Brain最新文献

{"title":"Reply: Classifying neurogenic dysphagia: neuroanatomical hierarchy versus clinical syndromology.","authors":"Corinne A Jones, Maggie-Lee Huckabee, Georgia A Malandraki, David Paydarfar","doi":"10.1093/brain/awaf368","DOIUrl":"https://doi.org/10.1093/brain/awaf368","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EIPR1 variants cause a neurodevelopmental disorder with endolysosomal and dense core vesicle defects.","authors":"Saikat Ghosh,Jaskaran Singh,Nadirah S Damseh,Mariasavina Severino,Raffaella De Pace,Adriana E Golding,Michal Jarnik,Poonam Thakran,Laurence Faivre,Jade Heitz,Anne-Sophie Denommé-Pichon,Antonio Vitobello,Lama AlAbdi,Firdous Abdulwahab,Safia Sumayli,Mashael Alqahtani,Huma Arshad Cheema,Iram Javed,JiHye Kim,Hanns Lochmuller,Hagar Mor-Shaked,Jennifer E Neil,Ganeshwaran H Mochida,Giovanni Zifarelli,Peter Bauer,Ehsan Barkhordari,Ehsan Ghayoor Karimiani,Henry Houlden,Bassam Abu-Libdeh,Shimon Edvardson,Orly Elpeleg,Reza Maroofian,Shunmoogum A Patten,Juan S Bonifacino","doi":"10.1093/brain/awaf371","DOIUrl":"https://doi.org/10.1093/brain/awaf371","url":null,"abstract":"EIPR1 (EARP-interacting protein 1, formerly known as TSSC1) is a WD40-domain protein that interacts with the EARP (endosome-associated recycling protein) and GARP (Golgi-associated retrograde protein) complexes in the process of delivering endosome-derived transmembrane cargos to the plasma membrane and the trans-Golgi network (TGN), respectively. Additionally, EIPR1 cooperates with EARP in the biogenesis of dense core vesicles. While these properties of EIPR1 were established in cultured cells and model organisms, the physiological and pathological importance of EIPR1 in humans remains to be determined. Here we report the identification of five EIPR1 homozygous missense variants [NM_003310.5:c.835C>G p.(Arg279Gly), NM_003310.5:c.813C>G p.(His271Gln), NM_003310.5:c.694C>T p.(Arg232Trp), NM_003310.5:c.47G>A p.(Arg16His) and NM_003310.5:c.419T>A p.(Val140Asp)] in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Cellular studies using a heterologous transfection system demonstrate that these variants reduce EIPR1 protein levels and its physical interaction with EARP and GARP complexes. Furthermore, we show that the Arg279Gly and His271Gln variants reduce the ability of EIPR1 to promote EARP association with endosomes in non-neuronal cells and dense core vesicle biogenesis in iPSC-derived neurons. Additionally, skin fibroblasts from one of the Arg279Gly affected individuals shows reduced recycling of internalized transferrin to the plasma membrane (an EARP-deficiency phenotype) and impaired retrograde transport of internalized Shiga toxin B-subunit to the TGN (a GARP-deficiency phenotype) compared to fibroblasts from an unaffected parent. Moreover, these patient fibroblasts exhibit enlarged lysosomes, increased levels of the lysosomal membrane protein LAMP1, and increased levels of the autophagic markers LC3B-II and SQSTM1, all phenotypes previously associated with GARP deficiency. Knockout of the orthologous eipr1 in zebrafish results in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients. Injection of WT human EIPR1 mRNA into eipr1 KO zebrafish rescues these defects, whereas mRNAs encoding the human EIPR1 variants Arg279Gly or His271Gln fail to do so, confirming the impaired activity of these variants. These findings identify EIPR1 as a novel genetic locus associated with a neurodevelopmental disorder and underscore its critical role in endosomal recycling and dense core vesicle biogenesis, processes essential for the development and function of the nervous system.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical cerebral microinfarcts spark cognitive decline","authors":"Gemma Solé-Guardia, Anil M Tuladhar, Frank-Erik de Leeuw","doi":"10.1093/brain/awaf377","DOIUrl":"https://doi.org/10.1093/brain/awaf377","url":null,"abstract":"This scientific commentary refers to ‘Synergistic effect between cortical cerebral microinfarcts and brain atrophy on cognitive decline’ by Huang et al. (https://doi.org/10.1093/brain/awaf301).