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Wilson's disease (WD) is usually diagnosed in children and young adults; limited data exist on late-onset forms.The aim was to characterize the clinical and paraclinical presentations, therapeutic management, and outcomes in patients with late-onset WD.Patients diagnosed with WD after age 40 years were identified from the French Wilson's Disease Registry (FWDR). Clinical, laboratory, and imaging findings and treatment were reported at diagnosis and last follow-up.Forty-five patients were identified (median age: 49, range: 40-64) and placed in three groups according to their clinical presentation: neurological (n = 20, median diagnostic delay: 20 months), hepatic (n = 13, diagnostic delay: 12 months), and family screening (n = 12), all confirmed genetically. Six neurological patients had an atypical presentation (1 torticollis, 2 writer's cramps, 2 functional movement disorders, and 1 isolated dysarthria), without T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) hyperintensities; 5 of 6 had no Kayser-Fleischer ring (KFR); 5 of 6 had liver involvement. In the neurological group, 84% of patients improved clinically, and 1 developed copper deficiency. In the hepatic group, 77% had cirrhosis; 6 patients required liver transplantation. In the screened group, 43% had mild liver involvement; 3 were not treated and remained stable; 24-h urinary copper excretion was normal in 33% of patients at diagnosis.In the FWDR, late-onset forms of WD affect 8% of patients, mostly with neurological presentations. Thirty percent of the neurological forms were atypical (isolated long-lasting symptoms, inconspicuous brain MRI, no KFR). With personalized treatment, prognosis was good. This study emphasized that WD should be suspected at any age and even in cases of atypical presentation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

This retrospective, multicenter study aims to assess the efficacy and safety in Wilson disease (WD) patients treated with trientine tetrahydrochloride (TETA 4HCl) after switch from trientine dihydrochloride (TETA 2HCl).In total, 68 WD patients with stable copper metabolism were identified to receive TETA 4HCl (Cuprior™) after previous treatment with TETA 2HCl. We analyzed biochemical markers such as urinary copper, serum copper, non-coeruloplasmin bound copper (NCC), and transaminases as well as clinical scores (APRI; FIB-4 score) at baseline with a follow-up (FU) of 12 months. Safety of TETA 4HCl treatment was based on reported adverse events (AEs).The study cohort reflects a common WD cohort with a mean age of 20.3 years at diagnosis and 38.3 years at baseline. There are no significant differences concerning serum copper, NCC, transaminases, APRI, and FIB-4 score in the 3-month FU. Six-month FU revealed a decreased AST (P = 0.008), APRI (P = 0.042), and FIB-4 score (P = 0.039). GGT varied only borderline significantly in the 3-month, but not in the 6-month FU. Comparison of urinary copper within the subsets did not reveal a difference to baseline in all FUs, suggesting stable control of copper metabolism. Few AEs during TETA 4HCl treatment were reported, most commonly gastrointestinal discomfort. Only three treatments with TETA 4HCl were discontinued.Copper parameters and liver function were stable after treatment switch to TETA 4HCl. Treatment with TETA 4HCl was generally well tolerated. This study indicates that the switch from TETA 2HCl to TETA 4HCl is safe and viable.

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.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.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, p0.05). 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.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.

Resume De transmission autosomique recessive, la maladie de Wilson est une affection genetique a l’origine d’une surcharge en cuivre progressive. Le gene ATP7B porte sur le chromosome 13 code une proteine ATP7B intracellulaire transporteuse du cuivre qui permet l’excretion cellulaire du cuivre excedentaire. Dans la maladie de Wilson, le deficit fonctionnel en ATP7B entraine un defaut d’elimination du cuivre dans la bile qui s’accumule alors dans le foie puis est libere sous forme libre dans la circulation sanguine. La maladie de Wilson est ainsi une affection initialement hepatique qui peut evoluer vers une atteinte multi-systemique avec une accumulation de cuivre dans le cerveau, l’œil, le rein, etc. si elle n’est pas diagnostiquee precocement. Les premiers symptomes sont le plus souvent hepatiques chez l’enfant et neurologiques chez l’adulte. Le diagnostic est porte sur un faisceau d’arguments cliniques, biologiques et radiologiques. L’interpretation du bilan cuprique associant typiquement une diminution de la ceruloplasminemie et de la cupremie totale avec une augmentation de la cuprurie des 24 heures, peut etre difficile, justifiant de doser le cuivre libre ou echangeable. Le rapport cuivre echangeable/cuivre total ou REC(relative exchangeable copper) est un excellent biomarqueur diagnostique. La biologie moleculaire permet de confirmer le diagnostic dans 98 % des cas. Les traitements associent regime pauvre en cuivre, chelateurs du cuivre ou sels de zinc. La transplantation hepatique est le traitement des formes hepatiques fulminantes et des cirrhoses decompensees. Cette maladie genetique rare a un bon pronostic si le traitement est initie precocement et poursuivi a vie. Il est donc important de connaitre les manifestations cliniques de la maladie et les tests diagnostiques pour l’evoquer rapidement afin d’assurer ensuite un suivi regulier clinique et biologique des patients.

