Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial

Acknowledgments This work was supported by the Stroke Association and British Heart Foundation [grant number TSA BHF 2013/01]. The work of Dr David Dickie and Dr Terry Quinn is funded by the Stroke Association. We would like to thank Christine McAlpine, Ruth Graham, Glasgow Royal Infirmary, UK; Lauren Pearce, Royal United Hospital, UK; Caroline Fornolles, Louise Tate, Frances Justin, Luton and Dunstable University Hospital, UK; Dean Waugh, Leeds Teaching Hospitals NHS Trust, UK; Donal Concannon, Altnagelvin Hospital, UK; Sharon Tysoe, Nina Francia, Nisha Menon, Raji Prabakaran, Southend University Hospital, UK; Amy Ashton, Caroline Watchurst, Marilena Marinescu, Sabaa Obarey, Scheherazade Feerick, University College London NHS Foundation Trust, UK; and Janice Irvine, Sandra Williams, and German Guzman Gutierrez, Aberdeen Royal Infirmary, UK; Caroline Fox and Joanne Topliffe, Broomfield Hospital, Essex, UK.Peer reviewedPublisher PD

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial

Background: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). Methods: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Findings: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference −0.17, 95% CI −0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. Funding: The British Heart Foundation and the UK Stroke Association

Using synovial fluid biomarkers to define a phenotype of osteoarthritis in the hip

Osteoarthritis (OA) is a chronic, multi-factorial, progressive joint disease. The understanding of OA has evolved away from a wear and tear phenomenon to a complex disease of the joint taken as a whole. A method of stratifying disease, and monitoring progression, is necessary for clinical decision making and for use as end points in future research studies to develop disease modifying OA drugs (DMOADs). The creation of such a tool requires detailed understanding of the disease biopathogenesis. Synovial fluid (SF) is the most likely target to generate the insight required due to its proximity to the intra-articular structures, whose changes are fundamental to the symptomatology of the disease. No work to date has identified any useful single biomarkers of OA and for progress to be made, a consideration of a number of proteins as a panel of markers, whose interrelations describe a signature of different disease states, is required. The emergence of the slow off-rate modified aptamer scan (SOMAscan), a broad spectrum proteomic platform, presents the opportunity to analyse 1310 proteins on a single sample of fluid that measures less than 1 ml. This thesis aims to examine the utility of the SOMAscan in OA biomarker discovery by validation against traditional bench assays, use multivariate statistical analysis methods to identify candidate markers of OA disease states, and contextualise their best clinical timing in the patient pathway by examining the treatment pathways of patients from initial presentation to final treatment. Synovial fluid samples from hip and knee joints were collected from patients with different stages of clinically classified disease including knee injury, early and late OA cohorts, and hip early and late OA cohorts with the early hip OA group requiring the development of an entirely new collection method. The performance of the SOMAscan was validated using ELISA and MSD assays that were performed on a curated list of proteins and compared to the same markers in the SOMAscan showing robust comparison. Multivariate regression analysis showed separation of the knee injury and late OA cohorts using PLS-DA, but the early group were not separable from the injury group. Markers identified by LASSO that were strongly associated with late disease included elevated TSG-6, TIMP-1 and R-spondin 4. These markers were also identified in the PLS-DA model generating potential targets for use in future OA studies. Hip SF analysis showed separation between the early and late OA groups on PLS-DA. LASSO analysis revealed 6 markers: TSG-6, DDR-2, Ephrin-A5, S100A7, MICB, IDS all of which were present in the top 50 marker model produced using PLS-DA. This combined analysis approach has shown differences between the hip groups, differences between hip and knee OA biology and suggested novel targets for future OA studies. An epidemiological study investigating the patient pathways, from presentation in primary care through to eventual arthroplasty, was conducted to identify where a diagnostic test would be best placed in the patient journey. Results showed marked variation in the rates of treatments offered to patients during their disease, with wide variation in analgesia, physiotherapy and intermediate surgical interventions. Most notably it showed that there was a continued increase in the use of opioid analgesia overall, particularly in the most deprived patients, indicating a need to investigate ways to harmonise this patient experience such that patients can be identified reliably at earlier stages of disease. In summary, the works in this thesis have validated the SOMAscan. A new system of biomarker discovery in OA, for use in SF analysis. The SOMAscan analysis of SF has shown a variety of differently expressed markers and pathways including well described OA processes in both knee and hip. It has suggested that early knee OA appears biologically closer to joint injury than to late knee OA, and that hip and knee OA appear to be biologically distinct processes with common thematic pathways as well as differences. This work has collected a new and unique SF cohort of human early hip OA SF to define a biological phenotype of late OA that discriminates between the groups studied. This work has further shown that the patient journey from presentation to definitive treatment is hugely varied, both in duration and treatments delivered, demonstrating that ongoing work is needed not only to identify biomarkers of early OA but to identify means of accessing patients earlier in their clinical disease states. Together these critical elements of disease description and patient identification require optimisation such that future OA biomarkers may be utilised as disease diagnosis, stratification and outcome tools in DMOAD studies

