Compliance with medications in Wilson’s disease Wilobs
Survey carried out with support from the French Agency for the Safety of Medicine and Healthcare Products (ANSM) and the Bernard Pépin Association for Patients with Wilson’s disease.
As in many chronic diseases, the use of long-term medication can be difficult at certain times. This subject is extremely important because interrupting treatment can cause a fulminant episode of Wilson’s disease that is not always reversible. Through this study, we therefore wish to better understand the problems encountered by patients with taking their treatments, and also why some patients do not experience any problems. This will enable us to improve the management of patients experiencing problems with their treatment.
Patients attending a reference centre are questioned about taking their medications, after signing an informed consent form.
Deep brain stimulation in severe, chronic dystonic forms of Wilson’s disease
Hospital Clinical Research Programme (PHRC) coordinated by S. Thobois (Lyon)
Wilson’s disease is a rare condition that notably causes hepatic and neurological symptoms. The neurological signs include abnormal movements and tremor, and may sometimes persist despite drug therapies. Deep brain stimulation is a treatment that has demonstrated its efficacy in certain types of dystonia (particularly in diseases that involve abnormal positions). However, this treatment has never been tested in Wilson’s disease. The aim of our project is therefore to study the efficacy of deep brain stimulation of the subthalamic nucleus and internal globus pallidus, in Wilson’s disease patients with disabling neurological signs despite appropriate drug therapies. This collaborative study by University Hospitals in Lyon and Paris will involve five patients and start in 2016.
The WILSTIM study, or the evaluation of improvements to writing skills in Wilson’s disease patients with dystonia following a session of inhibitory repetitive transcranial magnetic stimulation (rTMS) of the somatosensory cortex
(Approved by the Ethics Committee on 15 January 2014)
Despite the treatments available for Wilson’s disease, problems with writing skills may persist. To improve dystonia (muscle contractions) of the right hand which hamper writing, we are proposing a new treatment designed to inhibit this dystonia using a magnetic field delivered to the cranium for around twenty minutes. We hope that this procedure will cause a reduction in focal hand dystonia and thus improve writing more effectively than current drug therapies.
Skin abnormalities and Wilson’s disease
Some patients with Wilson’s disease suffer from skin lesions. A dermatology clinic was thus set up by the CNR Wilson at Hôpital Lariboisière for two years (ending April 2014) and its services were offered systematically to patients in order to collate the skin symptoms associated with Wilson’s disease to determine any links with treatment regimens.
Wilson’s disease in children in 2015
To improve knowledge of this rare disease, the CNR Wilson has been operating a national register since 2005 that contains data on all Wilson’s disease patients followed in France. The aim of this work is to better understand the epidemiology of the disease, the clinical and biological presentations suggestive of its diagnosis in children, the standard treatments proposed and its course.
Estimating fibrosis with a Fibroscan® in Wilson’s disease patients
- Wilson’s disease: a fibrogenic disease
Wilson’s disease can cause symptoms that will affect several organs. There are usually neurological signs (abnormal movements and stiffness), psychological disorders and liver damage. The liver symptoms may be isolated and of varying intensity, ranging from an asymptomatic abnormality to decompensated cirrhosis or fulminant hepatitis. A toxic accumulation of copper causes chronic liver lesions and an increase in fibrosis that may lead to cirrhosis, which has a common form of clinical presentation in both children and young adults. Until recently, histological examination of a specimen obtained by liver biopsy was considered to be the reference investigation to evaluate and quantify fibrosis. Other exploratory techniques are currently under study, and notably a wholly non-invasive determination using an apparatus called a Fibroscan.
- The aims of the study
To estimate liver fibrosis in Wilson’s disease patients in a prospective and non-invasive manner from Fibroscan measurements, and to correlate the findings of this non-invasive estimation with those obtained using liver biopsy, considered as the benchmark method.
Screening for hereditary metabolic disease with psychiatric symptoms (MOPSY).
Importance of serum ceruloplasmin (Cp) and copper (Cu) levels to the screening of Wilson’s disease in patients presenting with psychiatric disorders
The aims of the study are to:
- clarify the efficacy of determining serum Cp and Cu levels as part of the biological screening of Wilson’s disease in patients hospitalised in a psychiatric ward
- identify ATP7B gene mutations in patients presenting with abnormal serum copper levels
Efficacy of molecular analysis of the ATP7B gene in diagnosing Wilson’s disease
Various studies have reported cases of Wilson’s disease that were confirmed clinically and biochemically but in whom the two mutations could not be identified. The aim is to assess the efficacy of molecular genetics when diagnosing the disease in patients recruited in France.