Background: Wilson’s disease (WD) is one of the few genetic disorders that can be successfully treated with pharmacological agents. Copper-chelating agents (D-penicillamine and Trientine salts) and zinc salts have been demonstrated to be effective. There are two salts of trientine. Trientine dihydrochloride salt (TETA 2HCL) is unstable at room temperature and requires storage at 2–8 °C. Trientine tetrahydrochloride (TETA 4HCL) is a more stable salt of trientine that can be stored at room temperature. No comparative study between both of the salts of trientine has been performed to date. As the two chemical forms were available in France between 1970 and 2009, we conducted a study to evaluate their efficacy and safety profiles. Methods: This retrospective cohort study was conducted by reviewing data from the national WD registry in France. Forty-three WD patients who received TETA 2HCL or TETA 4HCL monotherapy for at least one year until 2010 were included. The primary endpoints were hepatic and neurological outcomes. Secondary endpoints were the events leading to a discontinuation of medication. Results: Changes in medication were common, leading to the analysis of 57 treatment sequences of TETA 4HCL or TETA 2HCL. The mean duration of treatment sequence was significantly longer in the TETA 4 HCL group (12.6 years) than in the TETA 2HCL group (7.6 years) (p = 0.011). Ten patients experienced both trientine salts: eight stopped TETA 4 HCL (six had a hepatologic phenotype and two had a neurological phenotype) because this treatment was not available anymore (mean duration 7.4 years). Three of these patients already experienced TETA 2 HCL before the sequence. Two patients with a hepatologic phenotype (one had a previous sequence of TETA 4 HCL before) stopped TETA 2 HCL because of cold storage issues (mean duration 42.8 years). The total number of sequences was 57. All of the patients were clinically stable. No difference in efficacy was detected. Both treatments were well tolerated, except for a case of recurrence of lupus erythematosus-like syndrome in the TETA 2HCL group. The major reason for interruption of TETA 4HCL was due to a discontinuation in production of this salt. The reasons for stopping TETA 2HCL were mainly due to adherence issues largely attributed to the cold storage requirement. Conclusions: The two salts of trientine were effective in treating patients with WD. However, interruption of TETA 2HCL was frequent, linked to the cold storage requirement. As adherence to treatment is a key factor in the successful management of WD, physicians need to be even more vigilant in detecting adherence difficulties in patients receiving treatment with TETA 2HCL.

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

ObjectiveTo evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.MethodsFrench 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.ResultsEighteen 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 (p< 0.0001 andp= 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 (p= 0.0007). Severe sepsis (p= 0.011) and intensive care unit admission (p= 0.001) before LT were significantly associated with death.ConclusionsLT 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 evidenceThis study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.

International audience; Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease and alpha-1 antitrypsin deficiency must be investigated in any patient with unexplained liver disease. Cystic fibrosis screening of new-borns is now implemented in most high-prevalence countries. The diagnosis of these diseases can be strongly suggested with specific non-invasive tests. Molecular analysis gene for these diseases is long and tedious but is recommended to confirm the diagnosis and help for the family screening. Liver biopsy is not systematic and is discussed when it helps diagnosis. Currently, for these three diseases, non-invasive fibrosis markers could identify patients with risk of cirrhosis and complications. 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.

