Summary Wilson disease (WD) is an autosomal recessively inherited mono- genic copper storag e disease. At least 50% of all patients with WD fi rst present with neurological or psychia tric problems. If treated early, patients can make a full recovery and then lead a near-nor mal life, but failure to make the diagnosis can result in severe irrevers- ible brain damag e and untimely death. explanation. Of note, the prevalence can be substantially higher in isolated populations (6 ). Genetics WD is a monogenic autosomal recessively inherited disorder. Th e causative gene en codes a copper-transporting P-type ATPase named ATP7B on chromosome 13q14.3 (7 \200\2239). In non-isolated populations, disease-causing ATP7B mutations are scattered across the entir e coding region and the adjacent splice sites, but there may be particular \200\230mutatio n hot spots \200\231. Th e distribution and frequency of the individual mutations varies be tween populations, with H1069Q being the most common mutation in European patients of Cauca sian origin (10). Mutations in the promoter region and large-scale ATP7B rearrangements hav e been reported, but are extremely rare (11, 12). Th e illness is named aft er S.A. Kinnier Wilson (1878 \200\2231937) who was born in the US A, but studied Medicine in Edinburgh and trained under Joseph Babinski in Paris. In 1905, w hilst working at the National Hospital for Nervous Diseases, London, he saw a female patien t who had developed severe dysarthria, a fi xed smile, and a coarse tremor of her hands and feet. She died at the age of 29 years. Wilson performed the autopsy himself and described a cir- rhotic liver and bilateral symmetrical destruction of the lenticular nucleus. He sub sequently extended his study to other patients with similar presentations (1). In the past, the use of inaccurate genetic screening techniques, which are now outdated, an d occasional over-generous inclusion of patients with clinically unconfi rmed WD suggested that a substan- tial proportion of WD patients only had one or indeed no detectable ATP7B m utation. However, a recently undertaken service evalua- tion of the UK WD/ ATP7B diagnostic genetic service confi rmed the detection of two mutations in >95% of all patients, but onl y if the entire coding region is sequenced (Ann Dalton, personal communi- cation). In our v iew, it is much more likely that the very few remain- ing patients with clinically confi rm ed WD but only one (currently) detectable ATP7B mutation have an additional unusual mutatio n within ATP7B , such as sequence changes in as yet unidentifi ed regulatory regions within its introns, rather than suggesting genetic heterogeneity (i.e. the presence of a second W D gene). A role for copper as a possible pathogenic agent was fi rst sug- gested by Rumpel in 1913 w ho described increased copper content in the liver. Cummings then demonstrated that excess copper is present in both liver and brain of WD patients (2). Essential background Epidemiology Th e prevalence of WD is estimated to be 1:30 000 with a (heterozy- gote) ATP7B mutation carrier frequency in the general population of 1:90 (3). Ou r own genetic studies confi rm that the genetic preva- lence of ATP7B mutations in newborns is at least as high as this (unpublished data). One can then extrapolate these data to pre dict approximately 2000 cases of WD in the UK, or 10 000 cases in the USA. However, the num ber of clinically diagnosed cases of WD is substantially lower. Why? Reduced penetrance is well recognized in other autosomal recessively inherited metabolic disorders, and case repo rts suggest that it may also occur in individuals with two ATP7B mutations (4, 5). Alternat ively, unusual presentations of WD, perhaps mimicking late-onset neurodegenerative or psych iat- ric disorders, may be more common than previously thought. Th e most worrying, but pur ely speculative, explanation would be that a substantial proportion of WD patients die undi agnosed in infancy or childhood. In our view, reduced penetrance is the most likely Pathophysiology Copper is required for a wide range of crucial biochemical mecha- nisms suc h as cellular respiration, iron oxidation, neurotransmit- ter synthesis, antioxidant defens e and connective tissue formation (13). Th e average diet provides about 2 \200\2235 mg of copper per day, but only about 1 mg/day is needed (14). Copper is mostly absorbed in the du odenum and proximal small intestine. Bound to albumin and the amino acid histidine, it is t hen transported to the liver in the portal circulation. Excess copper is excreted into the bile, and it is this excretion which is impaired in WD. Th e protein encoded by the WD gene , the ATP7B protein, is a copper-transporting P-type ATPase. ATP7B protein is mainly expres sed in hepatocytes Oxford Textbook of Movement Disorders 242 and functions in