The diagnostic journey of patients with mucopolysaccharidosis I: A real-world survey of patient and physician experiences

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease. Affected individuals have disease ranging from attenuated to severe with significant disease burden, disability, and premature death. Early treatment with enzyme replacement therapy and/or stem cell transplantation can reduce disease progression and improve outcomes. However, diagnosis is often delayed, particularly for patients with attenuated phenotypes. We conducted a survey of 168 patients and 582 physicians to explore health care seeking patterns and familiarity of physicians with MPS I symptoms. Patients with attenuated MPS I typically first presented with stiff joints or hernia/bulging abdomen, and patients with severe disease with noisy/difficult breathing, or hernia/bulging abdomen. There was a mean delay from time of symptom presentation to diagnosis of 2.7 years for patients with attenuated disease, with a mean of 5 physicians consulted before receiving a correct diagnosis. MPS I was most commonly misidentified by physicians as rheumatoid arthritis (48–72%), with a wide variety of suspected diseases, including lupus. CONCLUSION: Patient and physician real-world surveys show that MPS I is under-recognized and diagnosis of MPS I remains delayed, particularly in patients with attenuated disease. Across regions and specialties, physicians require differential diagnosis education in order to improve early detection and early treatment initiation of MPS I

IDUA mutational profile and genotype-phenotype relationships in UK patients with Mucopolysaccharidosis I

Mucopolysaccharidosis Type I is a lysosomal storage disorder with varying degrees of phenotypic severity caused by mutations in IDUA. Over 200 disease-causing variants in IDUA have been reported. We describe the profile of disease-causing variants in 291 individuals with Mucopolysaccharidosis Type I for whom IDUA sequencing was performed, focussing on the UK subset of the cohort. A total of 63 variants were identified, of which 20 were novel, and the functional significance of the novel variants is explored. The severe form of Mucopolysaccharidosis Type I is treated with haematopoietic stem cell transplantation, known to have improved outcomes with earlier age at treatment. Developing genotype-phenotype relationships would therefore have considerable clinical utility, especially in the light of the development of newborn screening programs for Mucopolysaccharidosis Type I. Associations between genotype and phenotype are examined in this cohort, particularly in the context of the profile of variants identified in UK individuals. Relevant associations can be made for the majority of UK individuals based on the presence of nonsense or truncating variants as well as other associations described in this report. This article is protected by copyright. All rights reserved

Gleason Grade Group 4 prostate biopsy with no cancer seen on final pathology in the magnetic resonance imaging and Prostate Specific Membrane Antigen‐Positron Emission Tomography era

Introduction The absence of prostate cancer on final surgical pathology after biopsy‐proven prostate cancer is a rare finding. Case presentation Case of pT0 prostate cancer following Gleason Grade Group 4 in 1 out of 12 cores from a transrectal ultrasound‐guided biopsy in a man who underwent both magnetic resonance imaging and 18F‐PSMA‐1007 Positron Emission Tomography prior to radical prostatectomy. Conclusion pT0 prostate cancer is rare. The use of novel imaging modalities may help in the workup of prostate cancer

Management of pain in Fabry disease in the UK clinical setting: consensus findings from an expert Delphi panel

Abstract Background Fabry disease is a rare, X-linked inherited lysosomal storage disorder, that manifests as a heterogeneous disease with renal, cardiac and nervous system involvement. The most common pain experienced by people with Fabry disease are episodes of neuropathic pain reported in up to 80% of classical hemizygous male patients and up to 65% of heterozygous female patients. No clear consensus exists within UK clinical practice for the assessment and management of pain in Fabry disease based on agreed clinical practice and clinical experience. Here we describe a modified Delphi initiative to establish expert consensus on management of pain in Fabry disease in the UK clinical setting. Methods Delphi panel members were identified based on their demonstrated expertise in managing adult or paediatric patients with Fabry disease in the UK and recruited by an independent third-party administrator. Ten expert panellists agreed to participate in two survey rounds, during which they remained anonymous to each other. Circulation of the questionnaires, and collection and processing of the panel’s responses were conducted between September 2021 and December 2021. All questions required an answer. Results The Delphi panel reached a consensus on 21 out of 41 aspects of pain assessment and management of pain in Fabry disease. These encompassed steps in the care pathway from the goals of therapy through to holistic support, including the use of gabapentin and carbamazepine as first-line analgesic medications for the treatment of neuropathic pain in Fabry disease, as well as the proactive management of symptoms of anxiety and/or depression associated with Fabry pain. Conclusions The consensus panel outcomes reported here have highlighted strengths in current UK clinical practice, along with unmet needs for further research and agreement. This consensus is intended to prompt the next steps towards developing clinical guidelines