History of Wilson disease: a personal account.

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.

Wilson's disease: the 60th anniversary of Walshe's article on treatment with penicillamine.

This historical review describes Professor Walshe's seminal contribution to the treatment of Wilson's disease on the 60th anniversary of his pioneering article on penicillamine, the first effective treatment for the condition.

Wilson's disease: the 60th anniversary of Walshe's article on treatment with penicillamine / Doença de Wilson: o 60° aniversário do artigo de Walshe no tratamento com penicilamina

ABSTRACT This historical review describes Professor Walshe's seminal contribution to the treatment of Wilson's disease on the 60th anniversary of his pioneering article on penicillamine, the first effective treatment for the condition.

RESUMO Esta revisão histórica enfatiza a contribuição seminal do Professor Walshe no tratamento da doença de Wilson (DW), com o seu trabalho pioneiro sobre o uso de penicilamina, o primeiro tratamento efetivo do mundo, publicado 60 anos atrás.

The copper rush of the nineties.

The nineties witnessed the discovery of the copper ATPases, enzymes which transport copper across the cytoplasmic membranes of bacteria and eukaryotes. In the same decade, several other key components of copper homeostasis have also been discovered, like copper chaperones and plasma membrane copper transporters. This has finally led to a molecular understanding of two inherited human diseases related to copper: Menkes disease, manifested by systemic copper deficiency, and Wilson disease, caused by defective secretion of excess copper. A historic perspective and untold stories of the events leading up to these discoveries are presented here.

[Samuel Alexander Kinnier Wilson].

Samuel Alexander Kinnier Wilson is considered a pioneer in extrapyramidal system research largely due to his dissertation on progressive lenticular degeneration, later known as "Wilson's Disease". His concept of neurological symptomatology was based on the clinical observations of Pierre Marie, Joseph Babinski and John Hughlings Jackson, who he observed when he was young. To keep focusing on the nature of actual symptoms while performing medical examinations is the essence of neurological symptomatology, which in turn form the spirit of neurology. This paper will discuss major events in Wilson's later life that would explain how his basic idea for neurological symptomatology was eventually formed.

Samuel Alexander Kinnier Wilson. Wilson's disease, Queen Square and neurology.

This historical article describes the life and work of the British physician Samuel Alexander Kinnier Wilson (1878-1937), who was one of the world's greatest neurologists of the first half of the 20th century. Early in his career, Wilson spent one year in Paris in 1903 where he learned from Pierre-Marie at Bicêtre Hospital. He subsequently retained uninterrupted links with French neurology. He also visited in Leipzig the German anatomist Paul Flechsig. In 1904, Wilson returned to London, where he worked for the rest of his life at the National Hospital for the Paralysed and Epileptic (later the National Hospital for Nervous Diseases, and today the National Hospital for Neurology and Neurosurgery) in Queen Square, and also at Kings' College Hospital. He wrote on 'the old motor system and the new', on disorders of motility and muscle tone, on the epilepsies, on aphasia, apraxia, tics, and pathologic laughing and crying, and most importantly on Wilson's disease. The other objective of our paper is to commemorate the centenary of Wilson's most important work published in 1912 in Brain, and also in Revue Neurologique, on an illness newly recognized and characterized by him entitled "Progressive lenticular degeneration, a familial nervous disease associated with liver cirrhosis". He analyzed 12 clinical cases, four of whom he followed himself, but also four cases previously published by others and a further two that he considered in retrospect had the same disease as he was describing. The pathological profile combined necrotic damage in the lenticular nuclei of the brain and hepatic cirrhosis. This major original work is summarized and discussed in the present paper. Wilson not only delineated what was later called hepato-lenticular degeneration and Wilson's disease, but also introduced for the first time the terms extrapyramidal syndrome and extrapyramidal system, stressing the role of the basal ganglia in motility. The present historical work emphasizes the special contributions made by Wilson to the study of movement disorders, including akinesia and bradykinesia in Parkinson's disease, and their relation to basal ganglia pathology.

Wilson's disease, 100 years later .

Texts published, in 1912, 100 years ago, by Sir K. Wilson on his eponymous disease in Brain, The Lancet and La Revue Neurologique highlight the relevance of his descriptions in the light of the current knowledge. Wilson's invocation of an "unknown toxin" appears today as a prophetic intuition as the presence of excess copper in the liver was mentioned for the first time a year later whereas the role of copper in this disease was not described until 1929. Progress has been made to better understand the physiology of Wilson's disease (WD). The ATP7B gene implicated in WD is located on chromosome 13 and more than 500 mutations and 100 polymorphisms have been to date identified. The phenotypic expression is highly variable, even within a family. This can partly be explained by environmental factors as nutrition. Modulator genes are also involved in the phenotypic expression of the disease. Most of symptoms observed in WD have already been described in detail by Wilson in 1912, but subsequent progress was made over the following 100 years, helping the physician diagnose WD. Hepatic and neurological symptoms are the most frequent expressions of the disease. Other extrahepatic features include renal manifestations, osteoarticular disorders, myocardial abnormalities, endocrine disturbances, realizing a multisystemic disease. The diagnosis of the disease is based on a combination of clinical symptoms, biological, radiological and genetic data and new tools (Brain MRI, relative exchangeable copper…) allow reducing delay to diagnosis. Therapeutic findings have also changed the disease prognosis. Treatment is based on the use of copper chelators to promote copper excretion from the body (D-penicillamine and Triethylenetetramine) and zinc salts to reduce copper absorption. Tetratiomolybdate appears to be a promising treatment. While significant progress has been made during this century, many physiological aspects of this disease remain unknown and require further research to find answers in the next 100 years.

Wilson's disease.

