Publications by authors named "Aurélia Poujois"

34 Publications

Wilson's disease: update on pathogenesis, biomarkers and treatments.

J Neurol Neurosurg Psychiatry 2021 Aug 2. Epub 2021 Aug 2.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.

Wilson's disease is an autosomal-recessive disorder of copper metabolism caused by mutations in and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. Decoppering treatments are used to prevent disease progression and reduce symptoms, but neurological outcomes remain mixed. In this article, we review the current understanding of pathogenesis, biomarkers and treatments for Wilson's disease from the neurological perspective, with a focus on recent advances. The genetic and molecular mechanisms associated with ATP7B dysfunction have been well characterised, but despite extensive efforts to identify genotype-phenotype correlations, the reason why only some patients develop neurological or psychiatric features remains unclear. We discuss pathological processes through which copper accumulation leads to neurodegeneration, such as mitochondrial dysfunction, the role of brain iron metabolism and the broader concept of selective neuronal vulnerability in Wilson's disease. Delayed diagnoses continue to be a major problem for patients with neurological presentations. We highlight limitations in our current approach to making a diagnosis and novel diagnostic biomarkers, including the potential for newborn screening programmes. We describe recent progress in developing imaging and wet (fluid) biomarkers for neurological involvement, including findings from quantitative MRI and other neuroimaging studies, and the development of a semiquantitative scoring system for assessing radiological severity. Finally, we cover the use of established and novel chelating agents, paradoxical neurological worsening, and progress developing targeted molecular and gene therapy for Wilson's disease, before discussing future directions for translational research.
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http://dx.doi.org/10.1136/jnnp-2021-326123DOI Listing
August 2021

NON-INVASIVE DIAGNOSIS AND FOLLOW-UP OF RARE GENETIC LIVER DISEASES.

Clin Res Hepatol Gastroenterol 2021 Jul 28:101768. Epub 2021 Jul 28.

Service d'hépatologie, Hôpital Rangueil, CHU Toulouse, Toulouse.

Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease, must be investigated in any patient with unexplained liver disease and/or unexplained neurological or neuropsychiatric disorders. The diagnosis is based on a combination of clinical, biological features, including copper balance. The exchangeable copper/total copper ratio is a new sensible and specific biological marker, useful for the diagnosis of the disease. Timely diagnosis and treatment will prevent serious complications from the disease. Neurological evaluation and familial screening are essential in patients with Wilson's disease.
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http://dx.doi.org/10.1016/j.clinre.2021.101768DOI Listing
July 2021

Designing clinical trials in Wilson disease.

Hepatology 2021 Jul 28. Epub 2021 Jul 28.

Departments of Medicine and Surgery, Yale University Medical Center, New Haven, CT, USA.

Background And Aims: Wilson disease (WD) is an autosomal recessive disorder caused by ATP7B gene mutations leading to pathologic accumulation of copper in the liver and brain. Adoption of initial treatments for WD was based on empiric observations. These therapies are effective, but there are still are unmet needs for which new treatment modalities are being developed. Randomized controlled phase 3 studies are lacking for current WD treatments.

Approach And Results: The first Wilson Disease Aarhus Symposium (May 2019) included a workshop on randomized clinical trial (RCT) design. The authors of the paper were organizers or presented during this workshop and this article presents their consensus on the design of clinical trials for WD, addressing trial population, treatment comparators, inclusion and exclusion criteria and treatment endpoints. To achieve adequate recruitment of patients with this rare disorder, the study groups should include all clinical phenotypes and treatment-experienced as well as treatment-naive patients.

Conclusions: The primary study endpoint should be clinical or a composite endpoint until appropriate surrogate endpoints are validated. Standardization of clinical trials will permit pooling of data and allow for better treatment comparisons, as well as reduce the future numbers of patients needed per trial.
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http://dx.doi.org/10.1002/hep.32074DOI Listing
July 2021

Cardiac involvement in Wilson disease: Review of the literature and description of three cases of sudden death.

J Inherit Metab Dis 2021 Jul 19. Epub 2021 Jul 19.

Department of Neurology, Rothschild Foundation Hospital, Paris, France.

Wilson disease (WD) is a rare genetic condition that results from a build-up of copper in the body. It requires life-long treatment and is mainly characterized by hepatic and neurological features. Copper accumulation has been reported to be related to the occurrence of heart disease, although little is known regarding this association. We have conducted a systematic review of the literature to document the association between WD and cardiac involvement. Thirty-two articles were retained. We also described three cases of sudden death. Cardiac manifestations in WD include cardiomyopathy (mainly left ventricular (LV) remodeling, hypertrophy, and LV diastolic dysfunction, and less frequently LV systolic dysfunction), increased levels of troponin, and/or brain natriuretic peptide, electrocardiogram (ECG) abnormalities, and rhythm or conduction abnormalities, which can be life-threatening. Dysautonomia has also been reported. The mechanism of cardiac damage in WD has not been elucidated. It may be the result of copper accumulation in the heart, and/or it could be due to a toxic effect of copper, resulting in the release of free oxygen radicals. Patients with signs and/or symptoms of cardiac involvement or who have cardiovascular risk factors should be examined by a cardiologist in addition to being assessed by their interdisciplinary treating team. Furthermore, ECG, cardiac biomarkers, echocardiography, and 24-hours or more of Holter monitoring at the diagnosis and/or during the follow-up of patients with WD need to be evaluated. Cardiac magnetic resonance imaging, although not always available, could also be a useful diagnostic tool, allowing assessment of the risk of ventricular arrhythmias and further guidance of the cardiac workup.
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http://dx.doi.org/10.1002/jimd.12418DOI Listing
July 2021

Pediatric Wilson's Disease: Phenotypic, Genetic Characterization and Outcome of 182 Children in France.

J Pediatr Gastroenterol Nutr 2021 Jun 1. Epub 2021 Jun 1.

