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

Wilson’s disease is an autosomal–recessive disorder of copper metabolism caused by mutations in ATP7B 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

Liver transplantation for late-onset acute liver failure in Wilson’s disease: the UK experience over two decades

BACKGROUNDS AND AIMS: Acute liver failure as the initial presentation of Wilson’s disease is usually associated with onset in childhood, adolescence or early adulthood. Outcomes after transplantation for late-onset presentations, at or after 40 years, are seldom reported in the literature METHODS: We report a case, review the literature and provide unpublished data from the UK Transplant Registry on late-onset acute liver failure in Wilson’s disease. RESULTS: We describe a 62-year-old man presenting with acute liver failure who was successfully treated with urgent liver transplantation. We identified seven cases presenting at age 40 years or over in the literature where individual outcomes were reported; three were treated with transplantation and two survived. We identified a further eight cases listed for transplantation in the UK between 1995 and 2014; seven were treated with transplantation and six survived. One patient was de-listed for unknown reasons. CONCLUSIONS: We discuss the need to consider Wilson’s disease in older adults presenting with acute liver failure and importance of making the diagnosis prior to transplantation. We suggest that urgent liver transplantation has good outcomes for late-onset presentations and recommend that urgent transplantation should always be considered in Wilson’s disease presenting with acute liver failure

From evidence-base to practice: implementation of the Nurse Family Partnership programme in England

The aims of this article are to highlight the issues that are relevant to the implementation of a rigorously evidence-based programme of support, the Nurse Family Partnership programme, into a national system of care. Methods used are semi-structured interviews with families in receipt of the programme in the first 10 sites, with the nursing staff, with members of the central team guiding the initiative and with other professionals. Analyses of data collected during programme delivery evaluate fidelity of delivery. The results indicate that the programme is perceived in a positive light and take-up is high, with delivery close to the stated US objectives. Issues pertaining to sustainability are highlighted - in particular, local concerns about cost set against long-term rather than immediate gains. However, local investment is predominantly strong, with creative methods being planned for the future. Overall, the study shows that within an NHS system of care it is possible to deliver a targeted evidence-based programme

Constipation preceding Parkinson's disease: a systematic review and meta-analysis

AJN is funded by Parkinson’s UK (grant reference F-1201). AJL has received honoraria from Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan and Orion. AS has received grant money from GE Healthcare and honoraria from UCB. AJN has received grants from Élan/Prothena Pharmaceuticals and from GE Healthcare

Neuroimaging correlates of brain injury in Wilson's disease: a multimodal, whole-brain MRI study

Wilson's disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focussed on specific sequences or regions of interest, often stratifying chronically-treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively-recruited patients with Wilson's disease (age range 16-68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding six months as having 'active' disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically-treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically-treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically-treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound ('free') copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically-treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson's disease

Training in neurology: lessons learnt.

There is no consensus on how to structure and deliver neurology training. The General Medical Council's annual National Training Survey indicates that the quality of UK neurology training is very variable, but does not explain this variation. We used the survey data to identify the four highest and lowest performing sites for neurology training across the UK. We conducted semistructured interviews with groups of local trainees and, separately, local trainers in an exploratory qualitative study, and identified common themes across a range of aspects of neurology training. Here we present our findings, share case studies from top-performing sites and make recommendations on how best to train a neurologist

Neuroimaging correlates of brain injury in Wilson's disease: a multimodal, whole-brain MRI study

Supplementary material: Supplementary material is available at Brain online at https://academic.oup.com/brain/article/145/1/263/6325019#supplementary-data .Copyright © The Author(s) (2021). Wilson’s disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to ‘de-copper’ patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focused on specific sequences or regions of interest, often stratifying chronically treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively recruited patients with Wilson’s disease (age range 16–68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding 6 months as having ‘active’ disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound (‘free’) copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson’s disease.The study was funded by a fellowship awarded to S.S. by the Guarantors of Brain and Association of British Neurologists. The Reta Lila Weston Institute and Wilson’s Disease Support Group UK provided additional financial support for MRI and participant-related costs, respectively. M.B. is supported by a Fellowship award from the Alzheimer’s Society (AS-JF-19a-004–517) and the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. D.L.T. was supported by the UCL Leonard Wolfson Experimental Neurology Centre (PR/ylr/18575). J.D.R. is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration

