Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease

Collins, Christopher; Yi, Fan; Dayuha, Remwilyn; Duong, Phi; Horslen, Simon; Camarata, Michelle; Coskun, Ayse K.; Houwen, Roderick H. J.; Pop, Tudor Lucian; Zoller, Heinz; Yoo, Han‐Wook; Jung, Sung Won; Weiss, Karl Heinz; Schilsky, Michael L.; Ferenci, Péter; Hahn, Si Houn

doi:10.1053/j.gastro.2021.02.052

Cited by 61 publications

(35 citation statements)

References 35 publications

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“…The measurements were made by immunoaffinity enrichment mass spectrometry. As the results of the study show, the test effectively identified WD patients in the group of the 92.1% of studied cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis [ 57 ].…”

Section: Diagnostic Approach To Patients With Wilson’s Disease Suspicionmentioning

confidence: 99%

Wilson’s Disease: An Update on the Diagnostic Workup and Management

Kasztelan-Szczerbińska

Cichoż‐Lach

2021

JCM

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Wilson’s disease (WD) is a rare autosomal recessive disorder of hepatocellular copper deposition. The diagnostic approach to patients with WD may be challenging and is based on a complex set of clinical findings that derive from patient history, physical examination, as well as laboratory and imaging testing. No single examination can unequivocally confirm or exclude the disease. Timely identification of signs and symptoms using novel biomarkers and modern diagnostic tools may help to reduce treatment delays and improve patient prognosis. The proper way of approaching WD management includes, firstly, early diagnosis and prompt treatment introduction; secondly, careful and lifelong monitoring of patient compliance and strict adherence to the treatment; and, last but not least, screening for adverse effects and evaluation of treatment efficacy. Liver transplantation is performed in about 5% of WD patients who present with acute liver failure at first disease presentation or with signs of decompensation in the course of liver cirrhosis. Increasing awareness of this rare inherited disease among health professionals, emphasizing their training to consider early signs and symptoms of the illness, and strict monitoring are vital strategies for the patient safety and efficacy of WD therapy.

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Section: Diagnostic Approach To Patients With Wilson’s Disease Suspicionmentioning

confidence: 99%

Wilson’s Disease: An Update on the Diagnostic Workup and Management

Kasztelan-Szczerbińska

Cichoż‐Lach

2021

JCM

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“…A pilot study was carried out in thirteen WD patients; the assay precision was <10% CV, and the protein was stable for a week in DBS at room temperature [ 48 ]. Later, in a large clinical series with 216 patients, the method resulted to have a sensitivity of 91.2% and a specificity of 98.1%, aiding to solve ambiguous cases without genetic diagnosis [ 49 ].…”

Section: Clinical Picture Of Wilson’s Diseasementioning

confidence: 99%

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

et al. 2021

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Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD’s phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.

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“…The result of the genetic analysis would arrive with the clinician late, after the evolution of the patient would be clear. With the recent progress in screening for WD[ 43 ], the genetic analysis in children with an early suspected disease would help predict future evolution. When nonsense, frame-shift, or splicing-site variants are identified in a pre-symptomatic period, the importance of this genotype-phenotype correlation for the prognostic is evident.…”

Section: Discussionmentioning

confidence: 99%

Acute liver failure with hemolytic anemia in children with Wilson’s disease: Genotype-phenotype correlations?

Pop¹,

Grama²,

Stefanescu³

et al. 2021

WJH

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BACKGROUND Wilson’s disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant (HSD17B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD. AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia. METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations (ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, ATP7B variants, and the HSD17B13:TA (rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations. RESULTS We analyzed the data of 51 patients with WD, 26 females (50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children (15.67%), all adolescent girls. The Kayser-Fleisher ring was present in 9 children (17.65%). The most frequent variants of the ATP7B gene were p.His1069Gln (c.3207A>G) in 38.24% of all alleles, p.Gly1341Asp (c.4021G>A) in 26.47%, p.Trp939Cys (c.2817G>T) in 9.80%, and p.Lys844Ter (c.2530A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939Cys (c.2817G>T) and p.Lys844Ter (c.2530A>T) variants were more frequent than in other less severe forms, in which p.His1069Gln (c.3207A>G) was more frequent. p.Gly1341Asp (c.4021G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17B13 genotype was evaluated. The overall HSD17B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease (26.92%) than those with ALF and hemolytic anemia (14.28%). CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069Gln (c.3207A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.

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Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease

Cited by 61 publications

References 35 publications

Wilson’s Disease: An Update on the Diagnostic Workup and Management

Wilson’s Disease: An Update on the Diagnostic Workup and Management

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

Acute liver failure with hemolytic anemia in children with Wilson’s disease: Genotype-phenotype correlations?

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