Wilson's disease: A 2017 update

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Wilson’s disease: A 2017 update Aurélia Poujois a,b,∗, France Woimant a,b a b

Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France National Reference Centre for Wilson’s Disease, AP-HP, Lariboisière University Hospital, Paris, France

KEYWORDS Wilson’s disease; Copper; ATP7B; Exchangeable copper; Liver transplantation

∗

Summary Wilson’s disease (WD) is characterised by a deleterious accumulation of copper in the liver and brain. It is one of those rare genetic disorders that benefits from effective and lifelong treatments that have dramatically transformed the prognosis of the disease. In Europe, its clinical prevalence is estimated at between 1.2 and 2/100,000 but the genetic prevalence is higher, at around 1/7000. Incomplete penetrance of the gene or the presence of modifier genes may account for the difference between the calculated genetic prevalence and the number of patients diagnosed with WD. The clinical spectrum of WD is broader as expected with mild clinical presentations and late onset of the disease after the age of 40 in 6% of patients. WD is usually suspected when ceruloplasmin and serum copper levels are low and 24 h urinary copper excretion is elevated. Recently, a major diagnostic advance was achieved with implementation of the direct assay of ‘‘free copper’’, or exchangeable copper (CuEXC). The relative exchangeable copper (REC) that corresponds to the ratio between CuEXC and total serum copper enables a diagnosis of WD with high sensitivity and specificity when REC > 18.5%. Moreover, CuEXC values at diagnosis are a marker of extrahepatic involvement and its severity. A value of >2.08 ␮mol/L is suggestive of corneal and brain involvement (Se = 86%, Sp = 94%), and the ® disease will be more clinically and radiologically severe as values rise. The use of FibroScan is becoming more widespread to assess liver stiffness measurements in WD patients. 6.6 kPa is considered to be a threshold value between mild and moderate fibrosis, whereas a value higher than 8.4 is indicative of severe fibrosis. More studies are now necessary to confirm the usefulness ® of Fibroscan in managing chronic therapy for WD patients. Treatment of this disease is based on an initial active and prolonged chelating phase (with D-Penicillamine or Trientine) followed by maintenance with Trientine or zinc salt. The two major problems that may be encountered are neurological worsening during the initial phase and non-compliance with treatment during maintenance therapy. Liver transplantation is the recommended therapeutic option in WD with acute liver failure or end-stage liver cirrhosis; its indication should be considered when neurological status deteriorates rapidly despite effective chelation. Regular clinical, biological and liver ultrasound follow-up is essential to evaluate efficacy, tolerance and treatment compliance, but also to detect the onset of hepatocellular carcinoma on a cirrhotic liver. There are hopes in the near future with the introduction of a new chelator and inhibitor of copper absorption, tetrathiomolybdate (TTM) and the development of gene therapy. © 2018 Elsevier Masson SAS. All rights reserved.

Corresponding author. E-mail address: [email protected] (A. Poujois).

https://doi.org/10.1016/j.clinre.2018.03.007 2210-7401/© 2018 Elsevier Masson SAS. All rights reserved.

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Introduction Wilson’s disease (WD) is characterised by an abnormal accumulation of copper in the liver and brain. It is one of the rare genetic disorders that benefits from effective treatments that have revolutionised their prognosis [1]. Diagnosing WD patients is therefore not only satisfying intellectually but has a real therapeutic impact. Since its first clinical description more than a century ago by Samuel Kinnier Wilson [2], our knowledge of WD has grown and our management of the disease continues to evolve. This article details the latest advances in its epidemiology and genetics, emphasises the clinical spectrum of the disease and its biological and imaging markers, before reviewing the current and future treatments for Wilson’s disease.

