Annals of Neurology最新文献

{"title":"A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.","authors":"Ezzat Hashemi, Isha N Srivastava, Alejandro Aguirre, Ezra T Yoseph, Esha Kaushal, Avni Awani, Jae K Ryu, Katerina Akassoglou, Shahrzad Talebian, Pauline Chu, Laura Pisani, Patricia Musolino, Lawrence Steinman, Kristian Doyle, William H Robinson, Orr Sharpe, Romain Cayrol, Paul J Orchard, Troy Lund, Hannes Vogel, Max Lenail, May H Han, Joshua L Bonkowsky, Keith P Van Haren","doi":"10.1002/ana.27117","DOIUrl":"10.1002/ana.27117","url":null,"abstract":"<p><strong>Objective: </strong>X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.</p><p><strong>Methods: </strong>We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.</p><p><strong>Results: </strong>Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.</p><p><strong>Interpretation: </strong>Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2025;97:296-312.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"296-312"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520470","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":"Association of Seizure Control with Mortality, Cognition, and Function in People With Dementia.","authors":"Ifrah Zawar, Mark Quigg, Soutik Ghosal, Vineet Punia, Yamile Calle-Lopez, Carol Manning, Jaideep Kapur","doi":"10.1002/ana.27125","DOIUrl":"10.1002/ana.27125","url":null,"abstract":"<p><strong>Objectives: </strong>The effects of seizure control on outcomes in persons with dementia (PWD) remain unclear. Our study aimed to investigate the impact of seizure control on mortality, function, cognition, and mood among PWD.</p><p><strong>Methods: </strong>This longitudinal, multicenter study is based on 39 Alzheimer's disease centers (ADCs) in the United States from September 2005 to December 2021. PWD were grouped by seizure status into recurrent (seizures in the past year), remote (prior seizures but none in the past year), and no seizures (controls). The primary outcome was all-cause mortality among seizure groups. We used Weibull survival analysis to assess the mortality risks by seizure status after adjusting for age, sex, education, race, ethnicity, hypertension, diabetes, hyperlipidemia, degree of cognitive impairment, dominant Alzheimer's disease (AD) mutation, brain trauma, stroke, Parkinson's disease, alcohol abuse, and depression. Cognition (Clinical Dementia Rating), function (physical dependence and nursing home residence), day-to-day activities (Functional Assessment Scores), and mood (Geriatric Depression Scale) were compared among seizure groups after adjusting for dementia duration and age.</p><p><strong>Results: </strong>Among 26,501 participants, 374 (1.4%) had recurrent seizures and 510 (1.9%) had remote seizures. In multivariable survival analysis, recurrent seizures were associated with a higher mortality risk than remote and no seizures (adjusted hazard ratio [aHR], 95% confidence interval [95% CI]; recurrent aHR = 1.79, 95% CI = 1.51 to 2.12; remote aHR = 1.17, 95% CI = 0.98 to 1.38). Median time-to-death for recurrent, remote, and no seizures was 2.4, 4.0, and 4.7 years, respectively. People with recurrent seizures had worse cognition, day-to-day function, and physical dependence than those with remote seizures and controls.</p><p><strong>Interpretation: </strong>PWD with poorly controlled recurrent seizures have worse mortality, functional, and cognitive outcomes than PWD with remote and no seizures. These findings underscore the need for timely identification and management of ongoing seizures in PWD. ANN NEUROL 2025;97:358-368.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"358-368"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542307","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":"Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept.","authors":"Krzysztof Kamiński, Katarzyna Socała, Michał Abram, Marcin Jakubiec, Katelyn L Reeb, Rhea Temmermand, Mirosław Zagaja, Maciej Maj, Magdalena Kolasa, Agata Faron-Górecka, Marta Andres-Mach, Aleksandra Szewczyk, Mustafa Q Hameed, Andréia C K Fontana, Alexander Rotenberg, Rafał M Kamiński","doi":"10.1002/ana.27124","DOIUrl":"10.1002/ana.27124","url":null,"abstract":"<p><strong>Objective: </strong>Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)-AS-1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.</p><p><strong>Methods: </strong>(R)-AS-1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of (R)-AS-1 on glutamate uptake was assessed in COS-7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of (R)-AS-1 on GLT-1 expression in mice.</p><p><strong>Results: </strong>(R)-AS-1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock- and 6 Hz-induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine-resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, (R)-AS-1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. (R)-AS-1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT-1 expression in vivo was observed after repeated treatment.</p><p><strong>Interpretation: </strong>Collectively, our results show that (R)-AS-1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2025;97:344-357.