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"17 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ageing and remyelination failure in people with multiple sclerosis","authors":"Trisha Mukherjee, Christopher E McMurran, Jonathon Holland, Cyrus Daruwalla, Gioia Riboni-Verri, J William L Brown, Robin J M Franklin, Alasdair Coles, Nick G Cunniffe","doi":"10.1093/brain/awaf373","DOIUrl":"https://doi.org/10.1093/brain/awaf373","url":null,"abstract":"One of the most promising strategies to delay, prevent, or reverse disability progression in multiple sclerosis (MS) is enhancing endogenous remyelination. While preclinical research has established a strong connection between ageing and remyelination failure, evidence for this same link in people with MS remains less secure. As clinical trials for remyelinating therapies progress, clarifying this relationship is essential. A deeper understanding could guide the selection of therapeutic candidates, refine patient selection, and optimise the timing of treatment delivery. In this review, we describe the available evidence that has investigated the impact of age on remyelination in people with MS. We categorise these into pathological, imaging and clinical studies. We explore the challenges in measuring remyelination in humans and determine the implications for the connection between remyelination and age. Current evidence suggests that there is reduced capacity for remyelination with advancing age in people with MS. However, these findings are at times inconsistent and the precise contribution of ageing to remyelination failure is unclear. There does not appear to be an age cut-off beyond which remyelination is not possible, as there are pathological data supporting remyelination occurring, to some extent, across all ages. Interestingly, the impact of age may vary by lesion location. Further targeted research, specifically exploring the relationship between ageing and remyelination, is needed. With emerging evidence that ageing processes might be malleable, we conclude that targeting the biology of ageing might also be an important strategy to therapeutically enhance remyelination.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"77 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reference proteins to improve Core 1 and Core 2 Alzheimer's disease CSF and plasma biomarkers.","authors":"Linda Karlsson,Shorena Janelidze,Nicolas R Barthélemy,Kanta Horie,Joseph Therriault,Lorenzo Gaetani,Giovanni Bellomo,Suzanne E Schindler,Jacob Vogel,Ida Arvidsson,Kalle Åström,Brian A Gordon,Cyrus A Raji,Tammie L S Benzinger,John C Morris,Johanna Nilsson,Ann Brinkmalm,Sebastian Palmqvist,Erik Stomrud,Gemma Salvadó,Alexa Pichet Binette,Massimiliano Di Filippo,Lucilla Parnetti,Pedro Rosa-Neto,Kaj Blennow,Randall J Bateman,Niklas Mattsson-Carlgren,Oskar Hansson","doi":"10.1093/brain/awaf375","DOIUrl":"https://doi.org/10.1093/brain/awaf375","url":null,"abstract":"Concentration-based fluid biomarkers represent an informative and cost-effective way to detect and monitor Alzheimer's disease (AD) pathology. However, non-AD-related inter-individual variation in biofluids can also affect biomarker concentrations. Here, we investigated whether normalization of cerebrospinal fluid (CSF) and plasma biomarkers to reference proteins, such as amyloid-β40 (Aβ40) and non-phosphorylated mid-region tau (np-tau), improves their robustness and reliability of representing AD pathology load. Using the Swedish BioFINDER-2 cohort (n=1702, 50.7% male, mean [SD] age 68.4 [12.2] years), we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus in a ratio with a reference protein (Aβ40 or np-tau) in univariate linear regression models. Fluid biomarkers included CSF and plasma measures of p-tau217, p-tau181, p-tau205, np-tau181-190, np-tau195-210, np-tau212-221, Aβ42, Aβ40, and CSF MTBR-tau243, SNAP-25, neurogranin, YKL-40, sTREM2, and plasma eMTBR-tau243. Biomarkers were measured with mass spectrometry assays and/or