Pathophysiology WD is a monogenic autosomal-recessive disorder of hepatocellular copper deposition caused by pathogenic variants in the copper-transporting gene, ATP7B. This gene codes for a copper transporting ATPase, located preferentially in the liver but also in the brain. ATP7B protein is involved in copper homeostasis and has two functions within hepatocytes: (1) the incorporation of copper into apoceruloplasmin to form (holo)ceruloplasmin which is excreted in the bloodstream, and (2) the physiological elimination of copper in the bile and faeces. Its dysfunction results in an accumulation of unbound copper in the liver which is then released in a free form into the bloodstream, and the urinary rather than biliary elimination of copper. The so-called ‘‘free copper’’ that escapes from the liver is then spread throughout the body with a predilection for the cornea and brain, causing oxidative damage and cellular apoptosis. From an initially hepatic disease, WD becomes a multisystemic disorder [3]. Although it is predominant in hepatocytes, ATP7B is also present in different brain regions but to a lesser extent than ATP7A, another ATPase. Unlike astrocytes that play a key role in regulating the massive intracerebral arrival of ‘‘free copper’’ via the bloodstream or cerebrospinal fluid [4], contribution of ATP7B and ATP7A to copper cerebral homeostasis remains incompletely understood.

Advances in genetics and epidemiology Next generation sequencing and Wilson’s disease Next generation sequencing (NGS) technologies now enable the rapid molecular diagnosis of large size molecules which is more comprehensive than that based on the Sanger reference method [5]. In France, the positivity rate of the molecular analysis is about 98%, so that only 2% of patients with proven WD have a single heterozygous mutation or even no mutation in the ATP7B gene [6]. To date, more than 600 mutations have been described, with single-nucleotide missense and nonsense mutations being the most common. Mutations more readily concern the central regions of the gene with a predilection for exons 8 and 14, especially in Europe [7]. In European countries (apart from Spain), the mutation with the highest allelic

frequency is the missense mutation p.His1069Gln on exon 14. In the absence of consanguineous marriage, the majority of patients are compound heterozygotes with a different mutation on each ATP7B allele. As mutations could also be carried by the same copy of the chromosome, clinicians need to consider genotyping asymptomatic parents in order to confirm that pathogenic variants occur in trans, i.e. each mutation comes from a different parent [5,8]. In case of impossibility to analyse the parents’ DNA, the molecular diagnosis of siblings could be investigated to help to obtain this information.

Cases of ‘‘pseudo-dominant’’ inheritance Cases of parent—child transmission have recently been reported and have prompted systematic family-wide screening despite the autosomal recessive nature of this transmission [9—11]. The first step of familial screening should focus on siblings as their risk of having two mutations is 25%. In a second step, offspring should be screened (0.5% risk), then parents, uncles, aunts and nephews as WD is a treatable disorder. In our experience, warning the index-case about the possible risk of WD in the family is not sufficient enough, so we propose a systematic large familial screening.

Clinical and genetic prevalence The first important publication on this subject referred to a world clinical prevalence of 30 per million, with a heterozygous carrier frequency of 1/90 [12]. In Europe, where the consanguinity rate is lower, the prevalence of WD was estimated at between 1.2 and 2/100,000 [13]. In France, a recent nationwide population-based study using data from the national health insurance system identified 906 cases of WD, yielding a crude prevalence of 1.5 cases per 100,000, which is in line with the European data [14]. However, two recent genetic publications suggested that the prevalence of WD is probably underestimated [5,15]. After NGS sequencing of the entire ATP7B gene in more than 1000 DNA samples from the general population, the frequency of heterozygous carriers of the ATP7B gene was found in both publications to be around 1/40, leading to a disease prevalence of approximately 1/7000. The discrepancy between the calculated genetic prevalence and the number of patients diagnosed with Wilson’s disease raises some major questions. An incomplete penetrance of the gene, or the presence of disease-modifying genes (COMMD1, ATOX1, XIAP, HFE, prion protein, methylenetetrahydrofolate MTHF reductase, apolipoprotein E) that cause mild phenotypes (pauci- or asymptomatic clinical expression, late onset) are now being studied [16,17].

Different clinical presentations A classic childhood and adolescent disease In the majority of cases, WD manifests its presence during childhood or teenage years in the form of liver symptoms. Data from the French Wilson’s disease registry covering 604

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3 systematic in all new WD patients (including neurological patients) so as to confirm hepatic involvement, and determine the presence of portal hypertension and oesophageal varices.