Hospices Civils de Lyon. National Center for Wilson's disease and Department of pediatric gastroenterology, hepatology and nutrition children's hospital of Lyon, France Claude Bernard Lyon 1 university Lyon, France Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, Le Kremlin-Bicêtre, France Competence centre for Wilson disease Pediatric Hepatology Unit, Reference Center for Biliary Atresia and Genetic cholestasis, Hôpital Necker-Enfants Malades, AP-HP, Université Paris Centre, Paris, France. Children's Hospital, Paediatric Gastroenterology Unit, Bordeaux, France, Children University Hospital, Metabolic Disease Department, Toulouse, France, APH, Timone Enfant, Service de pédiatrie multidisciplinaire, Marseille, France, Aix Marseille Univ, INSERM, MMG ; Marseille, France, University Hospital of Besancon, Paediatric Gastroenterology Unit, Besacon, France, Paul Brousse Hospital, Hepatobiliary Centre, Hepatobiliary Centre, France, Univ- Lille, CHU Lille, UMR1286 Department of Pediatric Gastroenterology Hepatology and Nutrition, Lille, France, CHU Rennes, Department of Pediatric Gastroenterology, Rennes, France Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France French National Rare Disease Reference Centre "Wilson's disease and other copper-related rare diseases", Rothschild Foundation Hospital, Neurology Department, Paris, France Inserm U1193, Hepatinov, University of Paris Saclay, Orsay, France;.

Objectives: To describe a cohort of Wilson's disease (WD) paediatric cases, and to point out the diagnostic particularities of this age group and the long-term outcome.

Methods: Clinical data of 182 paediatric patients included in the French WD national registry from 01/03/1995 to 01/06/2019 were gathered.

Results: Diagnosis of WD was made at a mean age of 10.7 ± 4.2 years (range 1-18 years). At diagnosis, 154 patients (84.6%) had hepatic manifestations, 19 (10.4%) had neurological manifestations, and 9 patients (4.9%) were asymptomatic. The p.His1069Gln mutation was the most frequently encountered (14% of patients).Neurological patients were diagnosed at least one year after they presented their first symptoms. At diagnosis, the median urinary copper excretion (UCE) was 4.2 μmol/24 hours (0.2-253). The first-line treatment was D-penicillamine (DP) for 131 (72%) patients, zinc salts for 24 (13%) patients, and Trientine for 17 (9%) patients. Liver transplantation was performed in 39 (21.4%) patients, for hepatic indications in 33/39 patients or for neurological deterioration in 6/39 patients, mean UWDRS of the latter went from 90 ± 23.1 before LT to 26.8 ± 14.1 (p < 0.01) after a mean follow-up of 4.3 ± 2.5 years. Overall survival rate at 20 years of follow-up was 98%, patient and transplant-free combined survival was 84% at 20 years.

Conclusion: Diagnosis of WD can be challenging in children, particularly at early stages of liver disease and in case of neurological presentation; hence the support of clinical scores and genetic testing is essential. Diagnosis at early stages and proper treatment ensure excellent outcomes, subject to good long-term treatment compliance. LT is a valid option for end-stage liver disease not responding to treatment and can be discussed for selected cases of neurological deterioration.
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http://dx.doi.org/10.1097/MPG.0000000000003196DOI Listing
June 2021

Sleep disorders in Wilson's disease.

Sleep Med 2021 07 30;83:299-303. Epub 2020 Aug 30.

French National Reference Centre for Wilson's Disease, Foundation Rothschild Hospital, Paris, France; Neurology Department, Foundation Rothschild Hospital, Paris, France.

Background/objectives: Wilson's disease (WD) is a rare genetic disorder that leads to copper overload, mainly in the liver then, in the brain. Patients with WD often complain about sleep disorders. We aimed to explore them.

Patients/methods: Sleep complaints and disease symptoms were compared in 40 patients with WD (20 patients with hepatic phenotype matched to 20 neurologic one) and 40 age, sex and BMI matched healthy controls.

Results: Patients with WD had more frequently (32.5 vs 10.0%, p < 0.05) and more severe (10.5 ± 6.0 vs 7.6 ± 4.8, p < 0.01) insomnia than controls and insomnia was more severe in neurologic than hepatic form of the disease (12.25 ± 5.89 vs 8.73 ± 5.8, p < 0.05). Insomnia severity was correlated with the severity of depressive symptoms (r = 0.53, p < 0.001). Compared to controls, patients reported more difficulties staying asleep and more consequences of insomnia on their quality of life. REM sleep behavior disorder was more frequent in WD (20 vs 0%, p = 0.005) than controls. Patients complained more frequently of nycturia (22.8 vs 7.6%, p = 0.003) than controls. Patients did not differ from controls for sleepiness, restless legs syndrome and obstructive sleep apnea syndrome. Patients did not report cataplexia.

Conclusion: In patients with WD, insomnia and REM sleep behavior disorder are the two main sleep complaints. Insomnia is more frequent in neurologic than hepatic form of the disease. Severity of insomnia is associated with the severity of depressive symptoms.
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http://dx.doi.org/10.1016/j.sleep.2020.07.007DOI Listing
July 2021

Associated co-morbidities in a retrospective cohort of orthostatic tremor.

J Neurol 2021 Feb 20;268(2):467-473. Epub 2020 Aug 20.

Service de Physiologie Clinique-Explorations Fonctionnelles, APHP, Hôpital Lariboisière, 75010, Paris, France.

Background: Orthostatic tremor (OT) is characterized by tremor in orthostatism. Primary OT is characterized by a high-frequency tremor at surface EMG recording and assumed to be idiopathic, whereas slow-frequency OT is classically associated with neurological pathologies. We report here a retrospective monocentric cohort study of primary (fast OT) and pseudo-OT (slow OT) patients to describe associated neurological and non-neurological co-morbidities.

Methods: Between November 2014 and October 2019, 27 patients with OT were selected from the EMG database of the Department of Clinical Physiology in Lariboisière' s hospital. Patients were classified in primary OT if tremor frequency was ≥ 13 Hz and in pseudo-OT if tremor frequency was < 13 Hz.