the transmembrane transportation of copper within hepatocytes. Th e copper translocation cycle occurs in several stages, during which ATP hydrolysis drives the trans location of the copper: (1) binding of target ion; (2) binding of ATP to the nucleotide-bin ding (N) domain; (3) ATP hydrolysis and phosphor- ylation of the phosphorylation (P) domain ; (4) translocation of the target ion; (5) dephosphorylation of the P-domain by the actuato r (A) domain (15). neurological problems will manifest with a combination of these features. Th e frequency of the respective neurological features var- ies widely from one case series to the next and is summarized in Table 23.1. Terms such as \200\230fl apping tremor \200\231 or \200\230wing-beating tremor \200\231 a re frequently described as pathognomonic features for WD in the lit- erature, but any other , more common, type of tremor such as rest, action, and intention tremor can occur as well. Th e most common form of tremor may be an irregular, jerky, and somewhat asym- metrical dy stonic tremor combined with dystonic posturing and (action-induced) dystonia in the hands s uch as writer \200\231s cramp with abnormal fi ne fi nger movements on formal testing. Inde ed, WD can result in any form or distribution of dystonia, including gen- eralized, segment al, and multifocal dystonia (22). Common sub- types of focal dystonia, such as blepharospas m or torticollis, can be part of the dystonic presentation but isolated cervical dystonia i s unlikely to be due to WD (23). ATP7B mutations lead to impaired function of the ATP7B protein with reduced excretion of co pper into the bile, leading to increased copper levels in the liver and other organs, in pa rticular the brain. Excess copper leads to increased oxidative stress, mitochondrial dysfun ction, and cell death. Clinical presentation WD typically presents in the second or third decade of life. Patients with hepatic problems tend to present earlier than those with neu- ropsychiatric symptoms, the mean age of onset being 11 years for patients with hepatic problems compared with a me an age of 17 years for those with neurological symptoms in a large case series (16). A rece nt multinational study comprising 1223 patients con- fi rmed that about 90% of all patients become symptomatic below the age of 30 years (17). However, statistics and mean ages of on set help little if you are confronted with a patient in your own clinic who may or may not have WD. WD can start very early, the young- est case probably being a two-year-old child w ho presented with impaired liver function (18). More worryingly for adult neurolo- gists, a fi rst presentation of WD has also been reported in septua- genarians (19). Presentation a s late as this is likely to be very rare indeed but \200\230late-onset \200\231 WD, arbitr arily defi ned as patients only becoming symptomatic at age >40 years, is now well recogniz ed and, with 46/1223 (3.8%) of all WD patients included in the multi- national study mentio ned above, more common than perhaps pre- viously thought (17). Dysarthria is a further very common symptom and can have ataxic, hypokinetic, and dysphonic features. It can be the fi rst neu- rological symptom and is present in the vast majority of all WD patients who have a neurological presentation (24, 25). Th e speech may not only be diffi cult, or indeed impossible, to understand because the words are not formed properl y, but also because the patient may speak rather fast with reduced volume and a strained ho arse voice. WD patients with dysarthria typically have slow tongue movements and may also d isplay particular orofacial dys- kinesias, namely involuntary grimacing with the mouth open and the upper lip contracted, resulting in the so-called risus sardonicus. Dysphagia can a lso be part of the clinical presentation. It may not only be due to slow and poorly coordin ated lip, tongue, pharynx, and jaw movements, but also caused by impaired oesophageal motil ity (26). Parkinsonian features such as slowness of movement, includ- ing hypomimia, reduct ion in amplitude and rhythm of fi ne fi nger movements or foot tapping and shuffl ing, and small stepped gait are further typical features. Textbooks frequently include WD in the dif f erential diagnostic list of causes for chorea. However, classi- cal choreiform movements are rare compared with choreoathetotic movements with slow writhing movements (with a stron g dystonic component). Th e grand master of WD in the UK, John Walshe, once stated: \200\230Th ere appears to be only one thing which all (WD) patients have in common namely that they are all diff e rent \200\231 (20). It has been pro- posed that the neurological manifestations of WD can b e divided into three distinct syndromes: (1) a dystonic syndrome character- ized by choreoa thetosis and dystonic postures, (2) an