A broader clinical spectrum

Figure 1 Age and phenotype at diagnosis from the French Wilson’s disease registry covering 604 patients. 51.6% of patients were under 16 years of age at diagnosis; 47% had a liver form, while 32.2% had a neurological phenotype and 20.8% were diagnosed on screening.

patients found that 51.6% of patients were younger than 16 years old at the time of diagnosis; 47% had a liver form of the disease while 32.2% had a neurological phenotype and 20.8% were diagnosed on screening (Fig. 1). The mean age of symptom onset in hepatic patients is usually earlier than in neuropsychiatric patients: 23.7 ± 8 years versus 28.0 ± 8 years in the Polish cohort of 627 patients [18] and 15.5 ± 9.6 years compared to 20.2 ± 10.8 years in the German cohort of 163 patients [19]. Moreover, the interval between symptom onset and diagnosis is two to three times longer in patients presenting with neurological symptoms than in those with hepatic symptoms (44.4 months vs.14.4 months) [19]. The spectrum of hepatic symptoms may be extremely variable at presentation. A Romanian study reported that 25.4% of patients had clinically asymptomatic disease at diagnosis, 21.8% presented with fulminant hepatic failure and 52.8% with a chronic liver disease [20]. Of the 107 WD patients followed in a French liver centre between 1974 and 2016, two-thirds were suffering from cirrhosis at diagnosis [21]. The inaugural neurological and/or psychiatric symptoms usually develop over a few weeks or months, the most common of them being tremor (rest, action or attitude) and dysarthria which are present in about 45% of neurological patients. Behavioural changes are sometimes associated with a pure psychiatric picture (depression, irritability, anxiety), while dystonic phenomena and Parkinsonian signs are the other presentations usually encountered. Cognitive changes may be subtle and are mainly linked to the involvement of basal ganglia and frontal subcortical loops. They are marked by executive dysfunctions which can range from a simple attentional disorder to marked frontal syndrome. Verbal intelligence, episodic memory, and visual and spatial abilities are usually preserved [22]. Neurologists are often puzzled by biological evaluations of the liver which may be normal, but liver damage is consistent in neurological patients, with compensated cirrhosis usually being detected by abdominal ultrasound [23]. Liver evaluations should be

Wilson’s disease may have a less classic presentation and become symptomatic at a late age. At Lariboisière University Hospital (Paris), we are following a family of two brothers and a sister whose diagnosis of WD was made after 60 years of age. The index case presented with a combination of writer’s cramp and discrete hepatic cytolysis for three years, and the diagnosis was made at the age of 62. Family screening was able to diagnose his 60-year old brother who also suffered from writer’s cramp and his 61year old sister who was asymptomatic. Of the 604 patients in the French Wilson’s disease Registry, 10% reported the first symptoms of the disease after 30 and 6.2% after 40 years of age, the mean age at diagnosis in the latter group being 48 ± 6.9 years (Fig. 1). 42% had an initial neurological presentation dominated by tremor, changes to handwriting and/or dysarthria, 39% had a liver phenotype, 11% were diagnosed as a result of family screening and 8% from an isolated Kayser-Fleischer ring. Diagnosis of these late-onset forms remains difficult despite their classic clinical presentation, as evidenced by the diagnostic time of 3.7 years in this population. The results of a large European multicentre study of 1223 patients [24] as well as some isolated clinical cases [25] have confirmed the French data. Follow-up of these patients has shown that they require lower doses of chelators as they are more prone to copper deficiency. The pathophysiology of late onset WD is probably different. To date, no mutation has been associated with late onset of the disease, but the existence of modifying genes (such as MTHF reductase or APOE) or an epigenetic mechanism is suspected [16,17]. Psychiatric symptoms are other manifestations of WD that need to be emphasise as they can be present at any time in the course of the disease and delay the diagnosis when present prior to hepatic or neurological symptoms. A recent review reported that 30—40% of patients have psychiatric symptoms at diagnosis and 20% had seen a psychiatrist prior to their WD diagnosis. All type of troubles is described with varied prevalence, from major depressive disorder (4—47%) to psychosis (1.4—11.3%). [26].

