The history of Wilson disease

INTRODUCTIONIn 1912, Samuel Alexander Kinnier Wilson (SAKW) (Figure 1A), a remarkable physician and neurologist, published his seminal article entitled ”Progressive Lenticular Degeneration: A Familial Nervous Disease Associated with Cirrhosis of the Liver ”.2 Although there had previously been scattered reports of neurological disease in patients also found to have cirrhosis, until SAKW’s work for his 1911 Doctor of Medicine (MD) thesis at Edinburgh University Medical School (Figure 1B),1 this particular association with liver disease had not been recognized formally. And so began the story of what became known as Wilson’s disease or increasingly more commonly known by the non-possessive eponym,3 Wilson disease (WD), since SAKW neither had the disorder nor owned it.FIGURE 1: (A) Samuel Alexander Kinnier Wilson (1878–1937): A photograph from the early 1920s. Included with the kind permission of his grandson, James B Kinnier Wilson. (B) Title page from SAKW’s 1911 MD Thesis, which is unusual as is it handwritten; awarded by Edinburgh University Medical School. Courtesy of the University of Edinburgh1.In this essay, we shall look at what came before and the journey after 1912 (Figure 2) through clinical associations, recognition of the role of copper, the disease genetics, therapeutic developments, and eventually, the cloning of the gene harboring mutations, which led to mutation analysis and an increased understanding of the cellular mechanisms involved in copper metabolism. Much remains to be understood and studied, but the strands that have led to our present knowledge are fascinating and highlight “translational medicine” as the product of serendipity and an alert mind (or as Pasteur would have it “a prepared mind”), [ … in 1854 during a lecture at the University of Lille, Pasteur declared “In the field of observation, chance favors only the prepared mind “], with insights into chemical and cellular detail and the application of advances in molecular genetics.FIGURE 2: Wilson disease: timeline (devised by the author)Now read on… SAKW’S EARLY YEARS, THE DRAW TO NEUROLOGY, AND HIS CAREER AS A NEUROLOGIST SAKW was born in Cedarville, New Jersey in the USA in 1878, the son of an Irish Presbyterian clergyman, the Reverend James Kinnier Wilson, and a Scottish mother, Αgnes Legerwood. After his father died of yellow fever in SAKW’s infancy, young Samuel Alexander returned with his mother and sister Εdina to Edinburgh,4 where he was educated at George Watson’s College [established as a hospital school in 1741, which then became a day school in 1871—later to merge with George Watson’s Ladies College in 1974] after which he studied at Edinburgh University. He was an exceptional student graduating MA in 1897 aged 19, with prizes in Latin, Greek, History, Fine Art, and Archaeology.5 He then paid his way through Medical School by supervising students studying Latin and Greek,4 and he graduated MB BCh, in 1902. [Medicinæ Baccalaureus et Baccalaurens Chirurgiæ (MB BCh)—also designated alternatively as MB BS, MB BChir, and BM BCh—is a primary (bachelor) medical degree awarded by medical schools in countries that follow the tradition of the United Kingdom. The historical degree nomenclature indicates that there are 2 degrees, but they are usually combined and considered together as 1. In the United Kingdom, an MD is awarded on subsequent successful completion of a research thesis.] SAKW was awarded first-class honors in Anatomy, Physiology, Medicine, Surgery, Midwifery, and Pathology.5 In 1903, he was appointed Junior House Physician (ie, Intern) to Dr Byrom Bramwell (1847–1931, later President of the Royal College of Physicians of Edinburgh, who was knighted by King George V in 1924) at the Royal Infirmary in Edinburgh. SAKW also worked for a Bachelor of Science degree in Physiology, for which he received a distinction (honors). Unusual for that stage in his career, he then took up a placement in Paris for 1 year (1903–1904), as a Carnegie research fellow working both clinically and in pathology with the famous neurologist Professor Pierre Marie (1853–1940), renowned for the neurological hereditary motor and sensory neuropathy “Charcot-Marie-Tooth” disorders, and the first description of acromegaly, at the Bicêtre Hospital in the southern suburbs of Paris; there he was befriended by many other famous neurologists in Paris, including Joseph Jules François Félix Babinski (1857–1932) and Georges Charles Guillain (1876–1961).6,7 While abroad, SAKW also visited Paul Emil Flechsig (1847–1929), a neuroanatomist, neuropathologist and psychiatrist, in Leipzig. These links also underscored his linguistic abilities, particularly in French and German. SAKW’s interest in neurology had been piqued by Dr Bramwell, but the opportunity in Paris was pivotal for his future choice of career, and his lifelong appreciation of French mores, and neurology and philosophy.7 In 1904, 5 papers with SAKW as author or co-author were published in French journals,6 including 4 in Revue Neurologique, which is the journal of the Société de Neurologie de Paris—co-founded by Babinski. The secondment in Paris gave him experience that likely enhanced his successful application in 1904 for a House Physician post at the National Hospital