ataxic syn- drome with postural and intention tremor as well as ataxia of the limbs, and (3) a parkinsonian syndrome with hypokinesia, rigidity , and resting tremor (21). In our view, this classifi cation is unhelp- ful \200\224the con siderable majority of WD patients who present with Cerebellar dysfunction with ataxia, intention tremor, and dysdia- dochokinesia may be under -recognized in WD and can be masked by the presence of additional dystonia or parkinsonism. However, it is not clear whether all WD patients reported to have ataxia in the literature really did have a cerebellar syndrome or simply could Table 23.1 Comparison of the frequency of common neurological abnormalities in di \200 ere nt case series Ref. (20)* n 136 Dystonia 15% Dysarthria Juvenile: 52% Adult: 27% Parkinsonism 45% Ataxia NA Chorea/Athetosis 11% Pyramidal signs NA (48) 31 65% 97% 52% (42%)** Rare 29% (49) 22 36% ? 82% 50% ? 32% (16) 282 35% ? 62% 28% 11% 16% (25) 119 69% 91% 66% (75%)** Chorea 16% Athetosis 14% Rare Th is case series concentrated on the neurological abnormalities at presentation. Th ese \201 gures refer to \200\230gait abnormalities \200\231; the authors did not di \200 erentiate between ataxia and other gait abnormalities such as parkinsonian gait. Modi \201 ed from ref. 25. CHAPTER 23 Wilson Disease 243 not walk heel to toe because of prominent (lower limb) dystonia in isolation or combined wi th other extrapyramidal features. present to the neurologist with cognitive impairment (42%), craniofacial dyskinesias (28%), cerebellar ataxia (46%), and reti- nal degeneration (75%) (35). Patients with homozygote m utations tend to have more severe disease, but heterozygote mutation car- riers can develop neurological symptoms as well. Serum cerulo- plasmin is undetectable in homozygous cases, ferritin is elevated, and copper as well as iron levels in serum are very low. Microcytic a nemia is frequently present. Of note, heterozygote ATP7B muta- tion carriers can also exhib it a mild decrease in ceruloplasmin lev- els (36). Seizures have been reported to be the presenting symptom of WD, but can occur at any stage of the disease in about 5% of all patients and are more common aft er initiation of treatme nt (27). Pyramidal features such as pathologically brisk tendon refl exes can occur (see Ta ble 23.1), but paralysis is not a feature of WD and the presence of sensory impairment prac tically excludes the diagnosis of WD (in the absence of dual pathology). Impaired ocular mo til- ity is a probably under-recognized, feature of WD, impaired verti- cal pursuit being t he most common abnormality (28). In contrast, deterioration of vision as such is not part o f WD and the pupils are normal. Copper levels in the blood of WD patients are typically low, despite the fact that WD is a copper-overload disease, because of the marked lowering of the (copper-transporting) cerulo plas- min protein. In contrast, serum non-ceruloplasmin-bound cop- per concentrations are u sually elevated above 25 g/dl (normal <15 g/dl) (14). Wilson described prominent psychiatric symptoms in eight of the twelve cases he reported in his thesis. A retrospective analysis of 195 cases came to the conclusion that 51% of these patients dis- played psychopathological features (29). A wide range of diff erent psychiat ric problems including anxiety, depression, psychosis, and personality disorders can occur. Of note, anxiety and depression, but also irritability and apathy, continue to be common e ven in treated and otherwise clinically stable patients (30, 31). Copper levels in a 24 hour urine collection refl ect the amount of non-ceruloplasmin bound copper in circulation and are very useful both as a diagnostic procedure and to monitor tre atment. Typically, >100 g (1.6 mol) is excreted during a 24-hour period in symp- tomati c patients, but >40 g (0.6 mol) in 24 hours may already indicate WD and requires furthe r investigation (14). A neurologist may not only encounter a WD patient in his own clinic, but also as a ward ref erral of the patient who initially comes to medical attention because of a general medical problem. Whilst the hepatic presentation is more common in children, it can still be the fi rst presentation of \200\230late-onset \200\231 WD when patients are in their forties or fi ft ies (17). Th us, the diagnosis of WD needs to be considered in any patient seen as a ward referral on a general medi- cal ward with the working diagnosis of \200\230hepatic en cephalopathy of unexplained cause \200\231. Other, non-hepatic, general medical presen- tat ions include haemolytic crisis and a variety of joint and bone diseases including spontaneo us fractures and premature osteoar- throsis (32). Rarely, WD can result in cardiomyopathy a nd arrhyth- mias. Endocrine abnormalities and renal manifestations have also been reported, but are rare as