Brain最新文献

Childhood-onset movement disorders are clinically and genetically heterogeneous, with over 500 implicated genes. Standard clinical genetic testing, including exome sequencing, has limited sensitivity for certain variants, including repeat expansions, structural variants (SVs), copy number variants (CNVs), and deep intronic changes. We evaluated the diagnostic utility of short-read whole genome sequencing (srWGS) and, in selected cases, long-read genome sequencing (lrWGS) in a real-world cohort of children and young adults with early-onset progressive movement disorders and prior nondiagnostic genetic testing. One hundred individuals (<30 years) with progressive movement disorders with a suspected genetic etiology were recruited from a tertiary pediatric movement disorders program. All had prior nondiagnostic testing. SrWGS (Illumina NovaSeq 6000) assessed single nucleotide variants (SNVs), CNVs, SVs, and repeat expansions; lrWGS (Pacific Biosciences) was applied to select unsolved trios. Variants were reviewed by a multidisciplinary team using standard variant interpretation guidelines and phenotype correlation. A molecular diagnosis was achieved in 27% (27/100) of cases, and candidate variants were identified in an additional 33% (33/100). Among solved cases, 81.5% (22/27) were identified from exome-level data, while 18.5% (5/27) required genome-level analysis to detect variants such as repeat expansions in HTT and FXN, an intragenic duplication in MECP2, an Alu insertion in ATM, and a deletion in FA2H. Genome-level analysis contributed an additional diagnostic yield of 5% (5/100) only. Notably, in 33.3% (9/27) of solved cases, variants had been previously reported but not recognized as diagnostic. LrWGS of 14 unsolved trios did not yield additional diagnoses. SrWGS provided a modest incremental yield over exome sequencing in early-onset movement disorders, with most diagnoses achieved through reanalysis of exome-level data. Findings highlight the importance of iterative variant interpretation and the need for improved analytic pipelines to fully realize the potential of genome sequencing.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neuroinflammatory disease with no effective treatment. In this study, we investigated whether dimethyl fumarate (DMF), an immunomodulatory agent approved for treating multiple sclerosis, exerts therapeutic effects relevant to HAM/TSP. Peripheral blood mononuclear cells (PBMCs) from 16 people living with HAM/TSP were used to evaluate the effects of DMF on cell viability, spontaneous proliferation, inflammatory cytokine production and HTLV-1 proviral load (PVL). DMF significantly inhibited lymphocyte proliferation in a concentration-dependent manner, with reductions of 42.1% at 10 µM, 56.3% at 25 µM, 60.6% at 50 µM and 69.9% at 100 µM. This suppressive effect was particularly evident in CD8+ T cells, CD4+ T cells and HTLV-1-infected CD4+ T cells. Furthermore, DMF reduced the production of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) released from these proliferating cells. A reduction in PVL was also observed in a subset of ex vivo PBMC cultures derived from individuals with HAM/TSP exhibiting high viral proliferative activity. These results suggest that DMF suppresses pathogenic immune activation in HAM/TSP and may therefore represent a promising therapeutic candidate for this disabling neuroinflammatory disorder.

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.