for the (Relief and Cure) of the Paralyzed and Epileptic [later the National Hospital for Nervous Diseases, and since 1990, the National Hospital for Neurology and Neurosurgery8], in Queen Square, Bloomsbury, London (Figure 3)9—which Robert Louis Stevenson romanticized as “…a little inclusion of tall trees and comely brick houses … It seems to have been set apart for the humanities of life and the alleviation of all hard destinies. As you go round it, you read upon every second door plate, some offer of help to the afflicted”.8,9FIGURE 3: The National Hospital for Nervous Diseases, Queen Square. Reproduced from Hamilton.9SAKW’s 6 glowing references for his application for the Queen Square post came from many sources, including Bramwell and Marie.5,6 Dr George Alexander Gibson MD, DSc, FRSE, FRCPE (1854–1913), a prestigious Scottish physician, wrote: ”I know of no one whom I could more confidently recommend for the vacancy at the National Hospital. Dr Wilson is admirably equipped for the prosecution of neurological work, an expert pathologist, conversant with the most modern methods of histological and bacteriological investigation, a skillful photographer (for clinical and pathological work), and a man of great clinical insight and of ready resource in treatment”.5 Clearly, here was a young physician (aged only 26) with exceptional skills and talents, and these are exemplified by his subsequent work. He was a house physician at Queen Square between 1904 and 1908 and then a Registrar10 (British equivalent to a Senior or Chief Resident) between 1908 and 1912. In addition to his enduring career-long appointment at Queen Square, he was the first physician in Britain to be given a purely neurological appointment at a general hospital, that is, junior neurologist (later Senior Neurologist) at King’s College Hospital, after resigning his assistant physician appointment at Westminster Hospital in 1919.10 He was the founding editor in 1920 of the Journal of Neurology and Psychopathology, now known as the Journal of Neurology, Neurosurgery and Psychiatry, and he wrote a renowned 2-volume textbook of neurology, which was published posthumously in 1940,11 edited by Dr Alexander Ninian Bruce, a neurologist in Edinburgh, and SAKW’s brother-in-law.6 Dr Bruce wrote in his foreword,11 “Dr Wilson possessed an encyclopedic mind; he read everything he could find about any subject which attracted his interest at the time, and he seemed to have the special gift of remembering anything he ever read.” SAKW also succeeded in private practice in Harley Street where he lived in Central London, and where fashionable private specialists in medicine and surgery have practiced since the 19th century. If it were not for SAKW’s untimely death in 1937, at age 58 from cancer, he might have enjoyed the rare distinction and possibly unique honor of being elected a Fellow of the Royal Society, having been proposed by the 1932 Nobel Laureates, Sir Charles Sherrington and Lord Edgar remarkable SAKW was as a man and as a that he was the and of the and that in the and he and the were the 2 the SAKW published on of and motor and and pathological and he was and in the or the but He was an of a with he would a of on the that was from an was unique in SAKW was that of that he in every of neurology and which he to He was a and with to students and junior In his his son James he could be and there was his He was a remarkable man life was before his MD A THE After 5 working SAKW his of the Royal College of Physicians of London and with a research from the Medical he his work on this neurological which his MD thesis University 1911 (Figure now and his published in in to Paris gave him the opportunity to present his at the Société de Neurologie de Paris on 1912. was by a article in Revue in After his was published in there was also a on this in the in These on the of Lenticular to the neurological the association with cirrhosis, and the possibly being a from the since the to be to copper As in his SAKW that the was not he in detail the clinical where pathological in patients with a of neurological in particular of the and the (Figure and and some It later came to through a (Figure between SAKW’s a University James Kinnier died in the neurologist, and James Kinnier Wilson’s James that a remarkable had been in the by SAKW of patients with It been that SAKW had been and to this through his with with whom he at the James Kinnier Wilson wrote that what SAKW most in was that the considered it of the of to by and the of He that SAKW both and enjoyed Wilson disease patients with neurological (A) of at in the of which SAKW received from Dr the of and (B) of in the and of to the of the and from Kinnier of James Kinnier Wilson the son of and the who on neurological and that the and of neurological that SAKW was and he that in these there was cirrhosis, but he that this was In his these and other were from a of 4 of whom he had and studied clinically a in 2 from at the National Hospital, Queen Square, and 6 from the 1 in et to his thesis was the of of the in of the patients in whom pathology with liver was (Figure and being of the and (A) Liver from in SAKW’s to (B) from the as in (A) of the of a who died of of the liver of for with from Kinnier was his to the clinical of and