Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
History
Dr. Samuel Alexander Kinnier Wilson, an American-born British neurologist, first described Wilson disease in his doctoral thesis, which was published in Brain in 1912 (the longest article ever to appear in Brain, at 214 pages). He had submitted the thesis in July of 1911 as a candidate for the degree of medical doctor at the University of Edinburgh and was awarded a gold medal for the excellence of his research.1,2
In his thesis, Wilson described a fatal disorder, affecting primarily young people, that often followed a familial pattern of inheritance. He encountered 4 cases—2 of them in siblings. He also found notes describing 2 other cases, both within the same families. The patients presented with extrapyramidal movement disorders indicative of abnormalities of the corpus striatum. The symptoms included tremor that increased with intentional movements, dysarthria, facial spasticity, and emotionalalism.2
Further examination of the patients revealed a loss of neurons, gliosis, and the formation of cavities within the lenticular nucleus, particularly the putamen and sometimes the globus pallidus and caudate. Wilson also documented profound cirrhosis of the liver accompanying the central nervous system changes, which often did not cause symptoms during the patient’s life, when the manifestations of Wilson disease were exclusively neurological.2
In his thesis, Wilson detailed the historical background of the disease, describing previously suspected cases that appeared in the literature. He noted an unrecognized case from 1854, described in 1860 in Wilhelm Frerichs’ Treatise on Disease of the Liver, which was later translated by the New Sydenham Society.2
In 1888, in his Manual of Diseases of the Nervous System, Sir William Gowers mentioned the case of a 10-year-old boy, Sydney M., and 4 relatives with similar symptoms, including facial grimacing, dysarthria, flexion contractures, and involuntary movements (chorea, dystonia, tremor). At autopsy, Gowers discovered cirrhosis of the liver without significant abnormalities of the nervous system. He made no further comment.2
Sydney’s sister, Charlotte, presented with involuntary movements that were more rhythmical and tremulous than those of her brother; the same pathological findings were noted at autopsy.2 A third sibling was 1 of the 6 cases that Wilson described in his thesis. Wilson focused on a passing observation made by Joseph Arderne Ormerod in 1890 about this third sibling. Ormerod mentioned a softening of the lenticular nucleus caused by inflammation, in addition to liver cirrhosis.2
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At about the same time, in 1890, Homén in Finland detailed similar cases in 3 siblings, Alfred, Wilhelm, and Anna K. They all presented with dysarthria, a gaping mouth, incontinence, contractures, involuntary movements, and spasticity. At autopsy, liver cirrhosis along with softening and cavity formation within the lenticular nucleus was noted in all of them.2
Wilson noted that the previous authors had never considered a possible pathogenetic link between the abnormalities in the liver and those in the lenticular nucleus. The first patient with the same condition whom Wilson encountered, in 1905, was being treated by Sir David Ferrier. Wilson made the connection between the patient’s presenting symptoms and those described by Gower.2
Wilson described a second patient, 20 years of age, with untidy handwriting, dysarthria, a gaping mouth with sialorrhea, involuntary movement, spasticity, contractures, emotionalism, and occasional confusion. Her brother first presented with psychiatric symptoms, claiming to hear God and the devil simultaneously. Neurological symptoms developed later.2
The fourth patient, 18 years of age, had jaundice along with neurological symptoms of clumsiness, rhythmical tremor, dysarthria, dysphagia, hypomimia, hypersalivation, and contractures. This was the first time that a patient manifested evidence of liver disease along with neurological symptoms. The fifth patient, Christopher J., 13 years of age, also presented with signs and symptoms of liver dysfunction.2
Wilson deduced that the condition was unrelated to alcohol use, syphilis, or previous infection. He suspected an etiology reflective of progressive toxicity, evidenced by fever, jaundice, and emaciation, with eventual rapid progression to neurological disease affecting movement.2
He particularly emphasized that no case of lenticular nuclear degeneration occurred without concomitant liver cirrhosis, hypothesizing that “the condition is acquired and due to a toxin that is not microbial, ‘but possibly … chemical and of the nature of a lipoid’, elaborated in the liver and delivered via the bloodstream.”
In 1913, just 1 year after the publication of Wilson’s original thesis, Rumpel suggested the possibility that excess copper was the pathogenic agent in this newly discovered condition. His suggestion was not examined further until 1948, when John Cumings reported that excess copper accumulated in both the liver and brain of patients with Wilson disease. Cumings proposed treatment with the chelating agent dimercaprol to slow progression of the disease by preventing further accumulation of excess copper.3
Researchers under the direction of Sir Rudolph Peters, a professor of biochemistry at Oxford, developed dimercaptopropanol as an antidote for the arsenical war gas “lewistite” because of the fear that Hitler would attack the British Isles with this chemical weapon.3 Dimercaptopropanol was the chelating agent suggested by Cumings to treat Wilson disease.3
In 1951, Cumings in London and Denny Brown and Porter at Boston City Hospital independently proved that dimercaprol effectively treated Wilson disease. Because of decreased efficacy and high rates of toxicity after repeated administration of dimercaprol, it was clear that other chelating treatments needed to be developed for the long-term management of Wilson disease.3
In 1952, Bearn and Kunkel and Scheinberg and Gitlin independently described ceruloplasmin deficiency in patients with Wilson disease. Treatments with high-protein diets, steroids, and another chelating agent, ethylenediamine tetra-acetic acid, proved ineffective.3
At about the same time, Professor Charles Dent at University College Hospital observed the excretion of an amino acid, dimethyl cysteine, in the urine of a patient with hepatocellular carcinoma following a partial liver resection. Dent made the connection between dimethyl cysteine as a metabolic byproduct of penicillin, also known as penicillamine.3
Throughout the 1950s, J. M. Walshe experimented further with penicillamine, discovering that when combined with tap water, it turned bright blue because of the chemical reaction between iron in the tap water and a sulfhydryl group in penicillamine; this reduced the toxic effects of penicillamine when ingested. When a patient with Wilson disease was treated with penicillamine by Dr. Charles Davidson at Harvard, significant amounts of copper were excreted in his urine without toxic side effects.3
In 1961, Schouwink, a Dutch neurologist, proposed an alternative treatment for Wilson disease, suggesting that zinc salts could effectively prevent the intestinal absorption of dietary copper. However, zinc did not promote copper excretion in the bile or urine, so that the removal of excess copper occurred slowly. The US Food and Drug Administration approved zinc as a supplemental treatment to be used for maintenance after initial treatment with a chelating agent.3
An increasing number of patients with Wilson disease demonstrated penicillamine intolerance, so that the development of an alternative, nontoxic chelating agent like penicillamine was needed. Dr. Hal Dixon at the University Department of Biochemistry at Cambridge proposed the use of triethylene tetramine because the structure of this compound mirrors those of existing nontoxic biological amines. Researchers later used triethylene tetramine to develop another chelating agent, trientine.3
These 3 therapeutics—penicillamine, trientine, and zinc—form the backbone for the current treatment and management of Wilson disease. However, not all patients respond as expected, providing incentive for further research and the development of alternative treatments for this condition.3
References
- Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain. 1912;34(4):295-509. doi:10.1093/brain/34.4.295
- Compston A. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver, by S. A. Kinnier Wilson, (from the National Hospital, and the Laboratory of the National Hospital, Queen Square, London). Brain. 1912:34;295–509. Brain. 2009;132(8):1997-2001. doi:10.1093/brain/awp193
- Walshe JM. The conquest of Wilson’s disease. Brain. 2009;132(8):2289-2295. doi:10.1093/brain/awp149
Reviewed by Harshi Dhingra, MD, on 9/28/2022.
