Diagnosis of Wilson Disease and Its Phenotypes by Using Artificial Intelligence.

Valentina Medici,Anna Czlonkowska,Tomasz Litwin,Cecilia Giulivi

doi:10.3390/biom11081243

Valentina Medici, Anna Czlonkowska + Show 2 more

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https://doi.org/10.3390/biom11081243

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Abstract

WD is caused by ATP7B variants disrupting copper efflux resulting in excessive copper accumulation mainly in liver and brain. The diagnosis of WD is challenged by its variable clinical course, onset, morbidity, and ATP7B variant type. Currently it is diagnosed by a combination of clinical symptoms/signs, aberrant copper metabolism parameters (e.g., low ceruloplasmin serum levels and high urinary and hepatic copper concentrations), and genetic evidence of ATP7B mutations when available. As early diagnosis and treatment are key to favorable outcomes, it is critical to identify subjects before the onset of overtly detrimental clinical manifestations. To this end, we sought to improve WD diagnosis using artificial neural network algorithms (part of artificial intelligence) by integrating available clinical and molecular parameters. Surprisingly, WD diagnosis was based on plasma levels of glutamate, asparagine, taurine, and Fischer’s ratio. As these amino acids are linked to the urea–Krebs’ cycles, our study not only underscores the central role of hepatic mitochondria in WD pathology but also that most WD patients have underlying hepatic dysfunction. Our study provides novel evidence that artificial intelligence utilized for integrated analysis for WD may result in earlier diagnosis and mechanistically relevant treatments for patients with WD.

Highlights

Wilson disease (OMIM 277900) is caused by homozygous or compound heterozygous variants affecting the ATP7B gene (OMIM 606882) on chromosome 13q14
Considering the above challenges, the aim of this study was to apply artificial intelligence to aid in the diagnostic process of WD and its hepatic or neurological manifestations
All patients were diagnosed with WD based on the Leipzig criteria, including low ceruloplasmin levels, increased 24 h urinary and hepatic copper levels, presence of Kayser–Fleischer rings, presence of neurological symptoms, Coombs-negative hemolytic anemia, and eventual genetic testing results if available, as previously described [20,21]

Summary

Introduction

Wilson disease (OMIM 277900) is caused by homozygous or compound heterozygous variants affecting the ATP7B gene (OMIM 606882) on chromosome 13q14 This gene encodes for a polypeptide that, when acting as a dimer, exhibits a plasma membrane copper-transport activity [1,2]. Most of the ATP7B gene variants observed in patients include nonsense and frameshift mutations along with deletions, but few of the truncated or modified ATP7B proteins still conserve some of the native activity. This might constitute the main reason underlying the inconclusive attempts to correlate genotype with phenotype [3,4] when including copper parameters [5].

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