In the almost 100 years since Wilson's description of the illness that now bears his name, tremendous advances have been made in our understanding of this disorder. The genetic basis for Wilson's disease - mutation within the ATP7B gene - has been identified. The pathophysiologic basis for the damage resulting from the inability to excrete copper via the biliary system with its consequent gradual accumulation, first in the liver and ultimately in the brain and other organs and tissues, is now known. This has led to the development of effective diagnostic and treatment modalities that, although they may not eliminate the disorder, do provide the means for efficient diagnosis and effective amelioration if carried out in a dedicated and persistent fashion. Nevertheless, Wilson's disease remains both a diagnostic and treatment challenge for physician and patient. Its protean clinical manifestations make diagnosis difficult. Appropriate diagnostic evaluations to confirm the diagnosis and institute treatment can be confusing. In this chapter, the clinical manifestations, diagnostic evaluation, and treatment approaches for Wilson's disease are discussed.

[Wilson's disease and Westphal-Strümpell pseudosclerosis: conceptual history in German-speaking countries]. / Wilson-Krankheit und Westphal-Strümpell-Pseudosklerose : Zur Ideengeschichte im deutschen Sprachraum.

The article investigates the hitherto little elaborated conceptual history of Wilson's hepatolenticular degeneration and Westphal's pseudosclerosis from the mid-nineteenth century up to present day, mainly in German-speaking countries. This disease exemplifies how neurological diseases have come into existence and also demonstrates how clinical descriptions of a few isolated cases merge into a nosological diagnosis, how recognized therapeutic measures are developed and how the underlying genetic causes are identified. For some time German-speaking neurologists were in disagreement about whether or not a disease described by Carl Westphal in 1883 was identical with one described by and later named after Kinnier Wilson. This article presents the publications by Adolf Strümpell, Alois Alzheimer, August Bostroem and Walther Spielmeyer as the major contributions of German-speaking specialists to a deeper understanding of an illness and investigates whether or not the two disease concepts represent identical illnesses or not. From 1970 onwards the "Morbus Wilson Center" in Leipzig became important for the development of recognized therapeutic measures and their application in medical practice in Eastern Germany (the former GDR) and its findings have been incorporated in the present Guidelines of the German Society for Neurology published in 2008 for the treatment of Wilson's disease.

Wilson's disease: An Indian perspective.

Wilson's disease (WD) is an autosomal recessive disease involving a defect of copper transport by the hepatic lysosomes. It leads to excess copper deposition in the liver, the brain, the kidneys and the skeletal system, affecting most commonly children or young adults and running an invariably fatal course if not adequately treated by de-coppering therapy. The last century has witnessed several changes, notable among these are: Increased awareness, improved diagnostic facilities leading to earlier recognition even in the pre-symptomatic phase, clear distinction from its mimics, aggressive therapeutic approaches owing to availability of effective treatment and an overall reduction in the morbidity and mortality. It is widely acknowledged that the disease is not as rare as once believed. Sir SAK Wilson published his landmark article in 1912, but it was only in 1968 that the first patient of WD was reported from our country. Publications from India on WD have focused on phenotypic characterization, documentations of lesser recognized aspects of the disease e.g. seizures, behavior abnormality, speech and cognitive impairment, sub-clinical affection of visual pathway, heart and autonomic function and pre-symptomatic detection. Attempts have been made to understand the clinical heterogeneity of the disease through identification of biochemical and immunological markers, magnetic resonance imaging, neuropathological study and genetic analysis for novel and/or known mutations. Assessment of impairment and severity and effect of various therapeutic interventions namely zinc sulphate on the long-term outcome and quality of life have also been studied. Nevertheless, clinicians often face difficulties in long-term care of these patients. Diagnostic errors leading to delay in diagnosis and initiation of treatment are common, even in patients with positive family history. There is no consensus regarding therapeutic protocols since the use of penicillamine, once a 'gold standard' for treatment, has been debated by experts. Mortality and morbidity of this potentially treatable disease and nonavailability of medications to the poor patients remain a major area of concern.

Impact of the discovery of human zinc deficiency on health.

The essentiality of zinc was recognized 46 years ago. Zinc deficiency resulting in growth retardation, hypogonadism, immune dysfunction and cognitive impairment affects nearly 2 billion subjects in the developing world. High phytate content of the cereal proteins consumed in the developing world, results in decreased availability of zinc for absorption. Zinc therapy has been very successful and life saving measure in patients with acrodermatitis enteropathica and Wilson's disease. Beneficial therapeutic responses of zinc supplementation have been ovserved in acute diarrhea in children, chronic hepatitis C, shigellosis, leprosy, leishmaniasis, and common cold. Zinc supplementation was effective in decreasing incidences of infection in elderly and patients with sickle cell disease. Zinc supplementation was effective in preventing blindness in 25% of the elderly with dry type of age related macular degeneration. Zinc supplementation in the elderly decreased oxidative stress and decreased generation of inflammatory cytokines. Zinc is an intracellular signaling molecule in monocytes, dendritic cells and macrophages and it plays an important role in cell-mediated immune functions and oxidative stress. Zinc is also an anti-inflammatory agent. These unique properties of zinc may have significant therapeutic benefits in several diseases in humans. In many diseases concurrent zinc deficiency may complicate the clinical features, affect adversely immunological status, increase oxidative stress and increase generation of inflammatory cytokines. Oxidative stress and chronic inflammation may play important causative roles in many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, and auto-immune diseases. It is therefore, important that status of zinc is assessed and zinc deficiency corrected in these chronic diseases. A controlled clinical trial of zinc supplementation in these disorders in order to document the preventive and therapeutic effects of zinc is warranted.