these factors in the formation of clinical heterogeneity of the disease, it is advisable to conduct an analysis in siblings who not only have the same genotype, but are also under the influence of similar environmental factors.

Objective. To evaluate the features of intrafamilial clinical polymorphism of WKD in childhood siblings and determine the range of factors influencing the course of the disease.

Materials and methods. In a retrospective study, we analyzed the health data of twenty two sibs from 11 families: 1 pair of monozygotic twins and 10 pairs of full sibs with a diagnosis of WKD established on the basis of a molecular genetic study or the diagnostic algorithm “Leipzig, 2001”.

Results. The same phenotype was observed in 8 out of 11 families: in 7 families H2/H2, in 1 family-H2+N. A different phenotype was observed in 3 families: in one — with the development of fulminant hepatitis in one of the siblings, in the other two — with the presence of neurological changes in the older sibling (H2+N/H2). In the groups of patients with neurologic changes, the values of the mean age of onset and diagnosis of WKD were significantly higher than in the group of children without these manifestations. The mean ceruloplasmin level was 14.2 ± 10.2 mg/dL in older children and 12.8 ± 5.7 mg/dL in younger children, while the median 24-hour urine copper levels were 223.6 [35.8; 1301] μg/dL and 45.2 [5.8; 414] μg/dL, respectively. Patients with at least one “severe” mutation in the genotype had lower values of ceruloplasmin (p = 0.013) and high copper in daily urine (p = 0.02) compared to patients with two “mild” mutations in the genotype.

Conclusion. The phenotypic variability of WKD in sibs is formed mainly by the accession of neurologic changes and acute liver failure developed as a result of late diagnosis or environmental factors. The ATP7B gene genotype and some epigenetic modifications may also determine the clinical picture, but further studies are required to assess their contribution.

Contribution:
Komarova A.D. — concept and design, statistical processing, writing text;
Vorobyeva N.L. — collection and processing of material;
Dzhurtubaeva D.R. — collection and processing of material;
Potapov A.S. — research concept, text editing;
Savostyanov K.V. — research concept, text editing.
All co-authors are responsible for the integrity of all parts of the manuscript and approval of its final version.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: November 12, 2024
Accepted: December 3, 2024
Published: January 31, 2025

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