Diagnostic biomarkers: the usefulness of exchangeable copper assays The classical triad usually associated with a diagnosis of WD (low serum copper, low ceruloplasmin and high urinary copper levels) may be absent in some cases. Indeed, the triad is incomplete or absent in 3% of patients with WD confirmed by genetic testing, and present in 16% of healthy heterozygous carriers. The calculation of potentially toxic non-ceruloplasmin-bound copper has been proposed as a diagnostic test but has proved unreliable because of its inaccuracy at low concentrations and the multitude of factors that influence ceruloplasmin concentrations in serum [27]. A major breakthrough was made in 2009 when the team

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at Lariboisière Hospital developed a method for the direct determination of labile copper, called exchangeable copper (CuEXC) and evaluated it as a diagnostic tool for WD [28]. The CuEXC assay is available for routine clinical use in the toxicology laboratories at Lariboisière Hospital (Paris) and the Hospices Civils in Lyon, and other laboratories are currently validating the technique in partnership with the reference centre. The determination of CuEXC offers two major advantages [29]: • it permits the calculation of relative exchangeable copper (REC) that corresponds to the ratio between CuEXC and total serum copper. REC is an excellent diagnostic biomarker with a sensitivity and specificity close to 100% for the diagnosis of WD when its value is >18.5% [30]. For example, it enables a differentiation of Wilsonian liver disease from liver disorders of other types (NASH, autoimmune, infectious) [31]. In addition, REC can make a major contribution to family screening, as it is possible to make a distinction between WD patients and heterozygous carriers or healthy subjects [32]; • The CuEXC value at diagnosis is a marker of extrahepatic involvement and its severity. A value >2.08 ␮mol/L is suggestive of corneal and brain involvement (Se = 86%, Sp = 94%), the disease being clinically and radiologically more severe and diffuse if the CuEXC value is high [33]. When a high CuEXC value is found at diagnosis, the initiation of chelating treatment should be sufficiently careful and slow to reduce the risk of neurological worsening. Therefore, when WD is suspected or during family screening, the three important copper tests to be performed are CuEXC, a ceruloplasmin determination and 24 h urinary copper. Abnormal REC results will make it possible to institute chelating treatment without delay pending a definitive confirmation of the diagnosis through a molecular biology study of the ATP7B gene.

Contribution of imaging investigations Non-invasive liver assessment Asymptomatic hepatic copper deposition in liver cells occurs early in the progression of WD, predominantly in the periportal regions and along the hepatic sinusoids. After episodes of acute hepatitis, fatty changes and periportal inflammation may develop. Piecemeal necrosis and fibrosis with inflammatory cell infiltrations may subsequently induce chronic active hepatitis, followed after several years by the insidious development of irreversible cirrhosis. In view of this variable hepatic involvement, imaging findings on the liver can be demonstrated using ultrasound (US), computed tomography (CT) and MRI, all of which are frequently performed in WD patients. Fatty infiltration, contour irregularity and right-lobe atrophy are common findings associated with WD but are indicative of nonspecific hepatic injury [34]. However, specific features have been demonstrated in WD and include the presence of a peri-hepatic fat layer, parenchymal heterogeneity with multiple nodular lesions, and an absence of caudate lobe hypertrophy [35]. In unenhanced CT scans, hyperdense nod-

ules and a honeycomb appearance are frequently observed (92% and 58% of patients with WD, respectively) [36]. With MRI, hypointense nodules on T2-weighted images, surface nodularity of the liver, and gallbladder fossa widening are common findings in WD patients and are associated with advanced hepatic dysfunction [37]. More recent MRI sequences may also be helpful to predict the percentage fat content of the liver, and to detect early WD when histological findings have revealed significant hepatic steatosis [38]. ® The use of FibroScan (or impulse elastometry/transient elastography) has recently become much more widespread in determining liver stiffness measurements (LSM) in WD patients [39]. 6.6 kPa is considered as a threshold value between mild and moderate fibrosis, whereas a value higher than 8.4 determines severe fibrosis [40]. In a retrospective study, Sobesky et al. reported data on fourteen newly diagnosed WD patients who had undergone a liver biopsy associated with LSM. The biopsy revealed that 11 of the 14 patients were suffering from cirrhosis (Metavir F4) and the three other patients were Metavir F2, F1 and F0, respectively. The mean LSM for the cirrhotic patients was 32.3 (±15.9) kPa, while it was 6.2 (±2.1) kPa for patients with mild or moderate fibrosis (F0 to F2) [41]. More studies are now necessary to confirm these values and the usefulness ® of Fibroscan in managing chronic therapy for WD patients. At present, US is the principal non-invasive method that should be performed annually in WD patients, with twiceyearly checks if cirrhosis is detected in order to look for hepatocellular carcinoma [42].