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"344-357"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602098","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":"Multiple Aneurysms and Cerebral Infarction in a Patient with Sneddon Syndrome.","authors":"Xintong Song, Xingquan Zhao, Qian Zhang, Yi Ju","doi":"10.1002/ana.27110","DOIUrl":"10.1002/ana.27110","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"256-258"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453963","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":"Sex Modifies the Severity and Outcome of Spontaneous Intracerebral Hemorrhage.","authors":"Cyprien A Rivier, Daniela Renedo, Sandro Marini, Jessica R Magid-Bernstein, Adam de Havenon, Jonathan Rosand, Daniel F Hanley, Wendy C Ziai, Stephan A Mayer, Daniel Woo, Lauren H Sansing, Kevin N Sheth, Christopher D Anderson, Guido J Falcone","doi":"10.1002/ana.27123","DOIUrl":"10.1002/ana.27123","url":null,"abstract":"<p><strong>Objective: </strong>The limited existing evidence on sex differences in the clinical characteristics of patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH) comes from small, single-center studies. Here, we performed an individual patient data meta-analysis of 3 randomized clinical trials and 1 multi-ethnic observational study of ICH to investigate the impact of sex on ICH severity and outcome.</p><p><strong>Methods: </strong>Inclusion criteria in our study were a neuroimaging-confirmed ICH. We evaluated whether sex was associated with ICH severity (hematoma volume and expansion) and poor functional outcomes (modified Rankin Scale >3) 3 or 6 months after the ICH.</p><p><strong>Results: </strong>A total of 4,812 ICH patients were evaluated (mean age 62, 40% female). Males with ICH were younger, more likely to be smokers and have diabetes, and less likely to be on anticoagulants (all p < 0.05). In multivariable analyses, male sex was associated with non-lobar location (odds ratio [OR]: 1.63; 95% confidence interval [CI]: [1.39-1.92]; p < 0.001), larger hemorrhages (beta: 0.16 [0.08-0.23]; p < 0.001) and a higher risk of hematoma expansion (OR: 1.43 [1.20-1.71]; p < 0.001). Despite the larger hemorrhage volume and higher risk of expansion, male sex was associated with a 24% lower risk of poor outcomes (OR: 0.76 [0.64-0.90]; p = 0.002).</p><p><strong>Interpretation: </strong>Compared to females, males with ICH have larger bleeds and higher risk of hematoma expansion. Despite the larger bleeds and higher risk of hematoma expansion, males with ICH have lower risk of poor outcomes. Our results suggest that the biology and clinical trajectory are different in females and males with ICH, supporting sex-specific research in this condition. ANN NEUROL 2025;97:232-241.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"232-241"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581142","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":"Distinct Constructs Underlie Patient-Reported and Performance-Rated Outcomes after Stroke.","authors":"Julie A DiCarlo, Abhishek Jaywant, Perman Gochyyev, Anna K Bonkhoff, Richard Hardstone, Kimberly S Erler, Jessica Ranford, Alison Cloutier, Nathan Ward, Kelly L Sloane, Lee H Schwamm, Steven C Cramer, David J Lin","doi":"10.1002/ana.27129","DOIUrl":"10.1002/ana.27129","url":null,"abstract":"<p><strong>Objective: </strong>Patient-reported outcome measures (PROMs), which capture patients' perspectives on the consequences of health and disease, are widely used in neurological care and research. However, it is unclear how PROMs relate to performance-rated impairments. Sociodemographic factors are known to affect PROMs. Direct damage to brain regions critical for self-awareness (i.e., parietal regions and the salience/ventral-attention network) may also impair self-report outcomes. This study examined the relationship between PROMs and performance-based measures in stroke survivors with arm motor impairments. We hypothesized that PROMs would be distinct from performance-based outcomes, influenced by sociodemographic factors, and linked to damage in brain circuits involved in self-perception.</p><p><strong>Methods: </strong>We longitudinally assessed 54 stroke survivors using patient-reported and performance-rated measures at 4 timepoints. We used factor analysis to reveal the outcome battery's factorial structure. Linear regression examined the association between classes of measures and sociodemographics. Voxel-lesion-symptom-mapping, region-of-interest-based analysis, and voxel-lesion-network-mapping investigated the relationship between classes of outcomes and stroke-related injury.</p><p><strong>Results: </strong>Performance-based and patient-reported measures formed distinct factors, consistent across recovery phases. Higher education (β1 = 0.36, p = 0.02) and income adequacy (β2 = 0.48, p = 0.05) were associated with patient-reported, but not performance-rated outcomes. Greater parietal lobe injury, irrespective of hemisphere, was associated with worse patient-reported outcomes; greater corticospinal tract injury related to worse performance-rated outcomes. Lesions with greater functional connectivity to the salience/ventral-attention network were associated with worse patient-reported outcomes (r = -0.35, p = 0.009).</p><p><strong>Interpretation: </strong>Our findings reveal important differences between performance-rated and patient-reported outcomes, each with specific associated factors and anatomy post-stroke. Incorporating sociodemographic and neuroanatomic characteristics into neurorehabilitation strategies may inform and optimize patient outcomes. ANN NEUROL 2025;97:242-253.