Elsevier

Revue Neurologique

Volume 169, Issue 12, December 2013, Pages 936-943
Revue Neurologique

History of Neurology
Wilson's disease, 100 years later…La maladie de Wilson, 100 ans après

https://doi.org/10.1016/j.neurol.2013.05.002Get rights and content

Abstract

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.

Résumé

Sir K. Wilson publia, en 1912, il y a 100 ans, une série d’article sur la maladie de Wilson dans Brain, The Lancet et La Revue Neurologique. Ces textes reflètent la pertinence de ses descriptions à la lumière des connaissances actuelles. Des progrès ont été réalisés ces dernières années pour mieux comprendre la physiologie de la maladie de Wilson (MW) et aider le médecin à faire le diagnostic plus précocement. Les symptômes hépatiques et neurologiques sont les manifestations les plus fréquentes mais les atteintes rénales, ostéo-articulaires, cardiaques et endocriniennes font de la MW une maladie multisystémique. Le diagnostic repose sur la combinaison de symptômes cliniques, biologiques, radiologiques et des données génétiques et de nouveaux outils (IRM cérébrale, dosage du cuivre échangeable relatif…) qui permettent de réduire le délai entre les premiers symptômes et le diagnostic. Les avancées thérapeutiques ont également changé le pronostic de la maladie. Le traitement est basé sur des chélateurs du cuivre (D-pénicillamine et la triéthylènetétramine) et des sels de zinc pour réduire l’absorption du cuivre. Le tétratiomolybdate semble être un traitement prometteur. Bien que des progrès importants aient été réalisés au cours de ce siècle, de nombreuses questions trouveront peut-être des réponses dans ces 100 prochaines années.

Introduction

Clinical description of the “progressive lenticular degeneration” published by Sir K. Wilson in Brain, The Lancet and La Revue Neurologique in 1912 has stood the test of time (Wilson, 1912a, Wilson, 1912b, Wilson, 1912c). This is particularly remarkable as Sir K. Wilson saw a very limited number of patients and had no clear ideas about the pathophysiology of the disease. However, subsequent progress was made over the next 100 years due to the contribution of many authors (Walshe, 2006). It appears therefore relevant to us to compare Wilson's initial description with recent data from both international literature and the French national cohort (unpublished data). To this end, we used several important points underlined by Wilson in his original description with citations from the original text published in La Revue Neurologique (Wilson, 1912a) to update the state of the art on Wilson's disease diagnosis and care.

Section snippets

« La dégénérescence lenticulaire progressive est une affection nerveuse très souvent familiale mais jamais héréditaire… » - “The progressive lenticular degeneration is a nervous affection often familial but never hereditary…”

“Familial but not hereditary” mentioned in the text by Sir K. Wilson corresponds to the autosomal recessive transmission as proposed in 1921 by Hall 11 years after Wilson's publications (Hall, 1921). Transmission in siblings is frequent (the risk of a sibling developing clinical disease is 25%). The risk of transmission from affected subject to their children in the absence of consanguinity is lower, estimated at 0.5%. However, few reports from the literature underline the importance of family

« …supposer que la cirrhose hépatique est primitive et qu’une toxine inconnue, d’origine hépatique, exerce une action élective sur les noyaux lenticulaires… » - “…assume that liver cirrhosis is a primitive and that an unknown toxin, from hepatic origin, exerts a selective action on the lenticular nuclei…”

Wilson's invocation of an “unknown toxin” is a prophetic intuition as the presence of excess copper in the liver was mentioned for the first time a year later (Rumpel, 1913), whereas the role of copper in this disease was not described until 1929 (Vogt, 1929). Vogt et al. showed that the disease is caused by copper overload. Copper, an essential trace element for all living organisms, is involved in various metabolic systems including mitochondrial function, biosynthesis of neurotransmitters,

« Les sujets sont toujours de jeunes gens dont l’âge varie de 10 à 25 ans… » - “Subjects are always young people ranging in age from 10 to 25 years…”

Indeed, Wilson's disease is rarely observed before 3 years of age, reflecting the considerable capacity of the liver to store copper excess. It becomes symptomatic in most cases at an age ranging between 5 and 35 years. However, in our experience, 12% of our series were diagnosed after the age of 30. In the literature, exceptional cases of Wilson disease have been diagnosed at the extreme ages of 2 (Beyersdorff and Findeisen, 2006) and 72 years by the discovery of Kayser Fleischer ring (

« …une cirrhose hépatique, qui est constante dans cette affection… » - “…liver cirrhosis, which is constant in this condition…”

Liver disease is generally constant; histology can show steatosis, fibrosis or cirrhosis, with a clinical spectrum ranging from asymptomatic cytolysis to acute liver failure (Ala et al., 2007). Non-specific symptoms such as nausea, anorexia, fatigue, abdominal pain may also be the expression of the disease.