Theme : L’observance des traitements medicamenteux dans le cadre des pathologies chroniques constitue un veritable probleme de sante publique. La maladie de Wilson est une maladie genetique rare qui, fait exceptionnel pour ce type de maladies, dispose de traitements efficaces. Malgre son caractere letal en l’absence de ces traitements, de nombreux patients disent oublier regulierement de prendre leurs comprimes. Nous nous demanderons quelle est la nature de ces oublis et s’il s’agit d’un simple defaut de memoire.Methode : Dans le cadre d’entretiens semi-structures aupres de dix patients non symptomatiques suivis au Centre de Reference de la Maladie de Wilson (Hopital Lariboisiere), nous tenterons d’elucider les processus qui sous-tendent ces comportements.Enfin, nous aborderons les questions ethiques que pose cette problematique et certaines reponses evoquees par les pouvoirs publics.Resultats : La croyance inconsciente en notre immortalite, la difficile liaison somato-psychique et la dimension traumatique de l’avenement de la maladie apparaissent comme de possibles entraves a une bonne observance.

Wilson's disease (WD), a rare genetic disorder responsible for copper accumulation in the body, is fatal if left untreated. Although there are effective treatments, adherence to treatment tends to be low. We evaluated the medication adherence of 139 patients using the Morisky scale. Adherence was correlated with age at diagnosis and at inclusion in the study, the form of the disease, the treatment, the duration of treatment, delivery and storage problems, depression, anxiety, the level of education, and the biological data. 32.4% of the patients had low adherence; their levels of exchangeable copper were significantly higher than those of the patients with high or medium adherence (P = .049). The average age of the patients at the time of the study was significantly higher in those with high adherence than in those with medium or low adherence (P = .043). 75.9% of the patients with high adherence had a neurological form and 26.7% of the patients with low adherence were asymptomatic (P = .0090). The duration of treatment was significantly longer in the patients with high adherence than in those with medium or low adherence (P = .0192). The type of treatment (chelators or zinc) had no impact on the level of adherence. Forty-four percent of the patients experienced problems dispensing and storing medications. Despite the availability of effective treatments for this rare disease, adherence problems occur with Wilson's disease in particular in asymptomatic patients. Although different factors are involved, sustained multidisciplinary management on a case-by-case basis is necessary.

Goal We studied time trends of admission in neurological rehabilitation units (NRU) among patients hospitalised for stroke from 2010 to 2014 and compared prognostic factors of functional gain, home return and inpatient survival. Methods Patients hospitalized for Stroke from 2010 to 2014 were selected from the French national hospital databases. Admission in rehabilitation was searched till 3 months. Predictive factors of functional gain, home return, in-patient survival, and the corresponding trends were studied using logistic regression. Results In 2014, global rehabilitation rate was 36.3% with 15.8 discharged in a NRU. The rate of patients managed in NRU rose between 2010 and 2014. An increase in the proportion of home return (+4%) and inpatient survival rate (+7%) were observed between 2010 and 2014. Almost 40% of patients with severe functional deficits benefited of a partial or complete recovery after their rehabilitation stay. NRU admission was associated with higher probability of functional gain (OR [odds ratio] =1.76 [confidence interval {CI} 95% 1.67-1.85]), home return (OR = 1.38 [CI 95% 1.29-1.47]) and inpatient survival (OR = 3.15 [CI 95% 2.83-3.52]). Conclusions A greater proportion of patients were admitted in NRU along with an increase of home return and in-patient survival, but too many patients remained excluded.

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

We aimed to review the sleep disorders described in Wilson’s disease (WD), focusing on their mechanisms and treatments. 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.

Background acquired copper deficiency (ACD) is a rare condition usually diagnosed from haematological changes. Aims characterize the diagnosis features and the evolution of patients with ACD revealed by neurological symptoms. Methods clinical, biological and 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. Sub-acute ascending paresthesias and gait disorder were the first symptoms. All patients had a posterior cord syndrome (PCS) with sensory ataxic gait associated with feet superficial hypoesthesia, 50% had also lateral cord signs. Electrodiagnostic tests diagnosed a lower limbs sensory neuropathy in four patients. Spinal cord MRI was normal in 3/7 patients. Anaemia and lymphopenia were found in 6/7 patients. Serum copper was always low and urinary copper was low or normal. Serum and urinary zinc were high in 4 patients. A decrease 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 in four patients. One had the two causes. After copper supplementation, copper balance then haematological disturbances were the first features to normalize gradually in two months. The radiological myelitis disappeared in ten months whereas neurological symptoms improved in 6/7 patients after a mean follow-up of 2 years. Conclusions progressive PCS with anaemia and lymphopenia must raise the possibility of an ACD. An early copper supplementation could increase the neurological prognosis.