Results: Leg tremor on standing represented 10.2% of all tremor recordings. Ten patients were included in the primary and 17 in the pseudo-OT group. Females were predominant (62.9%) (p = 0.04). Mean age at diagnosis was 64.8 ± 1.1 years. At the first visit, a movement disorder was associated with 30% of primary OT, among them one CADASIL patient, whereas extrapyramidal or cerebellar disorders were reported in 100% of pseudo-OT, among them three Wilson's disease patients. These pathologies all preceded primary OT and occurred concomitantly with pseudo-OT. Frequency remained unchanged during evolution, except pseudo-OT in two patients that completely resolved following the introduction of antiParkinsonian drugs. Treatment of primary OT was partially effective in 28% and in 50% of pseudo-OT patients.

Conclusion: In this monocentric study, movement disorders were present in 30% of primary OT patients. This result questions the term "idiopathic" or "primary" OT, but the small number of patients does not allow answering this issue.
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http://dx.doi.org/10.1007/s00415-020-10168-zDOI Listing
February 2021

A novel deep intronic variant in ATP7B in five unrelated families affected by Wilson disease.

Mol Genet Genomic Med 2020 10 8;8(10):e1428. Epub 2020 Aug 8.

Department of Biochemistry and Molecular Biology, Lariboisiere University Hospital, APHP, Paris, France.

Background: Wilson disease is an autosomal recessive metabolic disorder resulting from accumulation of excess copper especially in the liver and brain. This disease is mainly characterized by hepatic disorders and less frequently by neuro-psychiatric disturbances. This recessive disease is due to mutation in ATP7B, which codes for an ATPase involved in copper-transport across the plasma membrane. Molecular diagnosis of WD is positive in approximately 98% of cases. Also, in few cases, WD patients present a single deleterious mutation (heterozygous) or no mutation after sanger and NGS standard sequencing analysis of ATP7B. Therefore, in these problematic WD cases, we hypothesized that deleterious mutations reside in intronic regions of ATP7B.

Methods: Complete ATP7B gene was sequenced by Next Generation Sequencing including its promoter.

Results: Five unrelated families with Wilson disease shared the same novel, deep intronic NG_008806.1 (ATP7B_v001):c.2866-1521G>A variant in ATP7B. Analysis of RNA transcripts from primary fibroblasts of one patient confirmed the deleterious impact of the intronic variant on splicing and its likely pathologic effect in this compound heterozygote.

Conclusion: This discovery of a novel intronic mutation in ATP7B has improved the molecular diagnosis of WD in the French patient cohort to greater than 98%. Thus, we recommend complete sequencing of ATP7B gene, including introns, as a molecular diagnostic approach in cases of clinically confirmed WD which lack pathogenic exon or promoter variants in one or both alleles.
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http://dx.doi.org/10.1002/mgg3.1428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549599PMC
October 2020

Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.

Neurology 2020 05 12;94(21):e2189-e2202. Epub 2020 May 12.

From the Neurology Department (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital; National Reference Centre for Wilson's Disease (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital, Paris; Hepatobiliary Centre (R.S., D.C., D.S., J.-C.D.-V.), DHU Hepatinov, UMR-1193, AP-HP, Paul Brousse Hospital, Villejuif; Service de Neurologie (W.G.M.), CHU Bordeaux; Université de Bordeaux (W.G.M.), Institut des Maladies Neurodégénératives, CNRS UMR 5393, France; Department of Medicine (W.G.M.), University of Otago and New Zealand Brain Research Institute (W.G.M.), Christchurch; Hepatology, Gastroenterology and Nutrition Department (A.-S.B., A.L.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon; National Reference Centre for Wilson's Disease (A.-S.B., E.B., C.L., L.L.-F., O.G., A.L.), Hospices Civils de Lyon; Neurology Department (E.B., C.L.), Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon; CNRS (E.B., C.L.), UMR 5229, Institut des Sciences Cognitives Marc-Jeannerod, Bron; Faculté de Médecine Lyon Sud Charles-Mérieux (E.B., C.L., A.L.), Université Claude-Bernard Lyon 1; Neurology and Paediatrics Department (L.L.-F.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron; Hepatogastroenterology Department (O.G.), Edouard Herriot Hospital, Hospices Civils de Lyon; Internal Medicine Department (F.M.), National Reference Centre for Inborn Errors of Metabolism, Université François Rabelais; Neurology Department (J.B.), CHRU Bretonneau, Tours; Surgery, Oncology and Liver Transplantation Department (E.S.), CHRU Tours; Hepatology and Gastroenterology Department (C.V.) and Surgery and Liver Transplantation Department (B.H.), CHU Besançon; Neurology and Paediatrics Department (C. Bellesme), AP-HP, Bicêtre University Hospital, Kremlin-Bicetre; Pediatric Hepatology and Pediatric Liver Transplantation Unit (U.H) and National Reference Centre for Rare Pediatric Liver Diseases (U.H), Bicêtre University Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, DHU Hepatinov, AP-HP, Le Kremlin Bicêtre; INSERM (D.H.), UMR-S1174, Hepatinov, University of Paris Sud 11, Orsay; Hepatology and Gastroenterology Department (C. Bureau) and Neurology Department (F.O.-M.), CHU Toulouse; Centre D'investigation de la Fibrose Hépatique (V.L.), Hôpital Haut-Lévêque, CHU Bordeaux; and INSERM U1053 (V.d.L.), Université de Bordeaux, France. A. Poujois is currently at Neurology Department, Rothschild Foundation Hospital, and National Reference Centre for Wilson's Disease, Rothschild Foundation Hospital, Paris.

Objective: To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.

Methods: French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.

Results: Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved ( < 0.0001 and = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved ( = 0.0007). Severe sepsis ( = 0.011) and intensive care unit admission ( = 0.001) before LT were significantly associated with death.

Conclusions: LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.

Classification Of Evidence: This study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.
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http://dx.doi.org/10.1212/WNL.0000000000009474DOI Listing
May 2020

Semiquantitative Scale for Assessing Brain MRI Abnormalities in Wilson Disease: A Validation Study.