Reference values for exchangeable copper and the REC in children and adult control subjects
The diagnosis of Wilson’s disease remains difficult because it is based on a body of clinical, biological and radiological evidence. Serum levels of exchangeable copper (CuE) and calculation of the REC (ratio of exchangeable copper/total copper) have recently been described as promising markers for the diagnosis and monitoring under treatment of Wilson’s disease patients [1-2]. But no reference values for these parameters are currently available, particularly in children. During this study, the reference values for these two variables were evaluated in different age groups; i.e. in both children and adults.
The neuropsychological profile of children with Wilson’s disease
The neurological form of Wilson’s disease is characterised by abnormal movements and brain lesions, mainly in the subcortical region. In adults with neurological Wilson’s disease, the cognitive profile is dominated by executive dysfunctions, a slowing of information processing and poor learning skills. Our principal aim is to describe the cognitive profile seen in paediatric forms of Wilson’s disease using a global reference scale.
The assay of exchangeable copper in ATP7B « knock-out » mice
Exchangeable copper and the REC were studied in an animal model – ATP7B knock-out mice (deprived of the ATP7B gene) – in order to demonstrate their usefulness to diagnosis and treatment monitoring in Wilson’s disease in humans. The mice were sacrificed and their hepatic and cerebral copper levels were assayed. A histological examination of the liver was also performed. A correlation was found between histological features and the results of copper assays.
Neurological manifestations of chronic liver disease in children: a clinical and paraclinical description (the NHCE study)
Hepatic encephalopathy is a well-known complication of chronic liver disease. Long before it becomes severe, the patient displays minimal symptoms that are difficult to assess using a routine neurological examination. The main objective is to describe the profile of neurological manifestations occurring in the context of chronic liver disease in children (6-16 years old), not including severe stages of hepatic encephalopathy.
The ratio of 65Cu/63Cu copper isotopes determined in whole blood from control subjects and patients with Wilson’s disease (at the time of diagnosis and under treatment) has been found to differ. These initial results will be verified in a larger cohort of control subjects (children and adults) and a Wilson’s disease cohort (children and adults). These findings will be compared with the results of copper assessments (serum copper and exchangeable copper).
The usefulness of assaying exchangeable copper to the diagnosis of Wilson’s disease and the follow-up of patients
Since 2009, a new copper assay has been used at Hôpital Lariboisière and in Lyon. This assay of exchangeable copper is able to determine « toxic » levels of copper in the blood. It has thus been demonstrated that by calculating the ratio of exchangeable copper/total copper (REC) we have a new parameter that enables a rapid diagnosis of Wilson’s disease, while awaiting confirmation of the genetic study that can take several weeks.
We are now conducting a second study to determine whether the assay of exchangeable copper is a useful parameter when monitoring patients with Wilson’s disease.
The first French epidemiological study of Wilson’s disease
In the literature, the prevalence of Wilson’s disease is estimated at between 12 and 30 per million people.
Based on data from the French general health insurance scheme, or 77% of the country’s population of 64 million people, we sought to obtain an estimate of the number of cases of Wilson’s disease in France and hence the prevalence of this disease. We also collected data on the age, gender, regional origins and treatments of these patients. These data are now being compared with those in the French register on Wilson’s disease. This work is important to better understanding the management of this disease in France.
Liver transplantation in Wilson’s disease:
its role in the context of neurological indications
Liver transplantation (LT) is generally necessary in Wilson’s disease patients when their liver deteriorates abruptly (fulminant hepatitis) or when it no longer functions correctly and becomes rapidly exhausted (decompensated cirrhosis). LT is then highly effective and has an excellent long-term prognosis, but it requires the use of anti-rejection medications for life. Another situation may also necessitate LT: neurological forms of Wilson’s disease which continue to worsen despite chelation therapy or if the patient does not comply with treatment. We are currently performing an objective assessment of the efficacy of LT in these neurological indications among 17 Wilson’s disease patients with neurological symptoms who have been grafted since 1994. Analysis of these data will notably allow us to determine the best timing for LT and to further refine the inclusion and exclusion criteria for this major intervention.
Retrospective study comparing two trientine salts in the treatment of Wilson’s disease
A few years ago, two trientine salts were available to treat Wilson’s disease, but trientine dihydrochloride is currently the only salt on the market; however, it needs to be stored at between 2°C and 8°C. The manufacture of trientine tetrahydrochloride, which does not require cold storage, was halted in 2008.
The aim of this study is to compare the efficacy and safety of these two forms of trientine: to achieve this, we have reviewed the files of all patients who were followed at Hôpital Lariboisière before 2007 and treated for at least one year with one of the two salts.