the pathological of the disease that he to the in the of in first in to clinically a whom he had not for some and then in after the had to an to the and his research is it have been in to a journey to by and at is also a of SAKW’s on are the of his to this clinical and then the pathological of both and (Figure and are from this The detail is It is to that other reports had previously to patients with and neurological In his in a who now been to have had It is that in also a with this which was by one of the in (Figure who died aged in through the later of the neurologists had a with clinical to but recognized and by as this became known as Cirrhosis was an in some of these Dr Courtesy of in an to his in to a by published in 1911 with and cirrhosis, but page that and … for which were to but not be and that of the subject be the for some after SAKW published his in the neurological and other of what became known as his in and in in that and Wilson disease were the from the of and from a of with a by Pierre entitled the in 4 of his and from the from his and he also that it was an and became recognized in the as one and the The experience that patients could have a of neurological the of the that is, a SAKW had a of the more with a of other neurological is in the by et a the in neurological in through the The most from 4 and SAKW’s seminal the of clinical of been recognized and as Dr patients are ever the in a present and an clinical of SAKW not in his These in been by and a before SAKW’s but the of and association with took some to were at one to be to an of but they are or and in are to the of copper at the of the the first as a then at 6 and the (Figure a by an be (Figure and not be by New are now being to help with for as in et (A) a in the (B) of the copper at the of the in and from et the of of the SAKW had that not to be clinically Bramwell in and then and between and that liver could of clinical liver disease that in some patients could be the of are and in with or other clinical including and other by from the of Medical in New in and The of was first in detail in by et from at the Royal Hospital and School of Medicine in was an who had a to research and clinical As a medical student he had the of having his research published in and the Journal of also enjoyed a interest in medical and of medical about which he and the of in in which the was the London School of Medicine for in first Hospital in to was later appointed to the of the of Medicine and of the Liver Professor who in had been appointed to the of the of Medicine at the was then the first Professor of Medicine at the Royal and the first to be appointed to the of Medicine in a Medical School. was elected a Fellow of the Royal in in Professor Professor of Medicine at and later of the of Medicine and of the Liver with permission from until the and early SAKW had that the was to a but not to or and that it was but not of was to the that understanding of the recognized then with was in infancy, and that SAKW that it might be but not The to copper had been as a previously by in a with and including A recognition of this copper association came from at Queen Square in who increased copper in the and liver of patients with In the in a by et that on copper in was given to the copper and one of the who it had was found to have copper to increased copper the liver could from copper The in a by in at the Hospital, of in which that were given copper a of the of liver copper in was the primary as to being to an of as by et in took some to The primary role of copper in was by and in the of patients with with then as a copper the of the advances in the genetics, and of and first and in were by of a in a with who it not have this of in after in by and an and in by and an since is a SAKW’s on that is, have been in published from his of patients and that was in studied in and that this was an which he in a in The gene involved was not until on that The to and patients with copper had to the of with copper and the later analysis of copper in a of and the of copper on The of copper by the liver to the stage of in early disease and after of copper by and in disease the liver was with in neither was there a of in the of copper in and into the as in The copper in was by in and and in the of these not in THE TO copper was involved in was by the of the in in the for is a not only of copper but other including and that might be to and in he in the and in the the of in had to be given by and this copper was And this is Dr (Figure the is an of “translational that together a clinical to and the chemical of a studied for a in his of a to in the early was working in the at University College London with Dr (later Charles studying in the of patients with liver In one there was a which it was might be a the was and it that this in of a product of published this work in and not after he to in on a to work in the Liver at Hospital with Dr Charles a round the neurological for on the of a with Wilson disease who was not on his work on on chemical it would He that this might copper and a story a was and was by Dr some after about the and the received some and this led to a in copper seminal and led in on his to to more patients with who were given The as a in in the and the Journal of