Molecular Diagnosis of Wilson Disease

doi:10.1006/mgme.2000.3143

Molecular Genetics and Metabolism

Volume 72, Issue 3, March 2001, Pages 223-230

https://doi.org/10.1006/mgme.2000.3143 Get rights and content

Abstract

Wilson disease (WD) is caused by mutations in the ATP7B gene. The diagnosis is based on clinical and biochemical criteria but these are increasingly recognized to have low sensitivity. Genetic diagnosis is considered impractical due to the large coding region of the ATP7B gene and extreme diversity of mutations. We assessed the feasibility and utility of genetic diagnosis in WD. The coding region of the ATP7B gene was scanned by single-stranded conformation polymorphism (SSCP) analysis in 6 cases in whom the diagnosis of WD was uncertain. In addition, we attempted molecular diagnosis in 26 WD patients of similar ethnicity but variable disease manifestations. In 6 individuals in whom the biochemical/clinical diagnosis was uncertain, DNA analyses were useful for assigning their status with respect to WD. Molecular diagnosis identified presymptomatic individuals in families affected by WD and assigned heterozygote carrier or wild-type status to individuals previously diagnosed as affected. In 26 WD patients, 92% of disease alleles were identified. The most common mutations were H1069Q, L936X, and 2532delA representing 48, 10, and 8% of disease alleles, respectively. Three novel mutations were identified: Q898R, 3061(−1)g → a, and 3972insC. Genetic diagnosis is feasible for WD. Greater application of molecular diagnosis should enable an appreciation of the full spectrum of WD phenotype that is not possible with currently available diagnostic criteria.

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Cited by (36)