well (33). Th e penicillamine challenge (urine copper excretion aft er peni- cillamine administration) has only been standardized in children. MRI is a further very powerful investigation in pa tients with the neurological presentation of WD. Th e largest case series to date reported MRI abnormalities in 100%, but the characteristic \200\230face of the giant panda \200\231 sign was only present in 14%. Tectal plate hyper- intensity (75%), central pontine myelino lysis-like abnormalities (62%), and concurrent signal changes in basal ganglia, thalamus, a nd brainstem (55%) were considerably more common (37). We would strongly advise against rel ying on the results of CT imaging in cases of suspected WD. We do not see any justifi cation for a liver biopsy in WD patients with neurological presen tation in whom the clinical assessment and investigations listed above have already provide d substantial evidence for the diagnosis of WD. We would advise caution against undertaking a liver biopsy only because a patient has a neurological condition of undetermined etiolog y with a mild decrease of his ceruloplasmin levels, but normal MRI and normal 24 hour urine copper excretion. Of note, increased hepatic copper is not diagnos- tic for WD since a mil d increase can also be observed in heterozy- gote ATP7B mutation carriers. Furthermore, oth er diseases such as primary biliary cirrhosis may also lead to increased hepatic copper lev els. Investigations Th e Kayser \200\223Fleischer ring (KFR) is caused by copper deposition in D escemet \200\231s membrane of the cornea and usually starts at the upper pole (33). KFRs ar e present in 100% of some, but not all, case series of WD patients with neurological presen tation (14). It is not always clear whether a slit lamp was routinely used in all patients who did not have a KFR on bedside testing. It is easier to detect KFRs if the light of the ophthalmoscope is shone tangen- tially at the eyes, but the threshold should be low to refe r a patient with possible WD to ophthalmology for slit-lamp examination. Rarely, KFRs can a lso occur in other liver diseases such as primary biliary cirrhosis (34). Treatment British anti-lewisite (BAL), or dimercaptopropanol, was introduced as the fi rst chelating agent for WD by Denny Brown in 1951 (38). John Walshe \200\231s introduction of p enicillamine as the fi rst oral chelat- ing agent then revolutionized the treatment of WD. Trientine, also a chelating agent, was subsequently introduced as an alternative to penicil lamine, especially for those patients who cannot toler- ate penicillamine (2). Treatment wi th copper chelators to facilitate copper excretion from the body continues to be the key pr inciple of pharmacological treatment of WD, but has been complemented by use of zinc which reduces the copper levels in the body by inducing intestinal metallothionein in the duodena l enterocytes. Metallothionein preferentially binds copper, and so dietary copper Ceruloplasmin is the major copper-transporting protein in the blood with >90% of circulatin g copper bound to it in healthy individuals. Very low (<5 mg/dl) serum ceruloplasmin levels are strong evidence for WD. A mild to moderate reduction (<20 mg/dl) is consistent with th e diagnosis of WD and diagnostic in the pres- ence of KFRs (14). Ceruloplasmin may be low i n other general medical conditions with marked renal or enteric protein loss, and also in e ndstage liver failure and in patients with Menkes disease, an X-linked disorder of copper u ptake. An additional important cause of low ceruloplasmin is aceruloplasminaemia due to mut a- tions in the ceruloplasmin gene. Patients with this condition can Oxford Textbook of Movement Disorders 244 is subsequently lost due to the frequent shedding of the enterocytes during normal cell tur nover. Th e advantages and disadvantages of penicillamine, trientine, and zinc are now desc ribed in some more detail. A third chelating agent, ammonium tetrathiomolybdate, has only b een used in clinical trials and is neither licensed nor com- mercially available for the tr eatment of WD in the UK or the USA. Th erefore it will not be discussed any further. typically only has a few side eff ects such as abdominal discomfort (41, 42). Th e usual do se for adults is 150 mg/day in three doses (14). Which drug should you then choose for the WD patient in your clinic? It is important to realize that the \200\230top three \200\231 drugs, penicilla- mine, trientine, and zinc, have never been compared in modern head-to-hea d trials. At least some of the manuscripts and books published on this issue are rather dog matic and unilaterally favor one drug above all others. Fortunately, the American Associati on for the Study of Liver Diseases (AASLD) has published (in our view) eminently sensible t reatment recommendations (14): Penicillamine is the