Mov Disord 2020 06 17;35(6):994-1001. Epub 2020 Mar 17.

2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.

Background: MRI is a sensitive method for the assessment of brain abnormalities in Wilson disease, that is, T hyperintensities, T hypointensities, and atrophy, but a validated scoring system for the classification of radiological severity is lacking. The objective of this study was to develop and validate a brain MRI visual rating scale for Wilson disease.

Methods: The proposed Wilson disease brain MRI severity scale consists of acute toxicity and chronic damage subscores from predefined structures. The former, calculated by summing scores of T hyperintensities (excluding cavitation), is likely to be partially reversible with treatment. The latter, representing the sum of scores of T hypointensities and brain atrophy, reflects pathology that is not readily reversible. Validation was performed on MRI scans acquired using 1.5T system from 39 Wilson disease patients examined at baseline and after 24 months on anticopper treatment. Intraclass correlation coefficients of 5 ratings from 3 raters were calculated. Temporal evolution of the MRI severity score and its association with clinical severity, assessed using the Unified Wilson Disease Rating Scale part III, was calculated.

Results: Intrarater and interrater agreement were good (r > 0.93; P < 0.001; and r > 0.74; P < 0.001, respectively). In neurologic Wilson disease patients, the total MRI severity score improved over 2 years (P = 0.032), mainly because of reduced acute toxicity (P = 0.0015), whereas the chronic damage score deteriorated (P = 0.035). Unified Wilson Disease Rating Scale part III score was positively associated with chronic damage and total score at baseline (P = 0.005 and P = 0.003, respectively) and in month 24 (P < 0.001 and P = 0.001, respectively).

Conclusions: The Wilson disease brain MRI severity scale is a simple, reliable, and valid instrument that allows semiquantitative assessment of radiological Wilson disease severity. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28018DOI Listing
June 2020

Comprehensive and comparative exploration of the Atp7b mouse plasma proteome.

Metallomics 2020 02 9;12(2):249-258. Epub 2019 Dec 9.

Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France.

Wilson's disease (WD), a rare genetic disease caused by mutations in the ATP7B gene, is associated with altered expression and/or function of the copper-transporting ATP7B protein, leading to massive toxic accumulation of copper in the liver and brain. The Atp7b mouse, a genetic and phenotypic model of WD, was developed to provide new insights into the pathogenic mechanisms of WD. Many plasma proteins are secreted by the liver, and impairment of liver function can trigger changes to the plasma proteome. High standard proteomics workflows can identify such changes. Here, we explored the plasma proteome of the Atp7b mouse using a mass spectrometry (MS)-based proteomics workflow combining unbiased discovery analysis followed by targeted quantification. Among the 367 unique plasma proteins identified, 7 proteins were confirmed as differentially abundant between Atp7b mice and wild-type littermates, and were directly linked to WD pathophysiology (regeneration of liver parenchyma, plasma iron depletion, etc.). We then adapted our targeted proteomics assay to quantify human orthologues of these proteins in plasma from copper-chelator-treated WD patients. The plasma proteome changes observed in the Atp7b mouse were not confirmed in these samples, except for alpha-1 antichymotrypsin, levels of which were decreased in WD patients compared to healthy individuals. Plasma ceruloplasmin was investigated in both the Atp7b mouse model and human patients; it was significantly decreased in the human form of WD only. In conclusion, MS-based proteomics is a method of choice to identify proteome changes in murine models of disrupted metal homeostasis, and allows their validation in human cohorts.
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http://dx.doi.org/10.1039/c9mt00225aDOI Listing
February 2020

Sleep Disorders in Wilson's Disease.

Curr Neurol Neurosci Rep 2019 11 13;19(11):84. Epub 2019 Nov 13.

French National Reference Centre for Wilson's Disease, Fondation Rothschild Hospital, Paris, France.

Purpose Of Review: We aimed to review the sleep disorders described in Wilson's disease (WD), focusing on their mechanisms and treatments.

Recent Findings: REM sleep behavior disorder or sleepiness can be warning signs of future WD. These early symptoms may significantly reduce the time to WD diagnosis. Early anti-copper therapies (chelators or zinc salts), reducing copper accumulation in the brain and though saving brain tissue, can allow the complete disappearance of these sleep disorders and of course improve the other symptoms of WD. Insomnia, restless legs syndrome (RLS), daytime sleepiness, cataplexy, and REM sleep behavior disorder (RBD) are present in WD and should be explored with video polysomnography and multiple sleep latency test. Suggested immobilization test could be useful in the diagnosis of RLS in WD. Motor and non-motor symptoms, dysautonomic dysfunctions, drugs, and lesions of the circuits regulating wake and sleep may be involved in the mechanisms of these sleep abnormalities. Adapted treatments should be proposed.
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http://dx.doi.org/10.1007/s11910-019-1001-4DOI Listing
November 2019

New tools for Wilson's disease diagnosis: exchangeable copper fraction.

Ann Transl Med 2019 Apr;7(Suppl 2):S70

National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France.

Wilson's disease (WD) biochemical markers continue to evolve. Classical tests [serum copper, serum ceruloplasmin (Cp), urinary copper] have their own limits, and they are often insufficient to diagnose or exclude WD. So, calculated estimation of copper that is not bound to Cp has been proposed, but it is flawed. Therefore, we focused our research on a direct measurement of serum copper labile fraction. Exchangeable copper (CuEXC) offers a correct view of the free copper overload. It provides information on the spread and severity of WD. Relative exchangeable copper (REC) (percentage of exchangeable to total serum copper) that appreciates the toxic fraction of copper in blood is an excellent biomarker for WD diagnosis. These two tests are reliable and non-invasive. They give rapid answers for an appropriate diagnosis and make possible to start the treatment quickly without waiting for the result of the genetic tests. As early diagnosis and treatment are the keystones of successful management of patients with WD, different teams have already applied these tests in a routine framework to a large number of patients.
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http://dx.doi.org/10.21037/atm.2019.03.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531656PMC
April 2019

Challenges in the diagnosis of Wilson disease.

