Wilson Disease

Pathogenesis, Molecular Mechanisms, Diagnosis, Treatment and Monitoring

Karl Heinz Weiss, Michael Schilsky

• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128110775
• eBook ISBN: 9780128110782
• Topic: Medicine
• Subtopic: Gastroenterology & Hepatology

Wilson Disease: Pathogenesis, Molecular Mechanisms, Diagnosis, Treatment and Monitoring translates both clinical and experimental findings into a comprehensive approach for anyone involved in research and patient care. While the clinical variability of Wilson Disease poses a challenge from a diagnostic approach, the book uses the translational impact of new research findings to relate to new treatment concepts. Comprehensive chapters include common knowledge, guideline consensus statements, and discussions of clinical evidence. This is a must-have reference for researchers and clinicians in translational research.- Delivers a substantial overview of evidence driven diagnostic pathways and treatment concepts for Wilson disease- Provides an understanding of the translational impact of new research findings in Wilson Disease- Reveals the current controversies in treatment decisions for Wilson disease, providing the best decisions for optimal patient care

Part I

History of Wilson Disease

Chapter 1

History of Wilson Disease

James S. Dooley*; Rupert Purchase^† * UCL Institute for Liver and Digestive Health, University College London, London, United Kingdom
^† Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom

Abstract

This chapter reviews the key developments in the 20th century that led to the recognition of Wilson disease as an inherited, but treatable, copper storage disorder affecting the liver, brain, and other organs. In the 1950s–1980s, the development of oral drugs that can reduce the copper load transformed the prognosis of Wilson disease. The identification in the 1990s of the ATP7B gene, which is mutated in Wilson disease, offers the potential that gene therapy will one day provide a cure for Wilson disease.

Keywords

Wilson disease; Pseudosclerosis; Basal ganglia; Liver; Copper; Kayser-Fleischer rings; Ceruloplasmin; British Anti-Lewisite; d-Penicillamine; Trientine; Zinc; Tetrathiomolybdate; ATP7B

Introduction

There can be few diseases seen in the practice of medicine of such surpassing interest as Wilson’s disease (hepatolenticular degeneration, progressive lenticular degeneration, pseudosclerosis of Westphal-Strümpell). So protean are the signs and symptoms of this disease that it must be considered in the differential diagnosis of many syndromes. Thus, nervous system involvement is but one facet of an illness involving many organs … But the interest of Wilson’s disease spreads further than this. The very process of unravelling the biochemical lesion has led to a much wider understanding of the handling of copper in the body and hence to the formulation of logically designed therapy, so making Wilson’s disease not only one of the very few diseases of the nervous system but also of the liver for which there is a specific and effective treatment.

Walshe (1976) [1]

By the end of the 20th century, five notable developments had led to an understanding of Wilson disease (McKusick 277900 [2]) and its treatment:

1. 1. Samuel Alexander Kinnier Wilson’s seminal publication in 1912 [3] describing the symptoms, signs, and pathology of this condition that now bears his name.
2. 2. The recognition that Wilson disease is inherited as an autosomal recessive disorder [4, 5].
3. 3. The role of copper in the pathogenesis of Wilson disease [6, 7].
4. 4. The successful therapeutic use of agents that reduce copper levels in Wilson disease patients [8–13].
5. 5. The identification in 1993 of the gene (ATP7B) mutated in Wilson disease [14–16].

Despite progress, much remains to be achieved. Wilson disease remains a challenging condition to recognize, to diagnose, and often to treat. Future developments in cellular and molecular biology should lead to more successful outcomes for all Wilson disease patients.

The Definition of Wilson Disease

Kinnier Wilson’s MD Thesis, for which he was awarded the Gold Medal at Edinburgh University in 1911 and which was published in Brain in 1912 [3], is a remarkable achievement for such a young man (Fig. 1). He had qualified only 9 years before in 1902 from Edinburgh, Bachelor of Medicine (MB), and completed a BSc with first class honors the following year. He first worked at the National Hospital for the Paralysed and Epileptic (later the National Hospital for Nervous Diseases), Queen Square, London, in 1904 after completing a fellowship in Paris with the neurologist Pierre Marie at Bicêtre Hospital. After taking his membership of the Royal College of Physicians of London in 1907, he produced an acclaimed translation of the book by Meige and Feindel on tics and their treatment and in 1908 published work on apraxia. He then took up a British Medical Association Research Fellowship between 1909 and 1911, during which he did the work for his MD Thesis at Queen Square.

Fig. 1 Samuel Alexander Kinnier Wilson (1878–1937). A photograph from the early 1920s. (Reprinted by kind permission of his son, James Kinnier Wilson).

Several accounts from others are worth repeating here. Wilson was the first specialist neurologist appointed in the UK at King’s College Hospital in around 1918—they had all been general physicians with an interest in neurology until then. According to Macdonald Critchley who had been his House Physician, his registrar, and then his junior colleague, Wilson was interested in examination and detail but with the goal of addressing “why?” that is, why had such and such happened. He was always “probing, questioning, and speculating”; “he was the Marco Polo of the extrapyramidal system—but much more than that” [17]. This is clearly reflected in his thesis. He had a broad interest in neurology, and he was three-quarters of the way through writing his textbook of neurology [18] when he died aged 58 in 1937.

Within 10 years of starting his clinical career, Wilson had uncovered a new neurological entity, having collected 12 patients with what he recognized was a shared pattern of disease. He himself saw four of these patients and in three of these recorded their features and their pathology—particularly neuropathology—in minute detail. He also reviewed two cases seen at Queen Square previously and six other cases from the literature. His 213-page publication in the journal Brain is a lesson in observation, analysis, and synthesis of this new and until then confusing constellation of features. The detailed description of each patient’s neurological symptoms, signs, and, when done, neuropathology from postmortem is stunning—especially for someone only 10 years into his career.

On page 436 of his paper in Brain [3], Wilson wrote the following:

Progressive lenticular degeneration may be defined as a disease which occurs in young people, which is often familial but not congenital or hereditary; it is essentially and chiefly a disease of the extrapyramidal motor system, and is characterised by involuntary movements, usually of the nature of tremor, dysarthria, dysphagia, muscular weakness, spasticity, and contractures with progressive emaciation; with these may be associated emotionalism and certain symptoms of a mental nature. It is progressive, and, after a longer or shorter period, fatal. Pathologically it is characterised predominantly by bilateral degeneration of the lenticular nucleus, and in addition cirrhosis of the liver is constantly found, the latter morbid condition rarely, if ever, giving rise to symptoms during the life of the patient.

His observations led to a new concept of neurological wiring, with the basal ganglia, in which the pathological findings were seen, being recognized for their importance in extrapyramidal function—a new departure in neurology. This distinguished symptoms, signs, and pathology from the pyramidal system and corticospinal tract.

Broussolle et al. [19] state the following in their detailed review of Wilson’s work and contributions: “To summarize, Wilson’s description and analysis of the motor disorder suggest a combination of dystonia, akinesia, and extrapyram...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Foreword
• Part I: History of Wilson Disease
• Part II: Molecular Mechanisms
• Part III: Epidemiology
• Part IV: Diagnosis
• Part V: Treatment Decisions
• Part VI: Monitoring
• Part VII: Main Challenges in Diagnosis and Treatment
• Index