most widely used drug for WD. Decades of experience have shown that it is not only a powerful de-coppering agent in the initial stage of the therapy but is also an excellent thera- peutic agent for maintenance therapy in many patients, provided that th ey are monitored carefully for possible side eff ects of this compound. At the beginning of the therapy a hypersensitivity reac- tion can develop with fever, rash, lymphadenopathy, n eutropenia, and proteinuria. Non-specifi c nausea can also occur. However, the most serious early side eff ect is a deterioration in neurological sta- tus, which may be severe (39). Th is has been reported in 20 \200\22350% of patients with a neurological presentation and is not always revers- ible (33). It is thought to be due to mobilization of copper in the t issue by the chelating therapy with resulting increase in oxidative stress. However, an acu te deterioration can also be observed aft er initiation of treatment with trientine (40). L ong-term side eff ects of penicillamine treatment include bone marrow suppression with thro mbocytopenia and aplasia, nephrotoxicity, and skin complica- tions such as elastosis perfor ans serpiginosa and aphthous stoma- titis. Risk of neurological deterioration aft er initia tion of therapy may be lower if penicillamine is increased gradually (e.g. start the patien t on 250 mg/day for the fi rst week and then increase by 250 mg per week until he/she reach es the initial fi nal dose of the de-coppering stage, 1000 \200\2231500 mg in adults). Th i s should ide- ally be divided into three doses, but some patients fi nd it easier to take t he drug twice daily. Th e drug is better absorbed if not taken with food, but many patients fi nd it easier to take the medication with food. We start patients on vitamin E (400 IE p er day) for the fi rst 3 \200\2236 months, hoping that the antioxidant eff ect of this vita min might abolish or at least reduce some of the immediate penicilla- mine side eff ects. T h e typical maintenance dose is 750 \200\2231000 mg in adults. Pencillamine treatment carri es at least the theoretical risk of aff ecting pyridoxine metabolism. Th erefore we also re commend 50 g of vitamin B 6 twice weekly. Initial treatment for symptomatic patients should include a chelating agent (penicillamine or trientine). Trientine may be better tolerated (Class I, Level B) Treatment of pre- symptomatic patients or those on maintenance therapy can be accomplished with a chelating a gent or with zinc (Class I, Level B) We appreciate that these guidelines may lack precision (no clear preference for penicillami ne vs trientine for the treatment of symp- tomatic patients, no clear preference for zinc v s chelating agent for maintenance therapy) but they accurately refl ect the current uncerta inty. At the beginning of therapy, it is important to not only warn patients about possible side eff ects of the medication, but also to make them aware of the fact that it might take mont hs until the fi rst improvement is noticed. With all the therapeutic enthusiasm for one of the few near-curable movement disorders, it is cru- cial to be patient. It is then absolute ly crucial to monitor all WD patients for the rest of their lives. Th e minimum requirement in stable patients should include an annual neurological and general medical examination. In addition, we would strongly recommend annual assessment of copper excretion via a 24 hou r urine col- lection. Treatment with any chelating agent should be stopped 48 hours prior t o the start of the urine collection and then only be started again aft er the urine collect ion has fi nished. We use the target values of <0.6 mol/24 hour copper excretion in patie nts on penicillamine and <2.0 mol/24 hour in patients on trientine. Signifi cantly higher copper excretion may refl ect either poor com- pliance or simply the fact that the dose of the respective therapeu- tic agent is too low. Our annual reviews include a large number o f additional blood tests including ceruloplasmin, copper, liver func- tion tests, full bloo d count, iron and ferritin, renal function tests, and urinalysis. Trientine is perceived to be a less potent chelating agent than penicillamine but also appe ars to have a better side-eff ect profi le. Current evidence suggests that it is at least a valid alternative to penicillamine as fi rst-line drug treatment and certainly a very use- ful alternative for those patients who cannot tolerate penicillamine. It is important to s tress that the transient neurological deterioration seen aft er initiation with penicillami ne treatment can also occur aft er a patient has been started on trientine (40). Th erefore , simi- larly to our approach for the initiation of penicillamine treatment, we advise star ting the patient on a low dose of trientine, such as 300 mg/day for the fi rst week, and