The main forms of liver disease are acute hepatitis mimicking an acute viral hepatitis, autoimmune hepatitis, chronic liver disease, decompensated cirrhosis or fulminant hepatitis. Some

« Les malades ont toujours une dysarthrie… » - “Patients have always dysarthria…”

First neurological symptoms appear insidiously. Dysarthria is one of the key neurological feature, first occurring in 40% of patients with neurological form of our series, and described in the course of the illness in 91% of the patients in a Brasilian cohort (Machado et al., 2006). Speech disturbances are frequently associated with swallowing difficulties and hypersalivation. Dysarthria is often mixed, associating dystonia, ataxia, hypokinesia, reflecting the clinical symptoms observed

« Les muscles faciaux sont souvent fixés en sourire épanoui… » - “The facial muscles are often set in beaming smile…”

Patient's faces are often very evocative: the face is frozen, with an open mouth and peri oral muscle hypertonia which gives an appearance of a permanent smile. Facial dystonia leads to a facial appearance called “sardonicus” (Boudin and Pépin, 1959).

« Un état spasmodique de tous les muscles volontaires… » - “A spasmodic state of all voluntary muscles…”

Dystonic syndrome begins with focal signs or function dystonia (writer's cramp) and can progress in the absence of treatment to generalized dystonia. Dystonia can reach all body parts; sometimes mobile dystonia can evolve to fixed postures. Standing is sometimes unstable with axial dystonia opistotonos and hyperlordosis; walking on tiptoe is observed, as “cock gait” with arms retropulsion.

« …un tremblement involontaire bilatéral du type intentionnel… » - “…an involuntary bilateral tremor intention type…”

Tremor is the most frequently observed abnormal movement. This can be: a rest tremor, a postural tremor or action tremor, presenting sometimes as essential tremor and may affect the arms and head (Oder et al., 1991). Intention tremor called wing beating tremor is very suggestive of Wilson's disease. It may be asymmetrical and associated with cerebellar syndrome. Dystonia, chorea, Parkinson syndrome and tremor may be associated resulting in a mixed clinical presentation.

A cognitive-behavioral

« Les pupilles et le fond d’œil sont normaux… » - “The pupils and eye fundus are normal…”

Indeed, pupils and eye fundus are normal in Wilson's disease. Sir K. Wilson did not observe Kayser Fleischer ring (KF) which is a brown, gray or golden deposit located at the periphery of the cornea observed under slit lamp examination (Fig. 2). KF is initially seen in the upper and lower poles of the eye and reflect copper overload in the Descemet's membrane. Even if the ring is not specific for Wilson's disease as this can be observed, in exceptional circumstances in non Wilsonian cholestatic

« Une dégénération bilatérale symétrique du corps strié, surtout du putamen, mais aussi du globus pallidus… » - “A bilateral symmetrical degeneration of the corpus striatum, especially the putamen, but also the globus pallidus…”

New non-invasive techniques allow us to confirm what Sir K. Wilson observed in pathological studies. Magnetic Resonance Imaging (MRI) shows hyperintensity on FLAIR, T2 and diffusion of the lenticular nuclei, midbrain and dentate nuclei of the cerebellum (Fig. 3) (Sener, 2003). These abnormalities can be present in almost 20% of presymptomatic patients. The characteristic “face of giant panda” has been described on MRI T2, FLAIR and midbrain (Hitoshi et al., 1991). Asymmetrical lesions can

« La durée des cas aigus est de 4, 6, 10 mois; celle des cas chroniques peut être de 5 ans… » - “The duration of acute cases is 4, 6, 10 months and of chronic cases may be 5 years…”

Before the advent of treatment with chelators and zinc salts, WD was always fatal. Today, the prognostic of WD with medical treatment is generally good and neurological recovery can be complete in some cases. Spectacular regressions of pronounced neurological symptomatology may be observed. However, patients may frequently still keep a monotonous voice and a dystonic posture. MRI signal abnormalities decrease during treatment (Roh et al., 1994). The Kayser Fleischer ring fades gradually to

Conclusion

Rereading of texts published by Sir K. Wilson in 1912 on his eponymous disease highlights the relevance of his descriptions in the light of the current knowledge. Much progress has been made during the last 100 years, especially in therapeutic management that has changed the prognosis of the disease. Wilson's disease is now a metabolic disease with an effective treatment if it is started early and maintained for life. New diagnostic tools have recently (REC) been developed to shorten the time

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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