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Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening.

Methods

A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value.

Results

Serum ceruloplasmin below 11.5 mg/dL and cupremia below 60 μg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear.

Conclusion

Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.

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Acknowledgements

We would like to thank the patients and their families for their enthusiastic participation in this study, and Fundación DISA and Fundació Per Amor al Art (FPAA) for their generous financial support.

Author information

Authors and Affiliations

  1. Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil, Avda Maritima del Sur, s/n, 35016, Las Palmas de Gran Canaria, Spain

    Luis García-Villarreal, Teresa Ramírez-Lorenzo, Paloma Garay-Sánchez, Jesús M. González & Antonio Tugores

  2. Unidad de Gastroenterología, Hepatología y Nutrición Pediátrica, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain

    Andrea Hernández-Ortega, Luis Peña-Quintana & Daniel González-Santana

  3. Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain

    Ana Sánchez-Monteagudo & Carmen Espinós

  4. Asociación Canaria Para Investigación Pediátrica. Centro de Investigación Biomédica en Red, Fisiopatología de La Obesidad y Nutrición (CIBER OBN), Instituto Universitario de Investigación en Ciencias Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

    Luis Peña-Quintana

  5. Department of Clinical Biochemistry and Clinical Analyses, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain

    Marta Riaño

  6. Department of Nursery. Atencion Primaria, Las Palmas de Gran Canaria, Spain

    Raquel Moreno-Pérez

  7. Department of Gastroenterology, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain

    Alberto Monescillo

  8. Department of Gastroenterology. Hospital, Universitario Dr Negrín, Las Palmas de Gran Canaria, Spain

    Ildefonso Quiñones

  9. Department of Public Health, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

    Almudena Sánchez-Villegas

  10. Department of Pharmacy, Atencion Primaria, Las Palmas de Gran Canaria, Spain

    Vicente Olmo-Quintana

Authors
  1. Luis García-Villarreal
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Correspondence to Antonio Tugores.

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Luis García-Villarreal and Andrea Hernández-Ortega contributed equally to this work and should be both considered as co-first authors.

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García-Villarreal, L., Hernández-Ortega, A., Sánchez-Monteagudo, A. et al. Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity. J Gastroenterol 56, 78–89 (2021). https://doi.org/10.1007/s00535-020-01745-0

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