Brain assessments Brain MRI findings are always abnormal in WD patients with neurological signs, but may be normal in patients with psychiatric disturbances [43]. The lesions are mainly due to the direct effect of intracerebral copper deposits but may also result from the indirect effect of portosystemic shunts. Apart from the specific situation of portosystemic shunts, neurological patients typically present with bilateral high signal intensities on T2 and Flair-weighted images in the basal ganglia, the mesencephalon and cerebellum (Fig. 2). The classic sign of the ‘‘giant Panda face’’ remains uncommon (18%). White matter lesions are rare as are the cortical lesions described in severe forms (2.6%) [44] (Fig. 3). In the event of chronic liver disease with porto-systemic shunting of the blood, patients may present bilateral T1weighted sequence hypersignals of the internal globus pallidus and putamen that may extend to the hypothalamus and midbrain regions (Fig. 4). These MRI abnormalities correspond to the manganese deposits associated with astrocytic oedema [43]. Some neurological patients have T2*-weighted low signals similar to those seen in some iron-related pathologies such as NBIA (neurodegeneration with brain iron accumulation) with a ‘‘tiger-eyes’’ appearance. These MRI abnormalities, coupled with the fact that cupro-enzymes are involved in iron metabolism (ceruloplasmin has ferroxidase activity and some patients have high ferritin levels), suggest that iron is also involved in the pathophysiology of WD [45—48] (Fig. 3).

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Figure 2 Classical brain MRI findings in Wilson’s disease patients. Bilateral high signal intensities on Flair-weighted images in the basal ganglia (A), the mesencephalon (B) (with the sign of the ‘‘giant Panda face’’), and the cerebellum (C).

Figure 3 Atypical brain MRI findings in Wilson’s disease patients. Extensive white matter lesions and cortical lesions (A) on Flair-weighted images. T2*-weighted low signals (B) in the basal ganglia, similar to those seen in some iron-related pathologies.

Figure 4 Brain MRI findings in Wilson’s disease patients with porto-systemic shunts. Bilateral T1-weighted sequence high signals of the internal globus pallidus and putamen (A and B). These MRI abnormalities correspond to the manganese deposits associated with astrocytic oedema.

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WD patients with a hepatic phenotype may display abnormal brain MRI findings despite the absence of neurological symptoms. Discrete bilateral Flair sequence hypersignals in the putamen have been described in these patients. Decreased diffusion sequences in the putamen can also be detected before the onset of Flair anomalies [49].

Ophthalmological assessments Corneal deposition of copper called Kayser-Fleischer rings are typical for WD and classically detected by slit-lamp biomicroscopy. Anterior segment optical coherence tomography and Scheimpflug imaging are new alternatives to identify the characteristic hyper-reflective layer in the deep corneal periphery at the level of Descemet’s membrane. These methods allow non-ophthalmologists to look for and to quantify Kayser-Fleischer rings more easily [50,51]. Retinal involvement is less known but recent papers studied morphological and electrophysiological parameters of the retinal and visual systems of WD patients by optical coherence tomography (OCT), visual evoked potentials (VEP) and electroretinography (ERG) [52,53]. Macular and retinal fibres were reported thinner in patients with brain MRI lesions and functional impairment of retinal and visual pathways was demonstrated by differences in VEP and ERG between MRI+ and MRI− patients [53].

Current treatments General recommendations Treatment for WD is based on the lifetime use of copper chelating agents or zinc salts. Chelators (D-Penicillamine (DP) and Triethylenetetramine (TN)) induce the urinary excretion of copper and zinc salts (zinc acetate or sulphate) which inhibits the intestinal absorption of copper by inducing the synthesis of metallothioneins in enterocytes. Treatment should never be stopped, even during pregnancy, when in some cases the dosage may be reduced. Combination with a low-copper diet is recommended at the beginning of the chelation/zinc therapy. Then in stable WD patients who are adherent to medical therapy, dietary copper restrictions are less necessary with two food exceptions (shellfish and liver) [54]. The treatment consists of two phases: an initial active chelation phase and a maintenance phase when chelation should be more moderate to prevent copper deficiency [55].