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.

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.

In Wilson disease, a regular clinical, biological, and radiological follow-up is essential to ensure good efficiency and tolerance of treatment and observance. Ongoing monitoring should continue throughout life. It must be enhanced in the adolescents, when the follow-up is transferring in adult care and during pregnancy. The monitoring is quite different according to the phase of the disease. Indeed, the major difficulties are the risk of paradoxical worsening of neurological symptoms during the initial phase and the adherence to the treatment during the maintenance phase. The follow-up must also be adapted to the severity of the hepatic and neurological features. So, the regular evaluation is often carried out by a multidisciplinary team of specialists: pediatrician, hepatologist, neurologist, psychiatrist, dermatologist, physiotherapist, speech therapist, psychologist, dietician, and social worker. Biologists have also to be associated to these follow-up: blood cell count, liver function and coagulation tests, proteinuria, blood and urinary copper monitoring, etc. are essential to confirm the efficiency and the observance of treatment and to detect complications of treatment or overtreatment. Red flags concerning weak treatment compliance or copper deficiency need to be known.

Copper toxicity is strongly linked to its free fraction also called non-ceruloplasmin-bound copper. The assay of exchangeable copper (CuEXC), a new method of direct determination of so-called free copper, is reliable, rapid, and easy to set up. The relative CuEXC (REC) (ratio CuEXC/total serum copper) was studied in three different populations [Wilson disease (WD), ATP7B simple heterozygotes and normal subjects] and compared to the usual copper tests. A REC value >18.5% appears as an excellent biomarker for the diagnosis of WD offering 100% sensitivity and specificity, regardless of sex, age, or the degree of underlying liver failure. Moreover, another study reported that REC was always

Introduction Les chelateurs du cuivre (D-penicillamine et trientine) sont efficaces dans la maladie de Wilson (MW). Il existe 2 sels de trientine : dihydrochlorhyde (TETA2HCL) conserve au froid, et tetrahydrochlorhyde (TETA4HCL) conservable a temperature ambiante. Objectifs Evaluer la tolerance (avec la survenue d’evenement indesirable ayant conduit a l’arret du traitement) et l’efficacite (avec la survenue d’evenement hepatique ou neurologique) de ces deux traitements. Patients et methodes Etude retrospective menee a partir des donnees du registre national Wilson en France. Les deux sels de trientine ont ete disponibles en France entre 1970 et 2009. Quarante-trois patients wilsoniens traites par TETA 4HCL ou TETA 2HCL en monotherapie pendant au moins un an ont ete inclus. Resultats La duree moyenne de traitement etait significativement plus longue dans le groupe TETA 4HCL (12,6 ans) que dans le groupe TETA 2HCL (7,6 ans) (p = 0,011). Il n’y a pas eu de difference d’efficacite ni de tolerance, a l’exception d’un cas de lupus induit recurrent dans le groupe TETA 2HCL. La majorite des arrets de traitements par TETA 4HCL etait du a l’arret de production de ce sel, tandis que l’arret du TETA 2HCL etait en majorite du a des problemes de compliance. Discussion Les 2 sels de trientine sont efficaces dans le traitement de la MW avec une bonne tolerance et peu d’evenements indesirables. Toutefois l’arret du TETA 2HCL etait frequent, lie a la necessaire conservation au froid, tandis que la majorite (85 %) des arrets du traitement par TETA 4HCL etait du a l’arret de production du traitement. La recente autorisation de mise sur le marche europeenne du TETA 4HCL encourage l’utilisation de ce traitement dans la MW. Conclusion L’efficacite des deux sels de trientine dans la MW est equivalente, toutefois la compliance est moins bonne chez les patients recevant du TETA 2HCL conservable au froid, necessitant une vigilance accrue des prescripteurs lors du suivi.

