Wilson Disease

Anna Czlonkowska, Michael Schilsky

• Publisher: Elsevier
• Year: 2017
• Print ISBN: 9780444636256
• eBook ISBN: 9780444636270
• Topic: Medicine
• Subtopic: Neurology

Wilson Disease provides a comprehensive guide on this inherited genetic disorder that has devastating consequences for both the liver and neurologic/psychiatric health. This disease is of increasing interest to neurologists, hepatologists, and geneticists, but when the disease is diagnosed early, it is treatable, with patients living normal lives.This volume describes the molecular pathophysiology of WD and the clinical and pathological effects of copper. Separate sections address both diagnosis and medical and surgical approaches to treatment. Both adult and pediatric perspectives on diagnosis and treatment are addressed, and a section on genetics highlights advances in molecular diagnostics. Patient support groups that can aid in coping with this disease are also discussed, as are animal models for those interested in basic research on cell biology, pathophysiology, and treatment.- Addresses the molecular pathophysiology of WD and the clinical and pathological effects of copper- Offers coverage of both diagnosis and medical and surgical approaches to treatment- Includes perspectives on both adult and pediatric diagnosis and treatment- Edited work with chapters authored by leaders in the field from around the globe—the broadest, most expert coverage available

Chapter 1

History of Wilson disease

a personal account

John M. Walshe* Formerly of Addenbrookes Hospital, Cambridge and the Middlesex Hospital, London, UK
^* Correspondence to: J.M. Walshe, MD, ScD, FRCP, 58 High Street Hemingford Grey, Huntingdon PE 28 9BN, UK email address: [email protected]

Abstract

This chapter focuses on the historic aspects of the development of much of our current knowledge of the diagnosis and treatment of Wilson disease. Included are descriptions of the clinical signs of neurologic and hepatic disease, the natural history of disease progression, studies of disease pathogenesis and a unique perspective on the development of diagnostic testing and pharmacological therapy.

Keywords

Ceruloplasmin; Chelation therapy; Copper; Wilson disease; Zinc salts

“Begin at the beginning,” the King said very gravely, “then go on until the end, then stop.”

Alice's Adventures Through the Looking Glass,

Lewis Carroll

This admirable advice for any story teller is honored more often in the breach than the observance. The difficulty remains, where is the beginning and does the story have any definitive end? With the history of disease the probability is that there is, in all likelihood, no end. Knowledge and theories will continue to develop almost indefinitely. Well then, is there a beginning? Probably, but exactly where that is, is not always obvious. In this case, it might seem self-evident that the story begins with Wilson's original article in Brain in 1912, when he described four cases of what he called “progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver.” (Fig. 1.1) In addition he found four cases in the literature which fitted his description, one of which was dated back to 1890. Furthermore, there is a case report in Frerichs’ book of 1860 that was almost certainly a case of Wilson disease. Indeed, going back even further, Morgagni, in 1761, described several cases of liver disease associated with nervous symptoms which may possibly have been cases of Wilson disease.

Fig. 1.1 Dr. John Walshe (right) with Dr. James Kinner Wilson, son of neurologist Samuel Alexander Kinner Wilson, whose 1912 publication on hepatolenticular degeneration was being celebrated at the Centennial Symposium on Wilson's disease in London, October 5–6, 2012.

It is interesting that one of the defining physical signs of Wilson disease, the Kayser–Fleischer corneal rings, had been described 10 years before the disease to which they later became associated (Kayser, 1902). It is surprising, in view of the very detailed nature of his descriptions of his patients, that Wilson did not observe the corneal rings and indeed he refused to admit of their relationship to his disease for 10 years after his original publication (Wilson, 1922). These rings were for many years thought to pathognomonic of Wilson disease but it is now known that they can be found in other forms of liver disease, such as primary biliary cirrhosis and chronic cholestasis (Fleming et al., 1975).

Only 1 year after Wilson's original publication in Brain, the Austrian pathologist, Rumpel, reported finding an excess of copper in the liver of a patient dying of Wilson disease, an observation whose importance was completely missed (Rumpel, 1913). He also suggested that there was excess of silver in the eyes.

Another important observation which passed unnoticed was by Bramwell, whose house physician Wilson had once been (Bramwell, 1916). Bramwell described a family in which four siblings died, between the ages of 9 and 14 years, of rapid-onset liver failure and suggested that this might be related to Wilson disease. It would be interesting to see if any descendants of this family still exist so that they could be tested to see if they carry, in single dose, the mutation for Wilson disease.

The next important addition to knowledge came when Hall (1921) showed that this disease was inherited in a recessive mode, later confirmed in more detail by Bearn (1960), who studied 30 families he saw in New York whose ancestry could be traced back to Eastern Europe or Southern Italy.

It must be noted that in Wilson's original publication of only 4 patients, he described almost all of the signs and symptoms which we now know are characteristic of this disease (Wilson, 1912). He carried out his own pathologic studies and even traveled to Switzerland to collect the brain of a patient dying of his disease. Wilson did not believe that the liver pathology was a significant factor in the natural history of the disease, although one of his own patients actually died of bleeding esophageal varices.