Ann Transl Med 2019 Apr;7(Suppl 2):S67

Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France.

The understanding and management of Wilson disease (WD) have dramatically improved since the first description of the disease by K. Wilson more than a century ago. However, the persistent long delay between the first symptoms and diagnosis emphasizes challenges in diagnosing earlier this copper overload disorder. As a treatable disease, WD should be detected early in the course of the disease by any health professionals at any care level, but the rare prevalence of the disease explains the lack of awareness of referring physicians. The most important challenge is to train physicians to recognize atypical or rare symptoms of WD that will lead to discuss the diagnosis more systematically. Atypia can come from the age of onset, the liver [non-alcoholic steatohepatitis (NASH) presentation], the central or peripheral nervous system (neuropathy, epilepsy, sleep disorders…) or may be due to lesions of other organs (renal manifestations, osteo-articular disorders or endocrine disturbances). Isolated biological anomalies, rare radiological findings or inadequate interpretation of copper test may also lead to misdiagnosis. The second challenge is to confirm the diagnosis faster and more effectively so as not to delay the initiation of treatment, and expand family screening as the genetic prevalence is higher than previously expected. Generalization of the exchangeable copper assay and the next generation sequencing (NGS) are two promising ways to overcome this ultimate challenge. By drawing attention to the earliest and rare symptoms and to new biomarkers and diagnostic tools, we hope that this article will increase diagnostic awareness and reduce delays so that patients can start their treatment earlier in the course of the illness and thus have a better disease prognosis.
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http://dx.doi.org/10.21037/atm.2019.02.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531657PMC
April 2019

Exceptional involvement of medulla oblongata in Wilson disease.

Neurology 2019 04;92(16):770-771

From the Neurology Department (A.P., F.W.), National Reference Centre for Wilson's Disease (A.P., F.W.), and Neuroradiology Department (A.G.), AP-HP, Lariboisière University Hospital, Paris, France.

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http://dx.doi.org/10.1212/WNL.0000000000007321DOI Listing
April 2019

Sleep Abnormalities in Wilson's Disease.

Curr Treat Options Neurol 2018 Sep 27;20(11):46. Epub 2018 Sep 27.

French National Reference Centre for Wilson's Disease, University Hospital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Purpose Of Review: The aim of this article was to review the different sleep disorders associated with Wilson's disease (WD), their mechanisms and their treatments.

Recent Findings: Some of these disorders such as REM sleep behavior disorder or sleepiness can appear as a prodromal phase phenomenon in WD allowing an early treatment of the disease and sometimes a resolution of the sleep disorder. Sleep disorders in WD are frequent combining insomnia, daytime sleepiness, restless legs syndrome (RLS), cataplexy-like episodes, and REM sleep behavior disorder (RBD). Sleep recordings confirm these disorders. Mechanisms involved in these disorders are complex associating (a) lesions of the pathways regulating sleep and wake or mood but also controlling movement, (b) iatrogenic effects of the treatments, and (3) consequences of the motor or dysautonomic or metabolic disorders.
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http://dx.doi.org/10.1007/s11940-018-0531-4DOI Listing
September 2018

Answer to challenging issues in the management of Wilson's disease.

Clin Res Hepatol Gastroenterol 2019 02 27;43(1):e7-e8. Epub 2018 Aug 27.

Neurology department, AP-HP, Lariboisière university hospital, 75010 Paris, France; National reference centre for Wilson's disease, AP-HP, Lariboisière university hospital, 75010 Paris, France.

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http://dx.doi.org/10.1016/j.clinre.2018.07.006DOI Listing
February 2019

High genetic carrier frequency of Wilson's disease in France: discrepancies with clinical prevalence.

BMC Med Genet 2018 08 10;19(1):143. Epub 2018 Aug 10.

National reference Centre for Wilson's Disease (CRMR Wilson), Department of Neurology, Lariboisiere University Hospital, APHP, Paris, France.

Background: Wilson's disease (WD) is a rare autosomal recessive metabolic disease caused by ATP7B gene mutations tat cause excessively high copper levels, particularly in the liver and brain. The WD phenotype varies in terms of its clinical presentation and intensity. Diagnosing this metabolic disorder is important as a lifelong treatment, based on the use of copper chelating agents or zinc salts, is more effective if it's started early. Worldwide prevalence of WD is variable, with an average of 1/30,000. In France, a recent study based on French health insurance data estimated the clinical prevalence of the disease to be around 3/200,000.

Methods: To estimate the genetic prevalence of WD in France, we analysed the ATP7B gene by Next Generation Sequencing from a large French cohort of indiscriminate subjects.

Results: We observed a high heterozygous carrier frequency of ATP7B in France. Among the 697 subjects studied, 18 variants classified as pathogenic or probably pathogenic were found at heterozygous level in 22 subjects (22 alleles/1394 alleles), yielding a prevalence of 0.032 or 1/31 subjects.

Conclusions: This considerable and unexplained discrepancy between the heterozygous carrier frequency and the clinical prevalence of WD may be explained by the clinical variability, the incomplete penetrance and the existence of modifiers genes. It suggests that the molecular analysis of ATP7B should be interpreted with caution, always alongside copper assays (ceruloplasmin, relative exchangeable copper, 24 h-urinary copper excretion) with particular respect to exome sequencing.
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http://dx.doi.org/10.1186/s12881-018-0660-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086069PMC
August 2018

CCDC115-CDG: A new rare and misleading inherited cause of liver disease.

Mol Genet Metab 2018 07 9;124(3):228-235. Epub 2018 May 9.