th en increasing the dose by 300 mg each week until the patient has reached the fi nal initial dose of 1200 \200\2231800 mg/day. Th e maintenance dose is usually 600 mg twice daily. Oth er complications of trientine are iron defi ciency with sideroblastic anemia. Lupus-like re actions have also been reported in some WD patients on trientine, but most of them had been on penicillamine before (14). Offi cial guidelines state that food with very high concentrations of copper (shellfi sh, n uts, chocolate, mushrooms, and off al) should be avoided, at least in the fi rst year of tr eatment. However, com- mon sense needs to be used when dietary advice is given. Doctors sho uld show empathy for patients who already face the prospect of having to take medication fo r the rest of their lives. A gentle increase in the dose of the respective drug may be more appropri- ate than over-zealous dietary advice and criticism of the patient \200\231s life style. Liver transplantation is the only eff ective option for those WD patients who present with acute liver failure (14). Both clinical and radiological improvement has been reported in p atients with the neurological presentation of WD, but outcome has not always been benefi ci al (14, 43, 44). It is hard to justify liver transplanta- tion in a WD patient with pure ne urological presentation unless he/she has developed severe side eff ects on all the diff er ent WD drugs. Zinc is increasingly used as fi rst-line therapy for asymptomatic or presymptomatic patient s. It is generally very well tolerated and CHAPTER 23 Wilson Disease 245 Key advances Unfortunately, there have not really been any major breakthroughs in the diagn osis and treatment of WD over the past 5 \200\22310 years. Th e most important step forward would be a well-designed drug study comparing the effi cacy of penicillamine and trientine in the acute stage of the illness and a comparison of chelating agents versus zinc for mai ntenance therapy. A unifi ed WD rating scale has now been developed and evaluated which may prove useful in future drug studies (45). 3. Behari M, Pardasani V. Genetics of Wilson \200\231s disease . Parkinsonism Relat Disord 2010; 16 : 639 \200\22344 . 4. Czlonkowska A, Gromadzka G, Chabik G. Monozygotic female twins discordant for phenotype of Wilson \200\231s disease . Mov Disord 2009; 24 : 1066 \200\2239 . 5. Czlonkowska A, Rodo M, Gromadzka G. Late onset Wilson \200\231s disease: therapeutic implications . Mov Disord 2008; 23 : 896 \200\2238 . 6. Dedoussis GV, Genschel J, Sialvera, et al. Wilson disease: high prevalence in a mountainous area of Crete . Ann Hum Genet 2005; 69 : 268 \200\22374 . 7. Bull PC, Th omas GR, Rommens JM, Forbes JR, Cox DW. Th e Wilson disease gene is a putati ve copper transporting P-typ e ATPase similar to the Menkes gene . Nat Genet 1993; 5 : 327 \200\22337 . Future developments Liver cirrhosis and anemia in WD are at least partially due to copper-m ediated activation of acid sphingomyelinase and release of ceramide. Treatment with the aci d sphingomyelinase inhibi- tor amitriptyline prevented liver failure and prolonged survival in atp7b- defi cient rats, but it is currently unclear whether amitriptyl- ine treatment m ay also be of benefi t in human WD patients (46). Rescue of ATP7B protein function in hepat ocyte-like cells from WD-induced pluripotent stem cells using viral gene therapy has been r eported, but it is uncertain whether gene therapy will ever be a useful tool for the treatm ent of WD (47). Any new experi- mental therapeutic approach would need to be tested against best current medical practice. Th e single most desirable improvement for WD patients with a neurological presentation would be a form of therapy which would result in a more comple te recovery of brain function, compared with those people who only partially recover despit e optimal conventional drug therapy. However, it may be futile to target this goal since th is residual neurological dysfunction may refl ect irreversible brain damage. 8. Petrukhin K, Fischer SG, Pirastu M, et al. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene . Nat Genet 1993; 5 : 338 \200\22343 . 9. Tanzi RE, Petrukhin K, Chernov I, et al. Th e Wilson disease gene is a copper transporti ng ATPase with homology to the Menkes disease gene . Nat Genet 1993; 5 : 344 \200\22350 . 10. Ferenci P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing . Hum Genet 2006; 120 : 151 \200\2239 . 11. Cullen LM, Prat L, Cox DW. Genetic variation in the promoter and 5 \200 UTR of the co pper transporter, ATP7B, in patients with Wilson disease . Clin Genet 2003; 64 : 429 \200 \22332 . 12. M ller LB, Ott P, Lund C, Horn N. Homozygosity for a gross partial gene deletion of the C-termina l end of ATP7B in a Wilson patient with hepatic and no neurological manifesta tions . Am J Med Genet A 2005; 138 : 340 \200\2233 . 