immunoassays. In addition, we performed validation and extended analyses, comparing for example group-level diagnostic differences and longitudinal biomarker trajectories, in three independent prospective cohorts: BioFINDER-1, Knight Alzheimer Disease Research Center (ADRC), and Translational Biomarkers in Aging and Dementia (TRIAD), as well as in an Italian multiple sclerosis cohort. CSF Aβ40 normalization significantly strengthened the associations of several core CSF AD biomarkers, including CSF MTBR-tau243, p-tau isoforms and synaptic biomarkers, with tau-PET (ΔR²=0.064-0.24) and Aβ-PET (ΔR² = 0.016-0.28). Normalization to CSF np-tau mainly improved concordance with Aβ-PET (ΔR² = -0.0059-0.19). The strongest association with tau-PET was observed for MTBR-tau243/Aβ40 (R² = 0.78, compared to 0.65 for non-normalized MTBR-tau243), and with Aβ-PET for p-tau217/np-tau (R² = 0.65, compared to 0.46 for non-normalized p-tau217). Plasma biomarker associations with tau-PET improved when using normalization to plasma Aβ40 or np-tau (ΔR² = 0.004-0.14), with the strongest effect for eMTBR-tau243/np-tau (R² = 0.72 versus 0.60). Associations with Aβ-PET were enhanced with np-tau normalization (ΔR² = 0.018-0.16, strongest for p-tau217/np-tau: R² = 0.62 versus 0.53). The results were replicated in Knight ADRC and TRIAD. Furthermore, longitudinal analyses showed that Aβ40 normalization typically reduced inter-individual rather than intra-individual variability over time. Normalization did not enhance group-level differences in inflammatory CSF biomarkers in AD, nor did it improve biomarker associations in the multiple sclerosis cohort. In conclusion, normalization of CSF and plasma biomarkers to reference proteins, such as Aβ40 or np-tau, enhances their association with brain tau and Aβ pathology, making already high-performing AD fluid biomarkers even more accurate.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"21 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrophysiological connections linking medial pulvinar, anterior nuclei of the thalamus and the hippocampus","authors":"Masaya Togo, Dian Lyu, Weichen Huang, Sofia Pantis, Robert Fisher, Riki Matsumoto, Vivek Buch, Josef Parvizi","doi":"10.1093/brain/awaf342","DOIUrl":"https://doi.org/10.1093/brain/awaf342","url":null,"abstract":"The Papez circuit traditionally highlights the anterior nuclei of the thalamus (ANT) as the main relay of hippocampal (HPC) output to the cortex, a view that has shaped neuromodulation strategies in temporal lobe epilepsy (TLE). However, recent studies suggest that the medial subregion of the pulvinar (mPLV)— a thalamic nucleus that has undergone significant evolutionary expansion throughout the mammalian brain evolution— also forms functional connections with medial temporal lobe (MTL) structures, including the hippocampus (HPC). To date, however, there is a lack of causal evidence directly comparing the connectivity between the HPC and the two thalamic nuclei (mPLV and ANT) and between the two thalamic structures within the same brains. In this study, we investigated 41 patients with medial (mTLE, N=22) and non-medial temporal lobe epilepsy (non-mTLE, N=19) implanted with simultaneous depth electrodes in the HPC, ANT, and mPLV. Repeated single-pulse electrical stimulations were applied to compare the causal electrophysiological connectivity of these regions within the same individuals. Our intra-subject analysis revealed that anterior HPC stimulation evoked strong responses in both ANT and mPLV, with mPLV responses occurring significantly later than those in the ANT [linear mixed-effect model (LMM), Mean: 10.19ms, 95% CI [1.78, 18.59], (FDR corrected P = 0.040)]. In contrast, stimulation of the posterior HPC resulted in stronger (and a trend for earlier) responses in mPLV compared to ANT [LMM: Mean: 0.117, 95% CI [0.033, 0.201] (FDR corrected P = 0.012)]. This finding suggests anterio-posterior gradient of HPC connectivity. Furthermore, we found robust bilateral and bidirectional connectivity between ANT and mPLV. Stimulation of either elicited responses in the other, including contralateral thalamus. This represents clear evidence for both intra-thalamic and inter-thalamic connectivity within the human brain. Our findings offer new insights about the connectivity of human HPC with the thalamus and strong intra-thalamic exchange of electrophysiological activity within the human brain.