Over the next 30 years there were only minor advances in the understanding of the disease, whose course remained remorseless and invariably fatal. In 1922 Siemerling and Oloff described the association of sunflower cataracts with Kayser–Fleischer rings and noted the similarity to lesions caused by intraocular damage with intraocular copper fragments. Vogt (1929) and Haurowitz (1930) reported finding excess copper in the brain and liver of Wilson disease patients – an observation which was not followed up.

In 1945 Sir Rudolph Peters and his team in Oxford were able to report their earlier work in the development of the antiarsenical drug, dimercaprol (British anti-Lewisite, BAL). This was developed during the Second World War to combat anticipated attack by Hitler with the arsenical gas Lewisite. The importance of this became apparent in 1948 when Cumings showed that Wilson disease was indeed due to accumulation of excess copper in the brain and liver of all patients dying of this disease and postulated that treatment with BAL might halt the progress of the illness (Cumings, 1951). By coincidence, at the same time, Mandelbrote et al. (1948) reported their findings on the effect of BAL on copper excretion on a wide spectrum of patients with neurologic diseases; one of these patients had Wilson disease and in this particular patient there was a great increase in the copper excreted in the urine. This important observation was followed up in 1951 by Cumings himself in London and by Denny Brown and Porter (1951) in Boston. Both teams showed that courses of BAL resulted in significant improvement in their patients’ neurologic symptoms. However it soon became apparent that patients needed repeated courses of the drug and subsequent courses were less effective than the initial one. In addition the injections were painful and associated with a wide variety of toxic reactions. This was clearly not an ideal treatment.

The picture changed when, in 1956, I reported that penicillamine promoted a much larger excretion of copper in the urine than either BAL or the other medical chelating agent ethylenediamine tetraacetic acid (EDTA) (Walshe, 1956, 1960). Penicillamine is a breakdown product of penicillin and is excreted in the urine of all patients treated with penicillin, an observation I had made some years earlier when studying changes in amino acid metabolism in patients with liver damage (Walshe, 1956). This idea came to me when working in the Liver Unit under Dr. Charles Davidson, at the Boston City Hospital. Having seen one of Professor Denny Brown's Wilson disease patients who was not prospering on treatment with BAL, it occurred to me that penicillamine, with its –SH and –NH₃ groups, might have the right chemical structure to chelate copper and promote its excretion in the urine. Dr. Davidson was able to obtain for me 2 grams of penicillamine from Professor Sheehan at the Massachusetts Institute of Technology. Having taken 1 gram myself to prove its safety, I administered the second gram to Professor Denny Brown's patient and recorded the very satisfactory cupresis so induced. With this simple procedure the start of penicillamine therapy was launched.

In those far-off days there were no ethical committees to be approached for permission; life was a lot easier when trying out new ideas. By 1960 I was able to publish the first account of a patient with Wilson disease improving significantly as a result of this new therapy (Walshe, 1960). This was confirmed by similar studies by Scheinberg and Sternlieb, also in 1960.

Whilst these important advances in the treatment of this disease were progressing, so also was our understanding of its pathogenesis. In 1948 Holmberg and Laurell described the finding of a copper-carrying protein in the plasma which they named ceruloplasmin. In 1952, working independently in New York, both Bearn and Kunkel and Scheinberg and Gitlin showed that patients with Wilson disease all had low or absent concentrations of this protein (Bearn and Kunkel,1952; Scheinberg and Gitlin, 1952). Shortly after this Cartwright and his team (1954) in Salt Lake City published an important article on copper metabolism in Wilson disease, an article which inspired my own interest in this malady, in which they discussed the various therapies then available and their shortcomings. Despite these real advances Uzman, working in Denny Brown's department in Boston, believed that Wilson disease was due to an abnormality of peptide metabolism and that copper deposition was a side-effect and not the directly causative etiology of the disease (Uzman et al., 1956). This h...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Handbook of Clinical Neurology 3rd Series
• Foreword
• Preface
• Contributors
• Chapter 1: History of Wilson disease: a personal account
• Chapter 2: Epidemiology and introduction to the clinical presentation of Wilson disease
• Chapter 3: The genetics of Wilson disease
• Chapter 4: Genetic and environmental modifiers of Wilson disease
• Chapter 5: Pathogenesis of Wilson disease
• Chapter 6: Animal models of Wilson disease
• Chapter 7: Wilson disease – liver pathology
• Chapter 8: Wilson disease: brain pathology
• Chapter 9: Hepatic features of Wilson disease
• Chapter 10: Wilson disease: neurologic features
• Chapter 11: Cognitive and psychiatric symptoms in Wilson disease
• Chapter 12: Wilson disease in children
• Chapter 13: Other organ involvement and clinical aspects of Wilson disease
• Chapter 14: Diagnosis of Wilson disease
• Chapter 15: Wilson disease – currently used anticopper therapy
• Chapter 16: Liver transplantation for Wilson disease
• Chapter 17: Wilson disease: symptomatic liver therapy
• Chapter 18: Symptomatic treatment of neurologic symptoms in Wilson disease
• Chapter 19: Novel perspectives on Wilson disease treatment
• Chapter 20: Patient support groups in the management of Wilson disease
• Index