13. Madsen E, Gitlin JD. Copper and iron disorders of the brain . Annu Rev Neurosci 2007; 30 : 317 \200\22337 . 14. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update . Hepatology 2008; 47 : 2089 \200\223111 . 15. de Bie P, Muller P, Wijmenga C, Klomp LW. Molecular pathogenesis of Wilson and Menkes d isease: correlation of mutations with molecular defects and disease phenotypes . J Med Gene t 2007; 44 : 673 \200\22388 . Top clinical tips 16. Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR. Wilson disease: descrip tion of 282 patients evaluated over 3 decades . Medicine (Baltimore) 2007; 86 : 112 \200 \22321 . Always investigate patients with tremor and dysarthria for WD (in the absence of classical cerebellar features). \227\206 17. Ferenci P, Cz \202 onkowska A, Merle U, et al. Late-onse t Wilson \200\231s disease . Gastroenterology 2007; 132 : 1294 \200\2238 . Do not disregard the diagnosis of WD only because liver func- tion tests are normal and you could not see a KFR yourself in clinic. In case of doubt, refer the patient to Ophthalmolo gy for slit-lamp examination. \227\206 18. Beyersdorff A, Findeisen A. Morbus Wilson: Case report of a two-year-ol d child as fi r st manifestation . Scand J Gastroenterol 2006; 41 : 496 \200\2237 . 19. Ala A, Borjigin J, Rochwarger A, Schilsky M. Wilson disease in sep- tuagenarian siblings: raising the bar for diagnosis . Hepatology 2005; 41 : 668 \200\22370 . Do not disregard the possible diagnosis of WD only because the ceruloplasmin levels are nor mal. Ceruloplasmin is an acute-phase protein. and any acute general medical illness such as liver failure may result in elevation and thus false normal levels of ceruloplasmin. \227\206 20. Walshe JM, Yealland M. Wilson \200\231s disease: the problem of delayed diagno- sis . J Neurol Neurosurg Psychiatry 1992; 55 : 692 \200\2236 . 21. Marsden CD. Wilson \200 \231s disease . QJM 1987; 65 : 959 \200\22366 . 22. Svetel M, Kozi \207 D, Stefanova E, Se mnic R, Dragasevic N, Kostic VS. Dystonia in Wilson \200\231s disease . Mov Disord 2001; 16 : 719 \200\22323 . 23. Risvoll H, Kerty E. To test or not? Th e value of diagnostic tests in cervical Do not assume that it cannot be WD because the patient is \200\230too old \200\231. \227\206 dystonia . Mov Disord 2001; 16 : 286 \200\2239 . 24. Oder W, Grimm G, Kollegger H, Ferenci P, Schneider B, Deecke L. Neurological and neurop sychiatric spectrum of Wilson \200\231s disease: a pro- spective study of 45 cases . J Neur ol 1991; 238 : 281 \200\2237 . WD is complicated. Try to see these patients in a multidiscipli- nary clinic together with hepatologists or metabolic physicians. \227\206 25. Machado A, Chien HF, Deguti MM et al. Neurological manifestations in Wilson \200\231s d isease: report of 119 cases . Mov Disord 2006; 21 : 2192 \200\2236 . 26. Haggstrom G, Hirs chowitz BI. Disordered esophageal motility in Life-long close monitoring of WD patients may be more important than the initial decision a s to which drug the patient should be started on. \227\206 Wilson \200\231s disease . J Clin Gastroenterol 1980; 2 : 273 \200\2235 . 27. Dening TR, Berrios GE, Walshe JM. Wilson \200\231s disease and epilepsy . Brain References 1. Hoogenraad TU. S.A. Kinnier Wilson (1878 \200\223937) . J Neurol 2001; 248 : 1988; 111 : 1139 \200\22355 . 28. Ingster-Moati I, Bui Quoc E, Pless M, et al. Ocular motility and Wilson \200\231s disea se: a study on 34 patients . J Neurol Neurosurg Psychiatry 2007; 78 : 1199 \200\223201 . 71 \200\2232 . 2. Walshe JM. Th e conquest of Wilson \200\231s disease . Brain 2009; 132 : 2289 \200\22395 . Oxford Textbook of Movement Disorders 246 40. Dahlman T, Hartvig P, L fh olm M, Nordlinder H, L f L, Westermark K. Long-ter m treatment of Wilson \200\231s disease with triethylene tetramine dihydrochloride (trientin e) . QJM 1995; 88 : 609 \200\22316 . 29. Dening TR, Berrios GE. Wilson \200\231s disease: psychiatric symptoms in 195 cases . Arch Gen Psychiatry 1989; 46 : 1126 \200\22334 . 30. Portala K, Westermark K, von Knorring L, Ekselius L. Psychopathology in treated Wilson \200\231s disease determined by means of CPRS expert and self-rating s . Acta Psychiatr Sca nd 2000; 101 : 104 \200\2239 . 41. Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JK. Treatment of Wilson \200\231s disease with zinc. XV: Long-ter m follow-u p stud- ies . J Lab Clin Med 1998; 132 : 264 \200\22378 . 31. Svetel M, Potrebi \207 A, Pekmezovi \207 T, et al. Neuropsychiatric aspects of treate d Wilson \200\231s disease . Parkinsonism Relat Disord 2009; 15 : 772 \200\2235 . 32. Gold ing DN, Walshe JM. Arthropathy of Wilson \200\231s disease: study of clini- cal and radiolo gical features in 32 patients . Ann Rheum Dis 1977; 36 : 99 \200\22311 1 . 42. Czlonkowska A, Gajda J, Rodo M. Eff ects of long-ter m treatment in Wilson \200\231s di sease with D-penicillamin e and zinc sulfate . J Neurol 1996; 243 : 269 \200\22373 . 