AP-HP, Bichat University Hospital, Biochemistry, Paris, France; INSERM UMR-1193 "Mécanismes cellulaires et moléculaires de l'adaptation au stress et cancérogenèse", Université Paris-Sud, Châtenay-Malabry, France. Electronic address:

Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement. Biological results were similar to previously described patients, including hypercholesterolemia, elevated alkaline phosphatases and defects in copper metabolism. CDG screening and glycosylation study finally led to the molecular diagnosis of CCDC115-CDG. Besides pointing to the importance of CDG screening in patients with unexplained and severe liver disease, these reports expand the clinical and molecular phenotypes of CCDC115-CDG. The hepatic involvement is particularly addressed. Furthermore, hypothesis concerning the pathogenesis of the liver disease and of major biological abnormalities are proposed.
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http://dx.doi.org/10.1016/j.ymgme.2018.05.002DOI Listing
July 2018

Wilson's disease: A 2017 update.

Clin Res Hepatol Gastroenterol 2018 12 4;42(6):512-520. Epub 2018 Apr 4.

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

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 24h 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 >2.08μmol/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. 6.6kPa 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.
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http://dx.doi.org/10.1016/j.clinre.2018.03.007DOI Listing
December 2018

Dystonic Dysarthria in Wilson Disease: Efficacy of Zolpidem.

Front Neurol 2017 31;8:559. Epub 2017 Oct 31.

National Reference Centre for Wilson Disease, Neurology Department, University Hospital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Wilson disease (WD) is a rare genetic disorder characterized by copper overload in the liver and the brain. Neurological presentations are mainly related to the accumulation of copper in the basal ganglia, the brainstem, and the cerebellum. Dysarthria is a frequent symptom, with dystonic, spastic, or parkinsonian components and is usually resistant to medical or voice rehabilitation therapies. Here, we report the case of a patient with WD diagnosed at the age of 12, who presented a severe and constant dysarthria from dystonic origin which was unresponsive to benzodiazepines and anticholinergic drugs. When she was 25-year-old, she tried zolpidem at bedtime for sleeping difficulties and reported a paradoxical effect of this drug on her voice. To confirm the effect of zolpidem on her dystonic dysarthria, we realized a full evaluation of her dysarthria at baseline without zolpidem and after 4 days of treatment by 10 mg twice a day. Lexical access was evaluated by the semantic fluency; dysarthria by the Intelligibility Score, the spontaneous speech and reading rates, the maximum phonation time on the sustained vowel [a] and by a perceptive evaluation. Two hours after the intake of zolpidem, improvement of all the parameters tested, with the exception of the maximum phonation time, was observed. Semantic fluency increased by 59%, the spontaneous speech rate by 88% and the reading rate by 76%. General dystonia remained unchanged and the tolerance of zolpidem was satisfactory. Since then, the patient takes zolpidem 5 mg five times a day, and 4 years later shows persistent improvement in oral communication and a good drug tolerance. In this single-case study, we showed that regular daytime intake of zolpidem could have a persisting effect on a complex dystonic dysarthria that was resistant to usual medical treatments.
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http://dx.doi.org/10.3389/fneur.2017.00559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671475PMC
October 2017

Neurological presentations revealing acquired copper deficiency: diagnosis features, aetiologies and evolution in seven patients.

Intern Med J 2018 05;48(5):535-540

Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France.

Background: Acquired copper deficiency (ACD) is a rare condition usually diagnosed from haematological changes.

Aims: To characterise the diagnosis features and the evolution of patients with ACD revealed by neurological symptoms.

Methods: Clinical, biological and magnetic resonance imaging (MRI) data were prospectively analysed at diagnosis and during follow up under copper supplementation.

Results: Seven patients were studied over a 5-year period. Time to diagnosis ranged from 2.5 to 15 months. Subacute ascending paraesthesias and gait disorder were the first symptoms. All patients had a posterior cord syndrome (PCS) with sensory ataxic gait associated with superficial hypoesthesia of the feet; 50% had also lateral cord signs. Electrodiagnostic tests diagnosed a lower limb sensory neuropathy in four patients. Spinal cord MRI was normal in three of seven patients. Anaemia and lymphopenia were diagnosed in six of seven patients. Serum copper was always low, and urinary copper was low or normal. Serum and urinary zinc were high in four patients. Decreased copper intake (stoma/parenteral nutrition, malnutrition, malabsorption with lack of vitamin supplementation after bariatric or other digestive surgeries) was found in four patients, and the chronic use of denture adhesive paste containing zinc was discovered in four patients. One patient had both the causes recorded. After copper supplementation, copper balance and then haematological disturbances were the first features to normalise gradually in 2 months. Radiological myelitis disappeared in 10 months, whereas neurological symptoms improved in six of seven patients after a mean follow up of 2 years.

Conclusions: Progressive PCS with anaemia and lymphopenia must raise the possibility of an ACD. Early copper supplementation could increase the neurological prognosis.
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http://dx.doi.org/10.1111/imj.13650DOI Listing
May 2018

Inhibitory rTMS applied on somatosensory cortex in Wilson's disease patients with hand dystonia.

J Neural Transm (Vienna) 2017 Oct 8;124(10):1161-1170. Epub 2017 Jul 8.

Service de Physiologie Clinique-Explorations Fonctionnelles, AP-HP, Hôpital Lariboisière, 2, rue Ambroise Paré, 75010, Paris, France.

Hand dystonia is a common complication of Wilson's disease (WD), responsible for handwriting difficulties and disability. Alteration of sensorimotor integration and overactivity of the somatosensory cortex have been demonstrated in dystonia. This study investigated the immediate after effect of an inhibitory repetitive transcranial magnetic stimulation (rTMS) applied over the somatosensory cortex on the writing function in WD patients with hand dystonia. We performed a pilot prospective randomized double-blind sham-controlled crossover rTMS study. A 20-min 1-Hz rTMS session, stereotaxically guided, was applied over the left somatosensory cortex in 13 WD patients with right dystonic writer's cramp. After 3 days, each patient was crossed-over to the alternative treatment. Patients were clinically evaluated before and immediately after each rTMS session with the Unified Wilson's Disease rating scale (UWDRS), the Writers' Cramp Rating Scale (WCRS), a specifically designed scale for handwriting difficulties in Wilson's disease patients (FAR, flow, accuracy, and rhythmicity evaluation), and a visual analog scale (VAS) for handwriting discomfort. No significant change in UWDRS, WCRS, VAS, or FAR scores was observed in patients treated with somatosensory inhibitory rTMS compared to the sham protocol. The FAR negatively correlated with UWDRS (r = -0.6; P = 0.02), but not with the WCRS score, disease duration, MRI diffusion lesions, or with atrophy scores. In our experimental conditions, a single inhibitory rTMS session applied over somatosensory cortex did not improve dystonic writer cramp in WD patients.
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http://dx.doi.org/10.1007/s00702-017-1756-1DOI Listing
October 2017

Characteristics and prevalence of Wilson's disease: A 2013 observational population-based study in France.