Medicine and by and and at the College of Medicine in New other in the clinical of The the of and had a on the and of patients the subsequent the later of other it is now to to therapeutic of of in copper In the and early there had been a of papers on copper in in which both and were known to In this the Alexander who published a of papers on the had in that liver copper in in the of these to in the He published this work in his in and his experience with this at an Disease and at in in the in also from the the on the of at this and in later chance observation, led to the of in the United and et in that patients with being with copper led George to a of on and copper and in patients with with the of in was from of the of in and in the was after a who could not on of and who an He this with his Dr a and Fellow of King’s University in who was an expert on Dr that might be in his and the now and it to copper and to be an for have in for of were also by that copper in and and that this was by The was that the of copper in the and this of was in first by he also at the and then in a of 1 in which and were in a by George and a more to have but of this been of been studied in of a of have been in to for are in in And more have been and are being which of the is most and for which clinical remains an of and These and other of are in a Much work is being on methods for the of these to clinical and indicates that is usually and be As wrote that no patients are the and all his work and he was not to which patients would or would not to or on what was to be the for a of liver is after was first for by a led by and in And liver is a for patients with with liver and for with liver disease who are to medical of the liver the are to with other of liver and disease liver the other neurological as the primary for remains THE the gene is an as an to the and the of been studied in but this stage of work the of the of the and then cloning of the gene and of cellular In the of the to was as being on to the for In 1990, the was to between and of the The et for was the cloning of the disease gene early in being a in which copper is to copper and a of in the cloning of the gene 2 of whom from the disease the a from the The gene product is a of copper between and in the of copper between the and that copper to the (Figure to a of of copper to in the and into the of copper to and of copper into the as in of other have that have a of other in with Reproduced from et the liver through the and is into liver by the to to to the into the for into and to the for of which clinically as for of led to a of of copper and the recognition that there are more with of was for many by Professor Wilson and at the University of and been of but the not been since are now for mutation analysis to be as of the of and work also been to and a but to are to have a of the gene and of molecular work on to gene in other the of a gene for patients with work been If this be to as been in other it could be an therapeutic for 1 and 2 are and the is to copper to as a as since copper is for so many cellular and editor this in his article in not but The of this and other on the of copper not from the of copper to TO as the of the of on in molecular other of in clinical and have on other is in the by et in which a is (Figure read SAKW’s historical in and in this article one of the (Figure the is that now pathological that previously SAKW’s was published from and both are of the in in a with Wilson with permission from et been to more of in previously (or but now and began in London in the by (later at the of the Central in was known at the for the was and clinical with in was published by who to this with a historical on The first in in the became a to a from a between the Royal Medical Hospital and the been remarkable since are now for and or the in are in the in or so of patients with a neurological A the and known as of the of a is only in a of The is that previously only on as (Figure now be to in many of and and a and be in patients with and a of be with clinical and an for clinical and research in patients with where understanding the neurological and the of remains et that the what SAKW the a little a And are of advances in and to specialists clinical to clinical or in the of a at the on Wilson Disease and Disease in in and published later by et to who to so many in and died in The which is recognized as an is in the trees in the and is to for inclusion in clinical there are other the King’s in New Wilson published by et in to in patients with liver the Wilson’s Disease proposed by et in (later and also a from et While these be to the clinical in patients with other of in have also been As with other clinically and it is to as experience with other that to be from to the of on with many in research and and for have from the some of which are or have been The of the is by the of which have been the the in in been the Wilson led by Professor been in there are that a role in the of patients and and a to The in the USA year and the is The and of the disease that is been up the by a of and and cellular and molecular Much research is all involved a of for in what been and remains a clinical And this all began with Samuel Alexander Kinnier Wilson and his seminal work published a