Brain最新文献

Facioscapulohumeral dystrophy (FSHD) is primarily associated with contraction of the D4Z4 macrosatellite array at the 4q35 locus. While unaffected individuals carry 11 to 150 D4Z4 repeats, approximately 95% of FSHD patients (FSHD1) exhibit a contraction to 1-10 units, along with reduced DNA methylation. In another ∼3% of patients (FSHD2), the disease results from a digenic mechanism associated with the presence of a pathogenic variant in the SMCHD1 gene, leading to the epigenetic deregulation of the 4q35 locus. However, 1-2% of clinically diagnosed patients lack a defined genetic cause, highlighting diagnostic gaps. In prior work, we identified over 70 patients, clinically diagnosed with FSHD and carrying a complex structural variant of the 4q35 or 10q26 loci. A potential pathogenicity of these structural variants was evoked in some cases, in the absence of other FSHD-associated genetic features. Given their diagnostic relevance, we performed here detailed structural analyses of these rearrangements, in 7 representative cases carrying different structural variants of the 4q35 or 10q26 loci using high-resolution long-read sequencing technologies (Oxford Nanopore and PacBio) and suspected of FSHD. By comparing the advantages and limitations of several methodological long read sequencing strategies, we resolved the architecture and methylation patterns across the 4q35 and 10q26 loci at the nucleotide-level. We show that duplicated alleles arise from intrachromosomal recombination between LSau elements contained within D4Z4 and distal subtelomeric β-satellite elements, producing variable deletions within the proximal D4Z4 region, with breakpoints differing among patients. These complex structural variants are not detectable using standard technologies like Bionano Optical Genome Mapping and require manual curation for identification during routine molecular diagnosis procedures. Importantly, determining the pathogenic relevance of these rearrangements necessitates integrating structural and epigenetic features typically associated with FSHD. Our results underscore the importance of in-depth molecular characterization for patients with clinical FSHD who test negative for FSHD1/FSHD2 by conventional diagnosis methods. We further show that structural variants might be considered as likely pathogenic, in the absence of SMCHD1 variant. Overall, as structural variants at 4q35 are increasingly identified in patients clinically diagnosed with FSHD, their comprehensive analysis is crucial to refine diagnosis, guide genetic counseling, and ultimately improve clinical care for individuals clinically suspected of FSHD but presenting an atypical molecular profile.

It is not known what the relapse risk is after immunomodulatory treatment discontinuation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Evidence suggests "at least" 3 months of oral corticosteroids reduces the relapse risk after a single attack and that it may be possible to stop maintenance treatment in relapsing stable disease but the optimal duration of treatment is unknown. We therefore aimed to investigate relapse outcomes following maintenance treatment discontinuation. We conducted a cohort study of MOGAD patients seen in the Oxford Neuromyelitis Optica Highly Specialised Service between January 2010 and May 2025. Patients with MOGAD, at least 12 months follow-up, and who commenced and then discontinued maintenance treatment were included. Associations of factors including treatment duration prior to discontinuation, disease course at discontinuation (after a single attack/monophasic or relapsing course) and MOG IgG1 status on live cell-based assay were investigated. Primary outcome was time-to-relapse following treatment discontinuation. Cox regression was used. We included 190 MOGAD patients with 236 discontinued treatment intervals. 150 (63.6%) discontinuations were after a single attack and before a first relapse when disease course was monophasic, and 86 (36.4%) discontinuations occurred in patients who had a relapsing disease course. Most patients used corticosteroids alone (84.7% IT intervals), and non-steroid IT were used in 15.2% of IT intervals either alone or in combination with steroids. Post-discontinuation relapse occurred after 92 (39.0%) discontinuations at a median time of 5.4 (interquartile range 1.4-20.1) months after treatment cessation. Those who relapsed were more likely to have a relapsing course at time of discontinuation (50% vs 27.8%, P=0.001) and a positive/low positive pre-discontinuation MOG IgG1 result (89.8% vs 71.5%, P=0.005). In multivariable analysis, a relapsing course at time of discontinuation was associated with an elevated relapse risk (hazard ratio 1.95, 95% confidence interval 1.25-3.06, P=0.003). Overall, prolonged treatment durations prior to discontinuation beyond 3 months significantly reduced relapse risk. Optimal treatment durations were estimated as at least 10-18 months for patients treated after their onset attack and 20-30 months for relapsing patients, following which treatment discontinuation could be considered in patients who were relapse-free on treatment. Identifying the relapse risk when discontinuing maintenance immunomodulatory treatment in MOGAD should aid management decisions in patients presenting with their first attack and also in those on longer-term treatment for relapsing disease. Our findings, from a cohort predominantly treated with steroids, provide evidence to inform joint decision-making for stable patients who are considering treatment cessation.

Primary mitochondrial diseases (PMDs) affect ∼1 in 4,300 individuals, yet mitochondrial dysfunction is also a hallmark of common inherited and acquired disorders. While advances in genomics now allow molecular diagnosis in 30-60% of mitochondrial diseases, treatment remains largely supportive, leading to progressive disability and early mortality. Despite progress in gene-modifying approaches, no approved therapies exist for the majority of mitochondrial diseases, and none of the recent trials have met their primary endpoints, underlining the urgent need for innovative therapeutic strategies. Patients with PMDs have very variable phenotypes, further complicated by increased susceptibility to infections, chronic inflammation and metabolic abnormalities. Recently, it has become evident that certain mitochondrial pathologies, including the loss of mitochondrial membrane integrity, impaired mtDNA maintenance, quality control defects, or respiratory chain defects, result in the release of mtDNA into the cytosol. Infections or metabolic changes also trigger the release of mtDNA, leading to the activation of a sterile innate immune response and interferon signalling. Free mtDNA acts as a pathogen-associated molecular pattern (PAMP), activating innate immune pathways such as the cGAS-STING axis, initiating a sterile inflammatory response. This can be followed by the extracellular release of mtDNA to convey the inflammatory response systemically to communicate between cells or across organs. However, it is unclear whether these pathways worsen the disease phenotype (hyperinflammatory reaction) or, in contrast, rescue the symptoms due to upregulation of compensatory pathways. In this review, we summarise recent advances in understanding the mechanism of mtDNA release and how it activates innate immune signalling in PMDs. We also discuss the implications for pathogenesis, clinical phenotypes, and therapeutic development. Defining the role of circulating mitochondrial material as a biomarker or therapeutic target is a critical step for precision medicine approaches in PMDs. These pathways may also have wider implications for common metabolic, inflammatory, and neurodegenerative disorders with mitochondrial dysfunction.