Initial phase of active chelation Although no prospective comparative studies are available, the European guidelines place the two chelators on an equal footing and recommend one or the other as first-line therapy in symptomatic patients [56]. The choice of the chelator is often oriented by the tolerability profile of the treatment. DP is contraindicated in the event of allergy to penicillin and is known for its many side effects; these may become acute within three weeks (hypersensitivity reaction with fever, skin rash, lymphadenopathy or renal damage with pro-

teinuria) or chronic (nephropathy, cutaneous involvement of elastic tissue, autoimmune disorders, etc.). TN is much better tolerated (rare cases of sideroblastic anaemia, gastritis, lupus-like syndrome, skin rash). It causes four times fewer discontinuations of treatment than DP [57]. TN is currently available in a limited number of countries; moreover, the substance is unstable and should be stored in a tightly closed container at 2—8 ◦ C. A phase 3 study to test a new non-cold preservative formulation is currently under way. Controlling liver disease is easier than controlling neurological symptoms. A retrospective multicentre study that included 380 patients with the hepatic or neurological phenotype showed that after four years of treatment, the effect of chelators was greater in the liver than in the brain. Hepatic improvement was reported in 90.7% of patients receiving DP and 92.6% of patients on TN, whereas the neurological forms only improved in 67.5% of patients on DP and 55% of patients on TN [57]. This difference in outcome could partly be explained by the paradoxical neurological exacerbations (sometimes irreversible) that have been described at treatment initiation in 13.8% of neurological patients on DP and in 8% of those receiving TN [19,58]. Until now, the onset of neurological signs at the start of treatment has not been described in patients with a pure liver phenotype. The inefficacy of intracerebral chelation or excessive copper mobilisation by chelating agents is the most common hypotheses advanced to explain this paradoxical worsening [4]. In newly diagnosed neurological patients with CuEXC > 2.08 ␮mol/L, it is recommended to gradually increase the doses of chelators (by 150 mg every 10 days) with subsequent adjustments as a function of 24-h urinary copper excretion and the CuEXC assay, so as to reduce the risk of initial paradoxical worsening. According to a Polish retrospective study of 60 neurological patients, zinc salts can be proposed as first-line monotherapy in mild neurological forms. After an average follow-up of 12 years, the authors showed that using zinc salt as first-line monotherapy was as effective as DP on neurological symptoms and was better tolerated. However, some cases of neurological deterioration were also described (4.3%) [59]. In France, this indication has not yet been retained (www.has-sante.fr).

Maintenance phase and monitoring After several years of chelation, and when WD is well controlled, two options are currently available for the maintenance of patients. The first possibility is to pursue the use of a copper chelator, if possible TN which has fewer long-term side effects than DP. The second option is zinc monotherapy [56]. Zinc acetate inhibits the intestinal absorption of copper, causing mainly gastrointestinal disorders marked by gastric irritation, dyspeptic syndrome or abdominal pain. If these digestive disorders persist, a proton pump inhibitor can be associated with the prescription. Zinc sulphate (magistral formula), which is better tolerated, can also be proposed instead of zinc acetate, but its prescription is off-label in France. The main difficulty encountered during this maintenance phase is to ensure good compliance with the treatment. Adjustment of the dose is very important to prevent neurological complications due to copper defi-

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Wilson’s disease: A 2017 update ciency [60] which may be observed after numerous years of treatment, essentially with zinc salts but also with Trientine [61].

Asymptomatic forms Asymptomatic patients diagnosed from family screening also require lifelong treatment. The European guidelines recommend the introduction of zinc acetate therapy [56] or DP, coupled with annual monitoring of the copper balance. In our experience, such asymptomatic patients should be reassessed more frequently so as to ensure good compliance with the treatment, especially during the transition from childhood to adulthood.