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"94 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced adenoviral reactivity in Guillain-Barré syndrome after SARS-CoV-2 infection and vaccination","authors":"Roberto Bellanti, Ana Candalija Iserte, Claire Bergstrom Johnson, John Goodfellow, Marina Johnson, Wanwisa Dejnirattisai, Stephen Keddie, Joseph J Campo, Gavin Screaton, David Goldblatt, Michael P Lunn, Alexander J Davies, Simon Rinaldi","doi":"10.1093/brain/awaf376","DOIUrl":"https://doi.org/10.1093/brain/awaf376","url":null,"abstract":"Case reports and series suggested an association between SARS-CoV-2 and Guillain-Barré syndrome (GBS). However, the GBS epidemic which was predicted from early risk estimates did not materialise in overall case numbers, and no plausible mechanism for any link has been established. An increased risk of GBS following adenoviral vector-based COVID-19 vaccination has been more consistently demonstrated, but a pathophysiological explanation for this association has also not yet emerged. Here, we sought to identify whether patients with GBS following COVID-19 infection or vaccination had any distinct clinical or serological features differentiating them from one another or non-pandemic GBS, and to explore the potential mechanisms of any associations. Between March 2020 and October 2021, sera from patients with GBS (n=64) and controls (n=70) were collected. Clinical features were retrieved from medical records. GBS cases were evaluated for diagnostic certainty by Brighton criteria and classified as non-COVID-19 associated (GBS-NC, n=20), GBS after COVID-19 infection (GBS-AC, n=10), or GBS after COVID-19 vaccination (GBS-AV, n=34). The humoral responses to SARS-CoV-2 proteins and putative peripheral nerve antigens, and the cytokine profile of each group were established and compared. Antibodies cloned from the acute-phase plasmablasts of an individual with GBS-AC were also assessed for reactivity against SARS-CoV-2 and peripheral nerve antigens. Sera from GBS patients and from individuals who received COVID-19 vaccinations (n=36: 16 ChAdOx1, 10 Ad26.COV2.S/Janssen, and 10 Tozinameran/Pfizer–BioNTech) without developing GBS were tested for IgG reactivity against SARS-CoV-2 and adenoviral proteins. There were no clinical differences between the GBS groups. Patients with GBS-AC had a greater IgG reactivity to the S1 component of the SARS-CoV-2 spike protein compared to non-GBS COVID-19 controls. A minority of antibodies from cloned plasmablasts targeted SARS-CoV-2 proteins but there was no reactivity or cross reactivity with peripheral nerve antigens or tissue. There were no other serological or immunological differences between the GBS groups. However, when compared to uncomplicated vaccine recipients, GBS patients in toto, and each group individually, demonstrated significantly greater antibody reaction to a range of human adenoviral proteins. Compared to controls exposed to the same immunological stimulus, antibody reactivities to viral antigens are enhanced in patients with GBS. However, we found no mechanistic link between S1 and peripheral nerve reactivity or pathology. Serological responses to adenoviral proteins may be directly involved in the pathogenesis of Guillain-Barré syndrome, potentially contributing to cases with currently unexplained aetiology.