Carlos Casasnovas

Background: ADVANCE‐CIDP IVIG evaluated the efficacy and safety of immune globulin infusion (human) 10% solution (IVIG 10%; GAMMAGARD LIQUID, also known as Kiovig) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as a rescue treatment for patients relapsing during the ADVANCE‐CIDP 1 trial.Methods: Open‐label ADVANCE‐CIDP IVIG included adult patients with confirmed CIDP relapse (≥ 1‐point increase in adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] disability scores from pre‐treatment baseline) during ADVANCE‐CIDP 1, which assessed the efficacy and safety of hyaluronidase‐facilitated subcutaneous immunoglobulin (fSCIG) 10%. Patients received an induction IVIG 10% dose (2 g/kg) followed by maintenance infusions at the same monthly equivalent dose of pre‐randomization IVIG, 3‐weekly for 6 months. The primary outcome was the responder rate (≥ 1‐point decrease in adjusted INCAT scores at treatment cessation vs. pre‐IVIG 10% baseline, in patients receiving placebo in ADVANCE‐CIDP 1). Other outcomes included the responder rate across all patients relapsing on fSCIG 10% or placebo in ADVANCE‐CIDP 1, time to functional improvement (≥ 1‐point decrease in adjusted INCAT score), and change in adjusted INCAT scores and Rasch‐built Overall Disability Scale (R‐ODS) centile scores from pre‐IVIG 10% baseline.Results: Overall, 20 patients received IVIG 10% (n = 4 [fSCIG 10%‐relapse group]; n = 16 [placebo‐relapse group]). Responder rate (95% confidence interval) was 100.0% (80.6%–100.0%) in the placebo‐relapse group and 95.0% (76.4%–99.1%) in the overall‐relapse population. Across all patients, median time to functional improvement was 25 days. At treatment cessation, mean changes from pre‐IVIG 10% baseline in adjusted INCAT and R‐ODS centile scores were −1.9 and 12.9, respectively.Conclusions: IVIG 10% effectively treated CIDP relapse and improved functional abilities.

Background: There is no standardized treatment for acquired amyloid polyneuropathy (AAP) in domino liver transplant (DLT) recipients. Objectives: Our objective is to analyze the efficacy and safety of patisiran for the treatment of AAP in DLT recipients. Design: We performed a postauthorization prospective longitudinal study of DLT recipients with AAP who received patisiran treatment for 22 months. Methods: The primary endpoint was change in the Neuropathy Impairment Scale (NIS) from baseline. Other assessments included neurophysiologic study, quantitative sensory testing, 10 m walking test, and quality of life and disability questionnaires. As safety parameters we analyzed evidence of graft rejection, immunosuppression levels, and renal and cardiac adverse effects. Results: Four patients were recruited. The mean NIS at baseline was 8.5 ± 2.08. All patients presented clinical improvement after 22 months of treatment, with a mean NIS of 4.75 ± 2.27 points. The mean change from baseline in the NIS was −3.75 ± 0.71 (95% CI: −0.47 to 7.97). The use of patisiran was not associated with cardiovascular or renal side effects. No patient presented relevant changes in immunosuppression levels or graft rejection. Conclusion: Our study suggests that patisiran may improve neurological manifestations in DLT recipients with AAP, producing no relevant adverse effects.

Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180–200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5’ flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23–31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process.

The association between epilepsy and myasthenia gravis has rarely been reported, and when it has been reported, it has only been in a small case series. The aim of the present study was to report the frequency of epilepsy and myasthenia gravis and to describe a case series of patients with myasthenia gravis and epilepsy, focusing on their clinical characteristics and searching for a possible physiopathological mechanism. A retrospective, observational, adult center study was conducted in 2022. Patients were recruited from the database of the outpatient clinic of the Myasthenia Gravis and Epilepsy Unit of the Neurology Service, Hospital Universitari de Bellvitge. Five patients were included. The frequency of epilepsy in the myasthenia gravis cohort was 5/469 (1.1%), and the frequency of myasthenia gravis in the epilepsy cohort was 5/1432 (0.35%). All patients suffered from focal epilepsy, mainly temporo-central, which was drug-resistant in 3/5 Myasthenia gravis, which was generalized and with exacerbations in 3/5. Three patients were thymectomized (anatomopathology: thymic hyperplasia). Other autoimmune diseases were found in two (40%). Epilepsy onset preceded myasthenia gravis onset in all patients. Both diseases were considered autoimmune-related in 3/5, related to genetic predisposition due to altered innate immune system in 1/5, and due to chance or to treatment in 1/5. Epilepsy and myasthenia gravis are only infrequently associated. In adult patients, epilepsy onset precedes myasthenia onset in most cases. In some cases, epilepsy has an autoimmune etiology and coexists with other autoimmune conditions.