Introduction Dans la maladie de Wilson neurologique (MW), l’IRM cerebrale est habituellement anormale : atrophie globale et lesions symetriques des ganglions de la base, des noyaux denteles et du mesencephale. Objectifs Presenter certains aspects radiologiques IRM inhabituels de la MW, moins connus car rares. Patients et methodes Les IRM cerebrales atypiques de patients suivis au centre de reference de la maladie de Wilson (site coordonnateur de Paris) ont ete selectionnees parmi les 380 patients suivis annuellement. Resultats En T2/FLAIR, ont ete observes des hypersignaux (HS) isoles du mesencephale, des HS du bulbe, des HS asymetriques des noyaux denteles (aspect pseudo-tumoral), de la substance blanche dans les hemispheres cerebraux et en sous-cortical, de meme que des lesions corticales et du corps calleux. En T2*, les ganglions de la base pouvaient etre hypo-intenses. Une diminution du signal DWI dans le putamen a ete detectee chez certains patients hepatiques. En T1, un hypersignal pallidal etait possible. Discussion Les anomalies cerebrales T2/FLAIR dans la MW peuvent concerner aussi bien la substance grise que la substance blanche avec des atteintes diffuses ou localisees et parfois asymetriques. Les anomalies en T2* refletent l’existence de depots de fer en plus de la surcharge en cuivre. Sur les sequences T1, un hypersignal bi-pallidal peut se retrouver chez les patients presentant un shunt portosystemique en raison d’une surcharge en manganese. Conclusion La connaissance de ces images inhabituelles de la MW par les neurologues facilitera le diagnostic de cette maladie rare dont le delai diagnostique reste encore long dans les formes neurologiques.

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

Wilson’s disease (WD) is an autosomal recessive disorder characterized by copper accumulation in many organs. WD is caused by mutations in the ATP7B gene located on chromosome 13. Copper cellular metabolism is regulated by two copper-transporting ATPases (ATP7A and ATP7B). In WD, defective ATP7B function impaired both copper incorporation to ceruloplasmin and copper release into the bile, resulting in copper accumulation in the liver. In the absence of diagnosis and treatment at this stage, WD evolves towards a systemic disease, with copper accumulation in other organs including the brain, eyes, kidneys, etc. First symptoms are usually hepatic in children and neurological in adults. WD is characterized by low serum ceruloplasmin and total copper concentrations and increased urinary copper excretion. A new tool, the relative exchangeable copper is very useful for diagnosis and family screening. Differential diagnosis of copper abnormalities are reviewed. Molecular biology confirms the diagnosis in 95% of cases. Treatment is based on diet, copper chelators or zinc salts. Liver transplantation is the treatment of acute fulminant liver failure and of decompensated cirrhosis. It remains controversial in severe neurological forms. WD has a good prognosis if treatment is initiated early and continued all the lifetime. So, follow up of these patients is very important to make sure of the observance, the efficiency and the tolerance of the treatment and to search for hepatocellular carcinoma that is a late complication of the liver disease.

International audience; 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.

A 19-year-old man presented with a 1.5-month history of hypokinetic dysarthria, slight hypokinesia, and micrographia. Brain MRI showed fluid-attenuated inversion recovery (FLAIR) (figure 1) and T2 (figure 2) hyperintensities in the medulla oblongata and the mesencephalon. Copper tests reported high 24-hour urinary copper excretion, low serum copper, low ceruloplasmin, and high exchangeable copper. Kayser-Fleischer rings were present. ATP7B genetic analysis confirmed the diagnosis of Wilson disease (WD) with the presence of 2 mutations.