Clin Res Hepatol Gastroenterol 2018 02 23;42(1):57-63. Epub 2017 Jun 23.

Direction de la stratégie des études et des statistiques, Caisse Nationale d'Assurance Maladie, 50, avenue du Professeur-André-Lemierre, 75986 Paris cedex 20, France. Electronic address:

Background And Aims: Only a few epidemiological studies on the incidence and prevalence of Wilson's disease (WD) have been performed to date, and the results vary widely according to the reports. The aim of the study was to investigate the prevalence, ambulatory care and treatments of patients with WD in France.

Methods: Among the 58 million general health scheme beneficiaries (86% of the French population), people managed for WD in 2013 were identified using hospitalisation diagnosis in 2011-2013 or specific long-term disease status with a 100% reimbursement for specific healthcare in 2013. Data were derived from the Sniiram (National Health Insurance Information System database). Prevalence by age and sex were calculated.

Results: In 2013, 906 prevalent cases were identified, yielding a crude prevalence of 1.5 cases per 100,000; 1.65 per 100,000 in males and 1.44 per 100,000 in females. This prevalence is comparable to that reported in other population-based studies in European countries and to a study using a similar method. Almost 40% of patients were treated by D-penicillamine and 14.3% were treated by zinc acetate. Trientine, delivered on a compassionate basis, was not available in the reimbursement database. In 2013, 1.3% of patients underwent liver transplantation and 4% had already undergone liver transplantation in previous years. Fifteen per cent of patients received antidepressants, a higher rate than in general population.

Conclusions: This is the first French population-based epidemiological study of WD in a comprehensive population based on administrative data and constitutes an important step to understand the impact of WD and to study quality of care.
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http://dx.doi.org/10.1016/j.clinre.2017.05.011DOI Listing
February 2018

Wilson disease: brain pathology.

Handb Clin Neurol 2017 ;142:77-89

French National Reference Centre for Wilson Disease, Neurology Department, Lariboisière Hospital, Paris, France. Electronic address:

In Wilson disease (WD), brain cellular damage is thought to be due to copper deposition. Striatal lesions are the most characteristic lesions found in the brain of patients with neurologic symptoms, as emphasized in the initial reports of S.A.K. Wilson. WD brain lesions can be more diffuse, including in the pons, midbrain, thalamus, dentate nucleus, and, less frequently, corpus callosum and cortex. In rare cases, extensive cortical-subcortical lesions have been reported. Increased cellularity is noted in the lesions due to the proliferation of modified astrocytes named Alzheimer types of glia and specific cells, called Opalski cells, that are characteristic of WD. Although abnormalities in the putamen predominate in patients with dystonic syndrome, clinicopathologic correlations are scarce. Furthermore, the cerebral copper content is not correlated with the severity of the neuropathologic abnormalities or with the neuropsychiatric symptomatology. This fact raises the question of factors other than copper toxicity that may contribute to the pathogenesis of WD neurologic disturbances.
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http://dx.doi.org/10.1016/B978-0-444-63625-6.00008-2DOI Listing
March 2018

Contribution of TMS and rTMS in the Understanding of the Pathophysiology and in the Treatment of Dystonia.

Front Neural Circuits 2016 10;10:90. Epub 2016 Nov 10.

Service de Physiologie Clinique-Explorations Fonctionnelles, AP-HP, Hôpital LariboisièreParis, France; INSERM UMR965Paris, France; Sorbonne Paris Cité - Université Paris DiderotParis, France.

Dystonias represent a heterogeneous group of movement disorders responsible for sustained muscle contraction, abnormal postures, and muscle twists. It can affect focal or segmental body parts or be generalized. Primary dystonia is the most common form of dystonia but it can also be secondary to metabolic or structural dysfunction, the consequence of a drug's side-effect or of genetic origin. The pathophysiology is still not elucidated. Based on lesion studies, dystonia has been regarded as a pure motor dysfunction of the basal ganglia loop. However, basal ganglia lesions do not consistently produce dystonia and lesions outside basal ganglia can lead to dystonia; mild sensory abnormalities have been reported in the dystonic limb and imaging studies have shown involvement of multiple other brain regions including the cerebellum and the cerebral motor, premotor and sensorimotor cortices. Transcranial magnetic stimulation (TMS) is a non-invasive technique of brain stimulation with a magnetic field applied over the cortex allowing investigation of cortical excitability. Hyperexcitability of contralateral motor cortex has been suggested to be the trigger of focal dystonia. High or low frequency repetitive TMS (rTMS) can induce excitatory or inhibitory lasting effects beyond the time of stimulation and protocols have been developed having either a positive or a negative effect on cortical excitability and associated with prevention of cell death, γ-aminobutyric acid (GABA) interneurons mediated inhibition and brain-derived neurotrophic factor modulation. rTMS studies as a therapeutic strategy of dystonia have been conducted to modulate the cerebral areas involved in the disease. Especially, when applied on the contralateral (pre)-motor cortex or supplementary motor area of brains of small cohorts of dystonic patients, rTMS has shown a beneficial transient clinical effect in association with restrained motor cortex excitability. TMS is currently a valuable tool to improve our understanding of the pathophysiology of dystonia but large controlled studies using sham stimulation are still necessary to delineate the place of rTMS in the therapeutic strategy of dystonia. In this review, we will focus successively on the use of TMS as a tool to better understand pathophysiology, and the use of rTMS as a therapeutic strategy.
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http://dx.doi.org/10.3389/fncir.2016.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102895PMC
October 2017

Liver Transplantation in Wilson's Disease with Neurological Impairment: Evaluation in 4 Patients.

