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Genetical and Clinical Studies in Wilson's Disease

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Genetical and Clinical Studies in Wilson's Disease Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 246 Genetical and Clinical Studies in Wilson's Disease ERIK WALDENSTRÖM ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 UPPSALA ISBN 978-91-554-6845-3 2007 urn:nbn:se:uu:diva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o my family At vide, hvad man ikke véd, er dog en slags alvidenhed Piet Hein List of publications This thesis is based on the following papers, which will be referred to in the text by their Roman numerals: I Erik Waldenström, Arild Lagerkvist, Thérèse Dahlman, Kerstin Westermark, Ulf Landegren (1996) Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics 27:303-309. II Charlotta Olsson, Erik Waldenström, Kerstin Westermark, Ulf Landegren, Ann-Christine Syvänen (2000) Determination of the fre- quencies of ten allelic variants of the Wilson disease gene (ATP7B), in pooled DNA samples. European Journal of Human Genetics 8:933-938. III Kamilla Portala*, Erik Waldenström*, Lars von Knorring, Kerstin Westermark. Psychopathology and personality traits in patients with treated Wilson’s disease grouped according to gene mutations. Submitted IV Joakim Tedroff*, Erik Waldenström*, Vladimir Tolmachev, Hans Lundqvist, Bengt Långström, Kerstin Westermark. 61Cu liver uptake in Wilson disease studied with PET. Manuscript V John M. Walshe, Erik Waldenström, Virginia Sams, Hans Nordlinder, Kerstin Westermark (2003) Abdominal malignancies in patients with Wilson's disease. Quarterly Journal of Medicine 96:657-662. * The first two authors of papers III and IV respectively, contributed equally to the work. Reprints were made with permission from the publishers. Contents Introduction.....................................................................................................9 Copper ......................................................................................................12 Pathophysiology.......................................................................................15 Clinical presentation.................................................................................15 Diagnosis..................................................................................................17 Treatment .................................................................................................19 Aims of the investigation..............................................................................20 Material and methods....................................................................................21 Study I ......................................................................................................21 Study II.....................................................................................................22 Study III ...................................................................................................24 Study IV ...................................................................................................25 Study V.....................................................................................................26 Results and discussion ..................................................................................27 Study I ......................................................................................................27 Study II.....................................................................................................28 Study III ...................................................................................................30 Study IV ...................................................................................................32 Study V.....................................................................................................33 Conclusions...................................................................................................35 Acknowledgements.......................................................................................36 References.....................................................................................................37 Abbreviations 5’ UTR untranslated region upstream of a gene Atox1 antioxidant protein 1 ATP7A ATPase, Cu2+-transporting, D polypeptide – gene ATP7A ATPase, Cu2+-transporting, D polypeptide – protein, syn. MNKP ATP7B ATPase, Cu2+-transporting, E polypeptide – gene ATP7B ATPase, Cu2+-transporting, E polypeptide – protein, syn. WNDP bp base pair(s) CCS copper chaperone for superoxide dismutase CMGP cartilage matrix glycoprotein COMMD1 copper metabolism MURR1 domain-containing protein 1 Cox cytochrome c oxidase assembly protein Cu copper Ctr1 copper transporter 1 DMT1 divalent metal ion transporter 1 H1069Q histidine 1069 glutamine HCC hepatocellular carcinoma kDa kilodalton kb kilobases KF-rings Kayser-Fleischer rings LEC rat Long-Evans Cinnamon (coated) rat MNKP Menkes’ disease protein MURR1 mouse U2af1-rs1 (human) nt nucleotide PCR polymerase chain reaction PET positron emission tomography R1319X arginine 1319 termination codon ROS reactive oxygen species Sco synthesis of cytochrome c oxidase SSCP single-strand conformation polymorphism SNP single nucleoide polymorphism T977M threonine 977 methionine ULN upper limit of normal W779M tryptophane 779 methionine WD Wilson’s disease WNDP Wilson’s disease-associated protein Introduction Figure 1. SA Kinnier Wilson, (1978-1937) (Courtesy of JVK Wilson, son of Dr. SAK Wilson, reprinted with permission from Läkartidningen) S. A. Kinnear Wilson (fig. 1) published his seminal paper ”Progressive len- ticular degeneration: a familial nervous disease associated with cirrhosis of the liver” as his PhD thesis, for which he was awarded a gold medal at Edin- burgh University in July 1911, and the following year in Brain (Wilson 1912, fig. 2). He presented six previously described cases (Gowers 1888; Homén 1890; Ormerod 1890; Homén 1892), one from hospital records, one from interviewing the deceased patient’s 70 year old mother and four cases of his own. Friedrich Theodor von Frerichs, while working in Breslau in 1854, saw a 10-year old boy with a movement disorder and cirrhosis of the liver, and presented it in his textbook “Treatise on Diseases of the Liver” (von Frerichs 1861). While Wilson’s article was in press, he noted von Fre- rich’s case report and added this as a note in his monograph. He also added a case presented by Völsch of a patient with “Pseudosclerosis” and liver cir- rhosis (Völsch 1911). In 1883 Westphal and in 1898 Strümpell had pre- sented cases with neurologic disease consistent with what should become part of WD (Westphal 1883; Strümpell 1898), but did not notice any pathol- ogy of the liver. Ernst Homén, professor of pathological anatomy in Hel- sinki, believed that his findings in three siblings (out of 11) with liver cirrho- sis and lenticular degeneration, were due to congenital syphilis (Homén 1890; Homén 1892), which Wilson found highly unlikely. It thus became Kinnier Wilson who, by combining several cases of liver cirrhosis and len- ticular degeneration, described it as a new disease entity. 9 Figure 2. Title page of the main article in Brain in March 1912, reproduced with permission from Oxford University Press. 10 The German ophtalmologists Bernhard Kayser and Bruno Fleischer de- scribed a pigmented ring in the periphery of the cornea in some patients with neurologic disease (Kayser 1902; Fleischer 1903). This ring was later shown to be a clinical hallmark in WD, and now bears their name. In the 1930s, Gerlach and Rohrschneider showed that the pigment of KF-rings is com- posed of copper, not silver, which was previously believed (Gerlach and Rohrschneider 1934). A rare ophtalmological finding in WD is the so called sunflower cataract, first described just 10 years after Wilson’s monograph (Siemerling and Oloff 1922). These authors noticed the similarity between this cataract and that caused by a foreign body consisting of copper. Already one year following the appearance of Wilson’s paper, Rumpel noted excess copper in the liver of a patient with WD (Rumpel 1913). In- creased copper content in the brain was demonstrated as late as in 1948 by Cumings, who also proposed that dimercaprol, an agent that earlier the same year had been shown to increase copper excretion in urine in a patient with WD (Mandelbrote et al. 1948), might be used as a treatment for WD (Cumings 1948). In 1921, Hall stated that WD was an inherited disease and
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