Neuroimaging Correlates of Cognitive Deficits in Wilson's Disease

Data Availability Statement: Anonymised data are available on request to the corresponding author.Supporting Information: APPENDIX S1 available at: https://movementdisorders.onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fmds.29123&file=mds29123-sup-0001-supinfo.pdf (PDF document, 3 MB).Copyright © 2022 The Authors. Background: Cognitive impairment is common in neurological presentations of Wilson's disease (WD). Various domains can be affected, and subclinical deficits have been reported in patients with hepatic presentations. Associations with imaging abnormalities have not been systematically tested. Objective: The aim was to determine the neuroanatomical basis for cognitive deficits in WD. Methods: We performed a 16-item neuropsychological test battery and magnetic resonance brain imaging in 40 patients with WD. The scores for each test were compared between patients with neurological and hepatic presentations and with normative data. Associations with Unified Wilson's Disease Rating Scale neurological examination subscores were examined. Quantitative, whole-brain, multimodal imaging analyses were used to identify associations with neuroimaging abnormalities in chronically treated stable patients. Results: Abstract reasoning, executive function, processing speed, calculation, and visuospatial function scores were lower in patients with neurological presentations than in those with hepatic presentations and correlated with neurological examination subscores. Deficits in abstract reasoning and phonemic fluency were associated with lower putamen volumes even after controlling for neurological severity. About half of patients with hepatic presentations had poor performance in memory for faces, cognitive flexibility, or associative learning relative to normative data. These deficits were associated with widespread cortical atrophy and/or white matter diffusion abnormalities. Conclusions: Subtle cognitive deficits in patients with seemingly hepatic presentations represent a distinct neurological phenotype associated with diffuse cortical and white matter pathology. This may precede the classical neurological phenotype characterized by movement disorders and executive dysfunction and be associated with basal ganglia damage. A binary phenotypic classification for WD may no longer be appropriate. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Association of British Neurologists. Grant Number: N/A; Guarantors of Brain; Wilson's Disease Support Group UK; University College London Hospitals Biomedical Research Centre; Health Research; Open access funding enabled and organized by Projekt DEAL

Factors associated with breastfeeding cessation in nursing mothers in a peer support programme in Eastern Lancashire

<p>Abstract</p> <p>Background</p> <p>The UK has one of the lowest breastfeeding rates worldwide and in recent years the Government has made breastfeeding promotion one of its priorities. The UNICEF UK Baby Friendly Initiative is likely to increase breastfeeding initiation but not duration. Other strategies which involve provision of support for breastfeeding mothers in the early weeks after birth are therefore required to encourage UK mothers to breastfeed for the recommended duration. This paper examines the effects of maternal socio-demographic factors, maternal obstetric factors, and in-hospital infant feeding practices on breastfeeding cessation in a peer support setting.</p> <p>Methods</p> <p>Data on mothers from Blackburn with Darwen (BwD) and Hyndburn in Eastern Lancashire who gave birth at the Royal Blackburn Hospital and initiated breastfeeding while in hospital were linked to the Index of Multiple Deprivation (IMD). The data were analysed to describe infant feeding methods up to 6 months and the association between breastfeeding cessation, and maternal factors and in-hospital infant feeding practices.</p> <p>Results</p> <p>The mean breastfeeding duration was 21.6 weeks (95% CI 20.86 to 22.37 weeks) and the median duration was 27 weeks (95% CI 25.6 to 28.30 weeks). White mothers were 69% more likely to stop breastfeeding compared with non-White mothers (HR: 0.59; 95% CI, 0.52 to 0.67 [White mothers were the reference group]). Breastfeeding cessation was also independently associated with parity and infant feeding practices in hospital. There were no significant associations between breastfeeding cessation and marital status, mode of delivery, timing of breastfeeding initiation and socio-economic deprivation.</p> <p>Conclusion</p> <p>In this study ethnicity, parity and in-hospital infant feeding practices remained independent predictors of breastfeeding cessation in this peer support setting. However other recognised predictors such as marital status, mode of delivery, timing of breastfeeding initiation and socio-economic deprivation were not found to be associated with breastfeeding cessation.</p