Developmental and Inherited Liver Disease
2023, MacSween's Pathology of the Liver, Eighth Edition
A section on the approach to diagnostic histological interpretation is the overture to this chapter on inherited and developmental disorders. This initial section is split chronologically into the early neonatal and infantile period and later childhood and adulthood, with the intention of reflecting clinical practice as closely and succinctly as possible. Disorders of the biliary tree, bile formation and secretion and hepatocyte metabolism are the core of this chapter, a merger of Chapters 3 and 4 of previous editions. Considerations on the pathogenetic and/or clinical overlap among developmental, genetic and metabolic disorders were the rationale behind this change. The complexity of hepatocyte metabolism is reflected into the myriad of related pathological conditions. Two short new paragraphs on disorders of manganese metabolism and DNA repair and nuclear envelope have been added. Recent technological advances, particularly in genomics in the last 5 years, have resulted in a plethora of new entities and changes in terminology, challenging the authors to balance detail and application to clinical practice. Tables and figures from the previous edition have been largely kept due to their quality and contemporary relevance, and updated where necessary. Liver involvement in immunodeficiency and miscellaneous disorders precede the final section on anatomical anomalies. Vascular anomalies are now included in the chapters on vascular disorders.
Wilson's disease
2019, Medicine (United Kingdom)
Citation Excerpt :
The diagnosis is more challenging when liver disease is the presenting feature. Molecular analysis (if available) of ATP7B mutations can potentially be diagnostic, but will not necessarily detect all disease-producing mutations.2 A serum caeruloplasmin concentration of <0.2 g/litre (normal range 0.2–0.5 g/litre) is consistent with WD and diagnostic in a patient with Kayser–Fleischer rings.
Wilson's disease is a rare progressive genetic disorder of copper metabolism associated with hepatolenticular degeneration. Left untreated, it results in severe disability and death. The diagnosis is very easily overlooked but, if discovered early, effective treatments are available to prevent or reverse many manifestations of this disorder. The role of copper in disease pathogenesis, coupled with clinical, biochemical and genetic markers, is pivotal to establishing a clear diagnosis. Medical therapy involves chelating agents (e.g. penicillamine, trientine) and/or zinc salts. Liver transplantation corrects the underlying pathophysiology and can be life-saving. Knowledge of the Wilson's disease gene has opened up a new molecular diagnostic repertoire in the investigation of suspected patients and first-degree relatives.
Developmental and Inherited Liver Disease
2018, MacSween's Pathology of the Liver
A new section on the approach to diagnostic histological interpretation, is the overture to this chapter on inherited and developmental disorders. This initial section is split chronologically into the early neonatal and infantile period and later childhood and adulthood; with the intention of reflecting clinical practice as closely and succinctly as possible. Disorders of the biliary tree, bile formation and secretion, and hepatocyte metabolism are the core of this chapter, a merger of chapters 3 and 4 of the previous edition. Considerations on the pathogenetic and/or clinical overlap between developmental, genetic and metabolic disorders were the rationale behind this change. The complexity of hepatocyte metabolism is reflected into the miriad of related pathological conditions. Recent technological advances, particularly in genomics in the last five years, have resulted in a plethora of new entities and changes in terminology, challenging the authors to balance detail and application to clinical practice. Tables and figures from previous editions have been largely kept due to their quality and contemporary relevance, whilst new ones have been added to accommodate new advances (e.g. classification of mitochondrial disorders), a compromise to bridge between the two editions for the accustomed reader. Liver involvement in immunodeficiency and miscellaneous disorders precede the final section on anatomical anomalies. Vascular anomalies are now included in the chapters on vascular disorders.
Wilson's disease
2015, Medicine (United Kingdom)
Wilson's disease, is a rare progressive genetic disorder of copper metabolism associated with hepatolenticular degeneration. Left untreated, it invariably results in severe disability and death. The diagnosis is very easily overlooked but if discovered early, effective treatments are available that will prevent or reverse many manifestations of this disorder. The role of copper in disease pathogenesis, coupled with clinical, biochemical, and genetic markers, are pivotal to establishing a clear diagnosis. Medical therapy involves several chelating agents (e.g. penicillamine, trientine) and zinc salts. Liver transplantation corrects the underlying pathophysiology and can be lifesaving. Knowledge of the Wilson's disease gene has opened up a new molecular diagnostic repertoire in the investigation of a suspected patient and first-degree relatives.
The relationship between copper and steatosis in Wilson's disease
2013, Clinics and Research in Hepatology and Gastroenterology
Citation Excerpt :
Diagnosis was confirmed by the determination of total serum copper (< 70 μg/dl), of cupruria baseline (<100 μg/24 h) and hepatic parenchymal copper concentration (> 250 mcg/g dry weight) following hepatic agobiopsy [17,18]. The copper excretion in 24 hours urine following oral administration of d-penicillamine (n.v. < 300 μg/24 h), and gene mutations of ATP7B using molecular biology tests were also determined [19]. WD patients underwent percutaneous liver biopsy [20] with histological findings, copper and iron tissue content with hepatic iron index calculation (HII) [21] (n.v. < 1.9).
The histological similarities seen in Wilson's disease (WD) and non-alcoholic steatohepatitis (NASH) led us to verify possible correlations between glucose and/or lipid and/or iron metabolism alterations and hepatic steatosis in WD patients.
Thirty-five WD patients (20 females, 15 males, mean age 40.1 ± 5.4 years), and 44 NASH patients (25 females, 19 males, mean age 42.8 ± 6.7 years) were enrolled in the study. BMI, total/HDL/LDL-cholesterol, triglycerides and glucose serum levels were established in all subjects. HOMA index was calculated. Percutaneous liver biopsy with quantitative evaluation of steatosis and copper tissue content was performed in all WD patients and in NASH control group.
Significant difference was seen in baseline serum levels of glucose, HOMA index, total cholesterol, triglycerides, and ferritin between the WD group and NASH group (P < 0.05) but steatosis scored was similar between two groups. No correlation between the level of steatosis and metabolic factors studied was highlighted. In WD, hepatic parenchymal copper concentration was 753 ± 65.3 mcg/g dry weight against 54.5 ± 16.9 mcg/g dry weight in NASH patients (P < 0.05). Higher liver copper concentrations were seen in patients with severe steatosis compared to those with mild (P = 0.004) and moderate, (P = 0.038) steatosis. Positive significant correlation between liver copper content and steatosis scores (r = 0.87; r² = 0.76) was observed.
The hepatic steatosis in WD is not induced by metabolic comorbidities but by the accumulation of copper in the liver tissue. The hypothesise that the metabolic alterations could be co-factors in the pathogenesis of steatosis in these patients cannot be excluded.
Characteristics of neurological Wilson's disease without Kayser-Fleischer ring
2012, Journal of the Neurological Sciences
Citation Excerpt :
In our study, liver biopsy was done in 4 subjects without KF ring, and hepatic copper content was higher than 250 μg/g in 3 subjects in our study. Although ATP7B gene mutation analysis can be a highly confirmative test in some cases, genetic testing is considered to be impractical at times due to the large coding region of the ATP7B gene and the extreme diversity of mutations [32]. In our study, ATP7B gene mutation analysis was done for only 3 (till 2004) and 7 (from 2004) commonly mutated exons in the Korean population [22,23].
Although Kayser–Fleischer ring has been regarded as a key diagnostic feature of neurologic Wilson's disease, there have been previous reports of neurologic Wilson's disease patients without Kayser–Fleischer ring. We assessed the characteristics of neurologic Wilson's disease patients without Kayser–Fleischer ring.
We enrolled neurologic Wilson's disease patients from 4 university hospitals by review of medical records in this study. Patients with neurologic Wilson's disease were diagnosed based on the neurologic symptoms and international scoring system for the diagnosis of Wilson's disease. All subjects were divided into two groups according to the presence of a Kayser–Fleischer ring. We compared demographic data, laboratory findings and imaging findings of the liver and brain between the two groups.
There were 12 (26.7%) patients without Kayser–Fleischer ring out of a total of 45 neurologic Wilson's disease patients. The Wilson's disease patients without Kayser–Fleischer ring demonstrated a higher ceruloplasmin concentration and serum copper level than those with Kayser–Fleischer ring. In addition, liver cirrhosis and typical signal changes in brain magnetic resonance imaging were less common in neurologic Wilson's disease patients without Kayser–Fleischer ring.
Based on our results, the absence of Kayser–Fleischer ring can be regarded as a form of neurologic Wilson's disease with less copper involvement. In addition, it is important to understand these features and to perform further investigations if patients without Kayser–Fleischer ring are suspected of having neurologic Wilson's disease.

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^☆: A part of this work was presented at the American Association for the Study of the Liver Annual Meeting, Chicago, IL, November 4–6, 1998.

²: To whom correspondence should be addressed at current address: Department of Human Genetics, Box 1497, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574. Fax: (212) 426-9065. E-mail: [email protected].

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Regular ArticleMolecular Diagnosis of Wilson Disease☆

Abstract

J Hepatol

Gastroenterology

Gastroenterology

Biochem Biophys Res Commun

Am J Hum Genet

Lancet

Genomics

Genetic disorders of membrane transport. IV. Wilson disease and Menkes disease

Am J Physiol

Wilson's disease

Diseases of the Liver and Biliary Systems, 9th ed

Liver transplantation for Wilson's disease: Indications and outcome

Hepatology

Wilson's disease

Overcoming obstacles to the diagnosis of Wilson disease

Gastroenterology

The Wilson disease gene is a putative copper transporting P-typeATPase similar to the Menkes gene

Nature Genet

The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene

Nature Genet

Regular Article
Molecular Diagnosis of Wilson Disease☆