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"109 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning-based cell type profiles reveal signatures of Alzheimer's disease resilience and resistance.","authors":"Eloise Berson, Amalia Perna, Syed Bukhari, Yeasul Kim, Lei Xue, David Seong, Samson Mataraso, Marc Ghanem, Alan L Chang, Kathleen S Montine, C Dirk Keene, Maya Kasowski, Nima Aghaeepour, Thomas J Montine","doi":"10.1093/brain/awaf285","DOIUrl":"10.1093/brain/awaf285","url":null,"abstract":"<p><p>Neurological disorders result from the complex and poorly understood contributions of many cell types. It is therefore essential to uncover mechanisms behind these disorders and identify specific therapeutic targets. Single-nucleus technologies have advanced brain disease research, but remain limited by their low nuclear transcriptional coverage, high cost and technical complexity. To address this, we applied a transformer-based deep learning model that restores cell type-specific investigation transcriptional programs from bulk RNA sequencing, significantly outperforming previous methods. This enables large-scale and cost-effective investigation of cell type-specific transcriptomes in complex and heterogeneous phenotypes such as cognitive resilience or brain resistance to Alzheimer's disease. Our analysis identified astrocytes as the major cell mediator of Alzheimer's disease resilience across cerebral cortex regions, while excitatory neurons and oligodendrocyte progenitor cells emerged as the major cell mediators of resistance, maintaining synaptic function and preserving neuron health. Finally, we show that our approach could restore the whole tissue transcriptome, offering an unbiased framework for exploring cell-specific functions beyond single-nucleus data.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3665-3678"},"PeriodicalIF":11.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Remyelination of chronic demyelinated lesions with directly induced neural stem cells.","authors":"","doi":"10.1093/brain/awaf274","DOIUrl":"https://doi.org/10.1093/brain/awaf274","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"18 1","pages":"e94"},"PeriodicalIF":14.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD.","authors":"Andrea Cortese, Maike F Dohrn, Riccardo Curro, Sara Negri, Petra Lassuthova, Chiara Pisciotta, Stefano Tozza, Abdullah Al-Ajmi, Changyong Feng, Pedro J Tomaselli, Gorka Fernandez-Eulate, Saif Haddad, Matilde Laurà, Alexander M Rossor, Elisa Vegezzi, Stefano Facchini, James N Sleigh, Adriana Rebelo, Danique Beijer, Jacquelyn Raposo, Mario Saporta, Barbora Lauerova, Helena F Pernice, Pascal Achenbach, Ulrike Schöne, Tayir Alon, Marcus Deschauer, Isabell Cordts, Carolin D Obermaier, Natalie Winter, Peter D Creigh, Janet E Sowden, Tyler Rehbein, Stefania Magri, Alessandro Bertini, Paola Saveri, Paolo Ripellino, Jingyu Huang, Aleksandra Nadaj-Pakleza, Alison Ross, James K L Holt, Kathryn M Brennan, Rivka Sukenik-Halevy, Varoona Bizaoui, Yesim Parman, Esra Battaloglu, Arman Cakar, Hadil Alrohaif, Simon Hammans, Kishore R Kumar, Marina L Kennerson, Hülya Kayserili, Defne A Amado, Katrin Hahn, Paola Valentino, Francesca Cavalcanti, Carlo Gaetano, Franco Taroni, Geir J Braathen, Henry Houlden, Tanya Stojkovic, Stojan Peric, Alessandra Bolino, Stefano C Previtali, Lee Yi-Chung, Ayşe N Başak, Sherifa A Hamed, Ricardo Rojas-Garcia, Kristl G Claeys, Wilson Marques, Teresa Sevilla, Beate Schlotter-Weigel, Fiore Manganelli, Ruxu Zhang, David N Herrmann, Steven S Scherer, Pavel Seeman, Davide Pareyson, Mary M Reilly, Michael E Shy, Stephan Züchner","doi":"10.1093/brain/awaf021","DOIUrl":"10.1093/brain/awaf021","url":null,"abstract":"<p><p>Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicentre phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available. In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C>A (p.Ala153Asp), while other variants were identified, mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy. Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score ≤ 1). One-fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in a quarter of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion). In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"3737-3747"},"PeriodicalIF":11.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}