Eur Neurol 2017 19;77(1-2):5-15. Epub 2016 Nov 19.

Service de Neurologie C, Hôpital Neurologique, Bron, France.

Background: The aim of this work is to report our early experiences about the benefits of liver transplantation (LT) in the treatment of persistent neurological symptoms in Wilson's disease (WD) patients.

Methods: We describe our findings in 4 WD patients with neurological impairment or symptoms treated by LT: 2 patients had transplants due to worsening of neurological symptoms despite long-term appropriate medical treatment. The other 2 required LT because of symptoms associated with liver failure. Patients were evaluated using the modified Rankin scale and the Unified Wilson's Disease Rating Scale (UWDRS).

Results: The 4 patients experienced neurological improvement after LT. The pre-LT Rankin score of the 2 patients transplanted due to neurological impairment was 4 compared to 3 and 2, respectively, post LT. The pre-LT Rankin scores of the 2 WD cases transplanted because of hepatic failure were 1 and 2, respectively, compared to 0 in both cases post LT. UWDRS score improved in 2 cases and remained stable in 1 less severely impaired case. Brain MRI abnormalities proved partially reversible in 3 patients and remained stable for 1 patient.

Conclusions: These results suggest that LT could be envisaged for neurologically impaired WD patients.
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http://dx.doi.org/10.1159/000452658DOI Listing
September 2017

Bioavailable Trace Metals in Neurological Diseases.

Curr Treat Options Neurol 2016 Oct;18(10):46

School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, UK.

Opinion Statement: Medical treatment in Wilson's disease includes chelators (D-penicillamine and trientine) or zinc salts that have to be maintain all the lifelong. This pharmacological treatment is categorised into two phases; the first being a de-coppering phase and the second a maintenance one. The best therapeutic approach remains controversial, as only a few non-controlled trials have compared these treatments. During the initial phase, progressive increase of chelators' doses adjusted to exchangeable copper and urinary copper might help to avoid neurological deterioration. Liver transplantation is indicated in acute fulminant liver failure and decompensated cirrhosis; in cases of neurologic deterioration, it must be individually discussed. During the maintenance phase, the most important challenge is to obtain a good adherence to lifelong medical therapy. Neurodegenerative diseases that lead to a mislocalisation of iron can be caused by a culmination of localised overload (pro-oxidant siderosis) and localised deficiency (metabolic distress). A new therapeutic concept with conservative iron chelation rescues iron-overloaded neurons by scavenging labile iron and, by delivering this chelated metal to endogenous apo-transferrin, allows iron redistribution to avoid systemic loss of iron.
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http://dx.doi.org/10.1007/s11940-016-0426-1DOI Listing
October 2016

MR imaging features of focal liver lesions in Wilson disease.

Abdom Radiol (NY) 2016 09;41(9):1811-24

UMR INSERM 965, Hôpital Lariboisière, 2 Rue Amboise Paré, 75010, Paris, France.

Hepatic involvement in Wilson disease (WD) manifests as a diffuse chronic disease in the majority of patients. However, in a subset of patients focal liver lesions may develop, presenting with a wide range of imaging features. The majority of focal liver lesions in patients with WD are benign nodules, but there are reports that have described malignant liver tumors or dysplastic nodules in these patients. Because of the possibility of malignant transformation of liver nodules, major concerns have been raised with respect to the management and follow-up of patients with WD in whom focal liver lesions have been identified. The assessment of liver involvement in patients with WD is generally performed with ultrasonography. However, ultrasonography conveys limited specificity so that magnetic resonance (MR) imaging is often performed to improve lesion characterization. This review was performed to illustrate the spectrum of MR imaging features of focal liver lesions that develop in patients with WD. It is assumed that familiarity with the MR imaging presentation of focal liver lesions in WD may help clarify the actual nature of hepatic nodules in patients with this condition.
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http://dx.doi.org/10.1007/s00261-016-0744-5DOI Listing
September 2016

MR imaging features of liver involvement by Wilson disease in adult patients.

Radiol Med 2016 Jul 22;121(7):546-56. Epub 2016 Apr 22.

Université Paris-Diderot, Sorbonne-Paris Cité, 10 rue de Verdun, 75010, Paris, France.

Objective: To describe the magnetic resonance imaging (MRI) presentation of liver involvement in adult patients with Wilson disease (WD) and determine the most indicative appearance of this condition on MRI using a retrospective case-control study.

Materials And Methods: MRI examinations of 23 adult patients with WD (14 men, 9 women; mean age = 40.4 years) were analyzed by two blinded observers and compared to those obtained in 23 patients with chronic viral hepatitis (14 men, 9 women, mean age = 40.4 years) who were matched for age, gender and severity of chronic liver disease. Images were qualitatively and quantitatively analyzed with respect to imaging presentation. Comparisons were performed using univariate analysis.

Results: Honeycomb pattern of hepatic parenchyma was the most discriminating independent variable for the diagnosis of WD (odds ratio, 17.082; 95 % CI 2.092-139.497) (P = 0.0081) but had a sensitivity of 43 % (10/23; 95 % CI 23-66 %). Regular liver contours was the other variable that strongly correlated with the presence of liver involvement by WD (odds ratio, 11.939; 95 % CI 1.503-94.836) (P = 0.0190).

Conclusion: The honeycomb pattern is the most discriminating independent variable for the diagnosis of liver involvement by WD but has limited sensitivity. Familiarity with this finding may clarify the cause of diffuse hepatic parenchymal abnormalities in patients with unknown WD.
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http://dx.doi.org/10.1007/s11547-016-0635-4DOI Listing
July 2016
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