Introduction La maladie de Wilson se manifeste par divers symptomes hepatiques ou extrahepatiques avec un âge moyen de diagnostic de 18,5 ± 11 ans d’apres le registre Wilson France. Peu de donnees existent sur les formes a debut tardif. Objectifs Caracteriser sur le plan clinique et paraclinique les formes de maladie de Wilson diagnostiquees apres 40 ans pour faciliter leur diagnostic et la prise en charge therapeutique. Patients et methodes A partir du registre, 44 dossiers de patients diagnostiques apres 40 ans entre 1974 et 2016 ont ete extraits. Ils correspondaient a 8 % des 552 patients du registre en 2016. Parmi ces 44 patients, 33 (16F, âge moyen 48 ± 6,5 ans, 7 screening S, 7 revelations hepatiques H et 19 extrahepatiques EH) avaient un dossier complet et l’analyse des aspects demographiques, cliniques, biologiques, ophtalmologiques, genetiques, radiologiques et therapeutiques au diagnostic et lors du dernier suivi a pu etre realisee. Resultats Groupe S : REC > 15 % chez 4/5. Atteinte hepatique chez 3/7. Absence d’atteinte extrahepatique. Au total, 3 n’ont pas ete traites. Tous sont restes asymptomatiques. Groupe H : Delai diagnostique : 6 ans. 6/7 avaient une cirrhose et 5/7 un AKF. IRMc anormale chez 3/6. Au total, 3 ont ete greffes. Stabilite lors du suivi. Groupe EH : Delai diagnostique : 4 ans. Au total, 6 avec IRM normale et presentation atypique : torticolis (1), crampe de l’ecrivain (2), tremblement psychogene (2), AKF (1). 16/19 se sont ameliores, 1 a developpe une carence en cuivre. Discussion Cette etude retrospective a partir du registre Wilson France montre que 8 % des patients Wilsoniens ont un diagnostic tardif apres 40 ans. Le REC a toute sa valeur dans le depistage. L’existence de presentations neurologiques atypiques telles que dystonie focale ou troubles psychogenes avec IRM normale incitent a rechercher le diagnostic plus largement. Le risque de carence en cuivre iatrogene existe chez les patients pauci-symptomatiques. Conclusion L’âge ne doit plus etre un facteur limitant la recherche de maladie de Wilson ce d’autant que la presentation clinique reste tres heterogene, que le diagnostic est facilite par le REC et que la maladie est traitable.

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.

Hypersialorrhea, corresponding to excessive salivation is a symptom frequently reported in Wilson's disease, especially in its neurological form. The prevalence of this frequent complaint has not been often evaluated. During a 7-month period, 87 consecutive Wilson's disease patients answered to the simple question "do you have the sensation of excess saliva in your mouth?" to evaluate the frequency of this symptom. A sub-sample of 10 consecutive Wilson's disease patients with drooling was recruited to undergo quantitative and qualitative measures to evaluate the mechanism of hypersialorrhea. Excessive drooling or excess saliva was found in 46 % of patients followed at the French Reference Centre. Ninety-eight percent of them presented neurological symptoms and drooling was found in only one patient without neurological symptoms. Our study showed that patients with a complaint of excessive saliva produced significantly higher quantities of saliva at rest than controls. Endoscopic examination was abnormal in six patients. A significant decrease of swallowing frequency, longer swallow latencies, and poor swallowing capacities may partly explain the salivary stasis. Oropharyngeal sensitivity disorders were present in 50 % of our patients. The decrease of the swallowing frequency observed in all patients could be related to cognitive and behavioral abnormalities with initiation difficulties objectified by longer latencies triggered by all the ingested volumes. This study confirmed the hypothesis of a multifactorial origin of hypersialorrhea in patients who have been diagnosed in Wilson's disease. It was essential to evaluate drooling with a multidisciplinary consultation to better identify the underlying mechanisms and to implement strategies for speech therapy and therapeutic adaptation.

Acquired copper deficiency (ACD) is a rare condition usually diagnosed from haematological changes.To characterise the diagnosis features and the evolution of patients with ACD revealed by neurological symptoms.Clinical, biological and magnetic resonance imaging (MRI) data were prospectively analysed at diagnosis and during follow up under copper supplementation.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.Progressive PCS with anaemia and lymphopenia must raise the possibility of an ACD. Early copper supplementation could increase the neurological prognosis.

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.

Summary 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.

Background and Purpose— Stroke is the leading cause of death in women and the third leading cause in men in France. In young adults (ie, Methods— Hospitalization data were extracted from the French national hospital discharge databases and mortality data from the French national medical causes of death database. Time trends were tested using a Poisson regression model. Results— From 2008 to 2014, the age-standardized rates of patients hospitalized for ischemic stroke increased by 14.3% in patients Conclusions— An increase in cardiovascular risk factors and improved stroke management may explain the increase in the rates of patients hospitalized for ischemic stroke. The decrease observed for in-hospital stroke mortality may be because of recent improvements in acute-phase management.

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.