The case of liver transplantation In WD, liver transplantation (LT) is a life-saving curative treatment that provide functional hepatic ATP7B protein and enable the restoration of normal hepatic function, as well as alleviating portal hypertension. It is the gold standard treatment for fulminant hepatitis or decompensated liver cirrhosis. It also has a role in cases of liver adenocarcinoma that cannot be removed surgically. Out of the 31 WD patients who required liver transplantation in a French liver centre between 1974 and 2016, the indications were decompensated cirrhosis in 52% of cases, fulminant liver failure in 23%, severe neurological disease in 23.5% and primary liver cancer in 14% [21]. The long-term results of LT for hepatic indications are excellent, with patient survival rates of 87% at 5, 10, and 15 years according to the recent French study conducted by the reference centre [62]. The indication for LT in the context of neurological deterioration without liver failure is controversial but has been little studied. A recent pilot study suggested that LT could probably be useful in severe neurological forms that are resistant to well-conducted chelation therapy [63]. French experience in recent years has produced some encouraging results: in a group of 18 WD patients experiencing severe neurological worsening, and who underwent LT for a strictly neurological indication, the survival rates were 88.8% at 1 year and 72.2% at 5 years. After five years of follow-up, the patients had progressed from a major disability with permanent bed rest (modified Rankin 4.9 ± 0.4) to mild to moderate disability enabling them to walk alone (modified Rankin 2.3 ± 1.5; P < 0.0001). 60% had a major improvement in their neurological score (Unified Wilson’s Disease Rating Scale), 30% a moderate improvement, and 10% a lack of improvement [64]. This indication remains exceptional but forms part of the therapeutic arsenal available and merits discussion if this situation arises.

Therapeutic perspectives Tetrathiomolybdate Tetrathiomolybdate ammonium (TTM) is a specific chelator developed in the 1960s which reduces the intestinal absorption of copper and forms a powerful complex in the blood with copper and albumin that is then eliminated in bile.

7 Early studies showed that TTM acted rapidly (within a few weeks) by neutralising free copper, and it induced only very rare cases of neurological worsening following treatment initiation, unlike other conventional chelators. TTM also displays anti-inflammatory and anti-fibrotic properties by inhibiting several cytokines and has a satisfactory safety and tolerability profile [65,66]. An international phase 3 study is scheduled to start in 2018. It will compare the effects of TTM with those of standard chelation therapy..

Gene therapy Because most ATP7B is expressed in hepatocytes, the gene therapy approach currently under development aims to restore the hepatic metabolism of copper at a very early stage, before the onset of liver or neurological signs. Early animal studies involving the transduction of a new ATP7B gene via human immunodeficiency virus-derived lentiviral vectors (LV) have been promising and demonstrated hepatocyte transgene expression, a reduction in intra-hepatocyte copper levels and improvements of fibrosis [67]. Another study produced similar results after prenatal gene transfer by the injection of LV containing the human ATP7B gene in a murine model of WD. This study provided proof of principle for in utero gene therapy in WD [68]. Recently, the LV vector appears to have been supplanted by a smaller and more efficient parvovirus called recombinant adeno-associated virus (rAAV). The research team demonstrated sufficient restoration of copper metabolism six months after a single injection of rAAV [69]. The application of this technique in WD patients is the most promising in terms of liver-directed gene therapy for this disease. The first phase 3 clinical studies are expected to start in the coming months.

Hepatocyte/tissue transfer Another approach is based on the replacement of healthy hepatocytes using cell therapy to restore physiological ATP7B-dependent copper excretion into bile fluid [70—72]. In principle, the dysfunctional liver tissue needs to be repopulated with healthy liver cells that are then able to proliferate into functional hepatocytes and reconstitute the biliary canalicular network. However, this approach seems to be insufficient in WD as in this disease context, the tissue and architecture are damaged and the presence of inflammatory cells impairs the quality of engraftment [65].

Conclusion Through research and the data available in rare disease registries, our knowledge of WD is increasing. Genetic studies have suggested that this disease is not as rare as was previously thought, with attenuated or late forms. The exchangeable copper assay is a new biomarker that enables rapid and reliable diagnosis using the ratio REC and hence the initiation of chelation, pending the final outcome of the genetic study. Liver transplantation forms part of the therapeutic arsenal and may have a role in rare cases of fulminant neurological worsening that is resistant to standard chelating

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therapies. The future looks promising, with the development of new and effective treatments, including gene therapy, for which the phase 3 studies are now starting.

Disclosure of interest The authors declare that they have no competing interest.

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