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"242-253"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613157","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":"Efficacy and Safety of Sodium Oxybate in Isolated Focal Laryngeal Dystonia: A Phase IIb Double-Blind Placebo-Controlled Cross-Over Randomized Clinical Trial.","authors":"Kristina Simonyan, Lena C O'Flynn, Azadeh Hamzehei Sichani, Steven J Frucht, Anna F Rumbach, Nutan Sharma, Phillip C Song, Alexis Worthley","doi":"10.1002/ana.27121","DOIUrl":"10.1002/ana.27121","url":null,"abstract":"<p><strong>Objective: </strong>To examine the efficacy and safety of sodium oxybate versus placebo in a phase IIb randomized double-blind placebo-controlled 2-period cross-over clinical trial in patients with isolated laryngeal dystonia (LD).</p><p><strong>Methods: </strong>The study was conducted from January 2018 to December 2021, pausing during the COVID-19 pandemic, at Massachusetts Eye and Ear in 106 patients with alcohol-responsive (EtOH+) and alcohol-non-responsive (EtOH-) LD (53 to receive 1.5g of sodium oxybate first, 53 to receive matching placebo first). The primary outcome was a change from baseline in LD symptom severity 40 minutes after drug intake. Safety was based on vital signs, cognitive function, suicidality, daytime sleepiness, and adverse events. Patients, investigators, and outcome assessors were masked to study procedures.</p><p><strong>Results: </strong>Compared to baseline, EtOH+ but not EtOH- patients had a statistically significant improvement in LD symptoms following sodium oxybate versus placebo (EtOH+: 98.75% confidence interval [CI] = 0.6-26.9; p = 0.008; EtOH-: 98.75% CI = -6.2 to 18.7; p = 0.42). Statistically significant minimum drug efficacy in EtOH+ patients was found at ≥16% symptom improvement (OR = 2.09; 98.75% CI = 0.75-5.80; p = 0.036), with an average of 40.81% benefits (98.75% CI = 34.7-48.6). Drug efficacy waned by 300 minutes after intake without a rebound. No changes were found in cognitive function, suicidality, or vital signs. Common adverse events included mild dizziness, nausea, and daytime sleepiness.</p><p><strong>Interpretation: </strong>Sodium oxybate showed clinically meaningful improvement of symptoms in EtOH+ LD patients, with acceptable tolerability. Sodium oxybate offers the first pathophysiologically relevant oral treatment for laryngeal dystonia. ANN NEUROL 2025;97:329-343.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"329-343"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674623","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":"Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.","authors":"Kevin van Veenhuijzen, Harold H G Tan, Abram D Nitert, Michael A van Es, Jan H Veldink, Leonard H van den Berg, Henk-Jan Westeneng","doi":"10.1002/ana.27116","DOIUrl":"10.1002/ana.27116","url":null,"abstract":"<p><strong>Objective: </strong>We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).</p><p><strong>Methods: </strong>We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan.</p><p><strong>Results: </strong>Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters.</p><p><strong>Interpretation: </strong>Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2025;97:281-295.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"281-295"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563593","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":"In Memoriam - Charles Warren Olanow, MD.","authors":"Karl Kieburtz, Barbara G Vickrey","doi":"10.1002/ana.27187","DOIUrl":"https://doi.org/10.1002/ana.27187","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031609","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":"Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum.","authors":"Sandra Coppens, Nicolas Deconinck, Patricia Sullivan, Andrei Smolnikov, Joshua S Clayton, Kaitlyn R Griffin, Kristi J Jones, Catheline N Vilain, Hazim Kadhim, Samantha J Bryen, Fathimath Faiz, Leigh B Waddell, Frances J Evesson, Madhura Bakshi, Jason R Pinner, Amanda Charlton, Susan Brammah, Nicole S Graf, Michael Krivanek, Chee Geap Tay, Nicola C Foulds, Marjorie A Illingworth, Neil H Thomas, Sian Ellard, Ingrid Mazanti, Soo-Mi Park, Courtney E French, Jennifer Brewster, Gusztav Belteki, Shazia Hoodbhoy, Kieren Allinson, Deepa Krishnakumar, Gareth Baynam, Bradley M Wood, Michelle Ward, Kayal Vijayakumar, Amber Syed, Archana Murugan, Anirban Majumdar, Ingrid J Scurr, Miranda P Splitt, Corina Moldovan, Deepthi C de Silva, Kumudu Senanayake, Thatjana Gardeitchik, Yvonne Arens, Sandra T Cooper, Nigel G Laing, F Lucy Raymond, Heinz Jungbluth, Erik-Jan Kamsteeg, Adnan Manzur, Susan M Corley, Gianina Ravenscroft, Marc R Wilkins, Mark J Cowley, Mark Pinese, Rahul Phadke, Mark R Davis, Francesco Muntoni, Emily C Oates","doi":"10.1002/ana.27087","DOIUrl":"https://doi.org/10.1002/ana.27087","url":null,"abstract":"<p><p>Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.</p><p><strong>Objective: </strong>To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.</p><p><strong>Methods: </strong>We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.</p><p><strong>Results: </strong>Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant.</p><p><strong>Interpretation: </strong>This study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031606","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}