Introduction: The association between epilepsy and myasthenia gravis has rarely been reported, and only in small case series. Objective: To report the frequency of epilepsy and myasthenia gravis and to describe a case series of patients with myasthenia gravis and epilepsy, focusing on their clinical characteristics and searching for a possible physiopathological mechanism. Methods: A retrospective, observational, adult center study was conducted in 2022. Patients were recruited from the database of the outpatient clinic of the Myasthenia Gravis unit and Epilepsy unit. Results: Five patients were included. Frequency of epilepsy in the myasthenia gravis cohort was 5/469 (1.1%), and of myasthenia gravis in the epilepsy cohort was 5/1432 (0.35%). All patients suffered focal epilepsy, mainly fronto-central, and drug-resistant in half of them. Myasthenia gravis was generalized and with exacerbations in half of them. Three patients were thymectomized. Other autoimmune diseases were found in 2 (40%). Epilepsy onset preceded myasthenia gravis onset in all patients. Both diseases were considered autoimmune-related in 3/5 (60%). Conclusion: Epilepsy and myasthenia gravis are only infrequently associated. In adult patients, epilepsy onset precedes myasthenia onset in most cases. In some cases, epilepsy has an autoimmune aetiology and coexists with other autoimmune conditions.

Introduction Acquired amyloid neuropathy is an iatrogenic disease that appears years after a domino liver transplant. The objectives of our study are to analyze the efficacy and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. This post-authorization, prospective, longitudinal study included seven domino liver transplant recipients with acquired amyloid neuropathy who received treatment with tafamidis for 18 months. Methods The primary endpoints were the response rate, defined as those patients with an increase of < 2 points on the Neurological Impairment Score (NIS) from baseline, and the change in the NIS score from baseline. Secondary endpoints included the Quantitative Sensory Test, 10-m walk test, quality of life (Norfolk), and disability (Rasch-built Overall Disability Scale). As safety parameters, the evidence of graft rejection, changes in immunosuppressive trough levels and changes in antiviral and allogeneic cellular immunity before and 12 months after tafamidis treatment were also assessed. Results Six patients (85.7%) had responded at 18-months. Compared to baseline, we observed non-statistically significant improvement in mean NIS score at 6 months (− 2.54 points, CI − 5.92 to 0.84), 12 months (− 3.25 points; CI − 6.63 to 0.13), and 18 months (− 2.35 points; CI − 5.74 to 1.02). Changes in the Quantitative Sensory Test, 10-m walk tests and the quality of life and disability questionnaires were not statistically significant. The use of tafamidis did not induce relevant side effects or drug interactions. Also, no acute rejections events nor changes in functional adaptive immunity were observed. Conclusion Our study supports the safety and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. Tafamidis shows promise as a useful treatment in the clinical management of these patients. Future randomized placebo-controlled clinical trials with longer follow-up durations are needed.

Repeat expansions in FGF14cause autosomal dominant late-onset cerebellar ataxia (SCA27B), with pathogenic thresholds estimated between 250 and 300 AAG repeats. However, the complete sequences of pathogenic and non-pathogenic alleles remain largely unknown. Here, we identify FGF14 repeat expansions as the most commonly missed cause of cerebellar ataxia using a combination of short-read genome sequencing, long-range PCR and nanopore sequencing. We compare FGF14 alleles in 154 patients with ataxia and 802 controls and report an enrichment of pure FGF14 expansions above 180-220 repeats in patients. Conversely, AAGGAG and interrupted alleles are more frequent in controls. Distinct 5'-flanking regions correlate with repeat stability. SCA27B patients have a characteristic phenotype, including frequent episodic ataxia and downbeat nystagmus, similar to those with a novel nonsense variant (SCA27A). Interestingly, pathogenic and non-pathogenic repeats form different secondary structures. Our results emphasize the importance of sequencing both the repeat expansion and its flanking region for accurate clinical interpretation.

Background: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts.Methods: We developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient’s standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA).Results: ClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes.Conclusions: ClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses.

Background and purpose: Dominantly inherited GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene have recently been shown to cause spinocerebellar ataxia 27B (SCA27B). We aimed to study the frequency and phenotype of SCA27B in a cohort of patients with unsolved late‐onset cerebellar ataxia (LOCA). We also assessed the frequency of SCA27B relative to other genetically defined LOCAs.Methods: We recruited a consecutive series of 107 patients with LOCA, of whom 64 remained genetically undiagnosed. We screened these 64 patients for the FGF14 GAA repeat expansion. We next analysed the frequency of SCA27B relative to other genetically defined forms of LOCA in the cohort of 107 patients.Results: Eighteen of 64 patients (28%) carried an FGF14 (GAA)_≥250 expansion. The median (range) age at onset was 62.5 (39–72) years. The most common clinical features included gait ataxia (100%) and mild cerebellar dysarthria (67%). In addition, episodic symptoms and downbeat nystagmus were present in 39% (7/18) and 37% (6/16) of patients, respectively. SCA27B was the most common cause of LOCA in our cohort (17%, 18/107). Among patients with genetically defined LOCA, SCA27B was the main cause of pure ataxia, RFC1‐related disease of ataxia with neuropathy, and SPG7 of ataxia with spasticity.Conclusion: We showed that SCA27B is the most common cause of LOCA in our cohort. Our results support the use of FGF14 GAA repeat expansion screening as a first‐tier genetic test in patients with LOCA.

The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid–droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.