43. Schumacher G, Platz KP, Mueller AR, et al. Liver transplantation in neu- rologic Wilson \200\231s disease . Transplant Proc 2001; 33 : 1518 \200\22319 . 33. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson \200\231s disease . 44. Wu JC, Huang CC, Jeng LB, Chu NS. Correlation of neurological mani- festations and MR i mages in a patient with Wilson \200\231s disease aft er liver transplantation . Acta Neurol Scand 2000; 102 : 135 \200\2239 . Lancet 2007; 369 : 397 \200\223408 . 34. Tauber J, Steinert RF. Pseudo-Kayser \200\223Fleische r ring of the cornea associ- ated with non-Wilsonia n liver disease: a case report and literature review . Cornea 1993; 12 : 74 \200\2237 . 45. Leinweber B, M ller JC, Scherag A, et al. Evaluation of the Unifi ed Wilson \200\231 s Disease Rating Scale (UWDRS) in German patients with treated Wilson \200\231s disease . M ov Disord 2008; 23 : 54 \200\22362 . 35. McNeill A, Pandolfo M, Kuhn J, Shang H, Miyajima H. Th e neurologi- cal presentation of ceruloplasmin gene mutations . Eur Neurol 2008; 60 : 200 \200\2235 . 46. Lang PA, Schenck M, Nicolay JP, et al. Liver cell death and anemia in Wilson disease in volve acid sphingomyelinase and ceramide . Nat Med 2007; 13 : 164 \200\22370 . 36. Gromadzka G, Chabik G, Mendel T, et al. Middle-age d heterozygous carriers of Wilson \200\231s disease do not present with signifi cant phenotypic deviations related to copper metabolism . J Genet 2010; 89 : 463 \200\2237 . 37. Prashanth LK, Sinha S, Taly AB, Vasude v MK. Do MRI features distin- guish Wilson \200\231s disease from other early onset extrapy ramidal disorders? An analysis of 100 cases . Mov Disord 2010; 25 : 672 \200\2238 . 47. Zhang S, Chen S, Li W, et al. Rescue of ATP7B function in hepatocyte-lik e cells from W ilson \200\231s disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin . Hum Mol Genet 2011; 20 : 3176 \200\22387 . 48. Starosta-Rubinstein S, Young AB, Kluin K, et al. Clinical assessment of 31 patients wit h Wilson \200\231s disease: correlations with structural changes on magnetic resonance imag ing . Arch Neurol 1987; 44 : 365 \200\22370 . 38. Vilensky JA, Robertson WM, Gilman S. Denny-Brow n, Wilson \200\231s disease, and BAL (B ritish antilewisite (2,3-dimercaptopropano l)) . Neurology 2002; 59 : 914 \200\22316 . 49. Jha SK, Behari M, Ahuja GK. Wilson \200\231s disease: clinical and radiological 39. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurologic syndrome in patients wi th Wilson \200\231s disease with initial penicillamine therapy . Arch Neurol 1987; 44 : 490 \200\2233 . features . J Assoc Physicians India 1998; 46 : 602 \200\2235 . CHAPTER 24 Tic Disorders and Stereotypies Erika F. Augustine and Jonathan W. Mink Tics and stereotypies are among the most common movement dis- orders in childhood. Th ese e arly-onset involuntary movements are stereotyped in nature, but diff er in phenomenology, a ge at onset, and co-morbid conditions. Th is chapter will outline the key identi- fying fea tures, natural history, and treatment of each. involuntary movements, family history, and thorough examina- tion may provide clues to the diagnosis. An individual child may have multiple stereo typies; however, the overall repert oire of move- ments is relatively constant over time, in contrast with chronic tic disorder s where the catalog of tics evolves (see Table 24.1 for other features diff erentiating ste reotypies from tics). Stereotypies may demonstrate rhythmicity similar to tremor. Whereas t remor involves oscillation around a single joint, stereotypies involve mul- tiple limb part s. Also, the duration of expression of stereotypies is oft en shorter than that of tremor. As it relates to prominent head stereotypies without other common motor stereotypies, espec ially in the setting of motor delay or clumsiness, cerebellar pathology or alternate diagno ses (spasmus nutans, bobble-head doll, head tremor, or hydrocephalus) should be considered (6, 7). Stereotypies Stereotypies are involuntary, patterned, co-ordinated, repetitive, and non-ref l exive movements that occur in the same fashion with each repetition (1). Although these n on-functional movements are typi- cally simple, fl eeting, and rhythmic in appearance, more complex, sustained, and non-rhythmic movements can be seen. Stereotypies occur multiple ti mes daily, particularly in settings of excitement, nervousness, fatigue, or engrossment. Th ese predictable and some- times suppressible movements are brief, lasting seconds to minut es, and most commonly involve the head, torso, and upper extremities in a symmetric manner. Neurobiology The neurobiology of complex motor stereotypy is not well understood. Conventio nal imaging and electrophysiological studies are unrevealing in healthy children with stere