International audience; BACKGROUND & AIMS: Liver transplantation (LT) is the therapeutic option for severe complications of Wilson's disease (WD). We aimed to report on the long-term outcome of WD patients following LT. METHODS: The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5). RESULTS: Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III. CONCLUSIONS: Liver failure associated with WD is a rare indication for LT (\textless1%), which achieves an excellent long-term outcome, including renal function.

Introduction La maladie de Wilson (MW) entraine une surcharge en cuivre hepatique puis multisystemique si elle n’est pas traitee a vie. Une carence en cuivre (CaCu) par depletion therapeutique est possible. Objectifs Determiner la frequence des carences en cuivre chez les patients traites pour une MW, leurs caracteristiques cliniques et biologiques au diagnostic et leur evolution apres adaptation du traitement. Methodes Recherche parmi les 338 patients de la cohorte MW de Lariboisiere, des patients ayant presente une CaCu. Description du phenotype clinique de MW, de la dose et de la duree du traitement chelateur ou zinc ainsi que des caracteristiques cliniques, biologiques et radiologiques ayant conduit au diagnostic de CaCu. Analyse de leur evolution clinique, radiologique et biologique apres adaptation du traitement. Resultats Trois patients presentaient une CaCu 17 ± 14 ans apres l’initiation du traitement. Un avait une cirrhose et deux une atteinte neurologique. Deux etaient sous zinc et un sous chelateur et zinc. Au diagnostic, 2 patients avaient une pancytopenie et deux une ataxie proprioceptive avec paresthesies et neuropathie axonale. IRM cervicale normale. Cupremie et cuprurie etaient effondrees, zincemie et zincurie elevees. Tous avaient une carence en fer. Trois ans apres la diminution du traitement, l’ataxie proprioceptive s’ameliore. Discussion L’apparition d’une pancytopenie et/ou d’un syndrome cordonal posterieur progressif chez un patient wilsonien traite au long cours par zinc doit faire evoquer une carence en cuivre ce d’autant qu’il existe une carence en fer associee. Le dosage serique et urinaire du cuivre et du zinc confirme le diagnostic. Apres diminution drastique du traitement, l’evolution est favorable mais extremement lente. Conclusion Les patients atteints de MW necessitent une surveillance reguliere et au long cours afin de depister une exceptionnelle carence en cuivre iatrogene. Informations complementaires L’etude n’a beneficie d’aucun financement specifique.

Introduction La neuro-ferritinopathie est une maladie genetique entrainant une surcharge en fer cerebrale primaire (NBIA) touchant preferentiellement les ganglions de la base. Elle est marquee par une atteinte motrice et cognitive. Observation Le diagnostic de neuro-ferritinopathie a ete pose chez MS a 42 ans. Les symptomes avaient debutes 17 ans auparavant par une dystonie focale du pied qui s’est progressivement generalisee. Le diagnostic a ete porte sur l’aspect de surcharge en fer a l’IRM cerebral et confirme par la biologie moleculaire du gene FTL. Un traitement chelateur du fer a ete debute, couple a un suivi clinique et paraclinique regulier. Cette observation decrit l’evolution cognitive sur 6 annees du patient. Au diagnostic, une atteinte circonscrite a la vitesse de traitement graphomoteur et des troubles attentionnels etaient observes. La memoire episodique anterograde verbale et visuelle, les raisonnements perceptifs et verbaux ainsi que les fonctions instrumentales etaient intactes. Sur le plan moteur, une choreo-dytonie a predominance distale etait associee a une dysarthrie. Au fur et a mesure de l’evolution sont apparues une atteinte de la memoire de travail, puis une majoration du ralentissement de la vitesse de traitement ainsi qu’une atteinte de l’efficience cognitive globale. Parallelement, des symptomes anxio-depressifs ainsi qu’une impulsivite comportementale ont ete notes et les mouvements choreo-dystoniques se sont discretement aggraves. Discussion L’evolution clinique de MS a ete dominee par l’aggravation des mouvements choreo-dystoniques et de la dysarthrie ainsi que des troubles cognitifs et comportementaux dont le profil apparait comme cortico sous cortical (ralentissement psychomoteur et troubles des fonctions executives principalement). Conclusion L’etude de l’histoire naturelle de cette maladie rarissime confirme la deterioration cognitive lente dans cette pathologie touchant les ganglions de la base ainsi que la presence de troubles neuropsychiatriques concomitants. Informations complementaires Pas de financement.