Neurology最新文献

{"title":"Association of Plasma Biomarkers With Longitudinal Atrophy and Microvascular Burden on MRI Across Neurodegenerative and Cerebrovascular Diseases.","authors":"Erlan Sanchez, Gillian T Coughlan, Tim Wilkinson, Joel Ramirez, Saira Saeed Mirza, Andrée-Ann Baril, Allison A Dilliott, Andrew Frank, Anthony E Lang, Ayman Hassan, Bruce G Pollock, Christopher J M Scott, Connie Marras, Corinne E Fischer, Dallas Seitz, Daniela Andriuta, Dar Dowlatshahi, David A Grimes, David F Tang-Wai, Demetrios J Sahlas, Ekaterina A Rogaeva, Elizabeth Finger, John F Robinson, Kubra Tan, Malcolm A Binns, Maria Carmela Tartaglia, Michael J Borrie, Michael J Strong, Miracle Ozzoude, Nuwan D Nanayakkara, Rafaella A Goncalves, Robert Bartha, Robert A Hegele, Sali M K Farhan, Sandra E Black, Sanjeev Kumar, Sean P Symons, Seyyed M H Haddad, Stephen H Pasternak, Stephen R Arnott, Tarek K Rajji, Thomas Steeves, Walter Swardfager, Nicholas J Ashton, Hlin Kvartsberg, Henrik Zetterberg, Douglas P Munoz, Mario Masellis","doi":"10.1212/WNL.0000000000213438","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213438","url":null,"abstract":"<p><strong>Background and objectives: </strong>Plasma biomarkers of Alzheimer disease (AD), neuroinflammation, and neurodegeneration are increasingly being used in clinical trials for diagnosis and monitoring of dementia. However, their association with longitudinal structural brain MRI changes, an important outcome measure across neurodegenerative and cerebrovascular diseases, is less known. We investigated how baseline plasma biomarkers reflect MRI markers of progression over time in patients with neurodegenerative and cerebrovascular diseases.</p><p><strong>Methods: </strong>This longitudinal cohort study included patients from the Ontario Neurodegenerative Disease Research Initiative diagnosed with AD or mild cognitive impairment (AD/MCI), Parkinson disease (PD), frontotemporal dementia spectrum disorders (FTD), or cerebrovascular disease (CVD), followed annually for 2 years. Recruitment took place at specialized university-based dementia, movement disorders, and/or stroke clinics in the province of ON, Canada. MRI outcomes included markers of cerebral atrophy (ventricular CSF and regional gray matter volumes) and of small vessel disease pathology (white matter hyperintensity [WMH], perivascular spaces, and lacunar volumes). Hemorrhagic markers at baseline were also included. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau181 and tau217 (p-tau181, p-tau217), and β-amyloid (Aβ_42/40) were quantified from blood samples collected at baseline using Simoa and used as predictors in linear mixed models adjusted for time (months), age, sex, apolipoprotein E (<i>APOE</i>)-ε4 carrier status, kidney function, vascular risk factors, microtubule-associated protein tau (<i>MAPT</i>) diplotypes, waist-hip circumference ratio, and disease duration.</p><p><strong>Results: </strong>We analyzed 1,240 MRIs from 473 patients (age: 69.2 ± 7.4 [range: 49-87]; 32.8% women). Elevated baseline levels of GFAP, NfL, p-tau181, and p-tau217, and to a lesser extent decreased levels of Aβ_42/40, were significantly associated with more cerebral atrophy and WMH burden at baseline (|<i>B</i>| = 0.02 to 1.69, <i>p</i> = 0.044 to <0.001) and with progression over time (|<i>B</i>| = 0.001 to 0.028, <i>p</i> = 0.049 to <0.001) in the pooled disease-agnostic group. Within disease-specific cohorts, GFAP and NfL were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, PD, FTD, or CVD. P-tau181 and p-tau217 were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, CVD, PD-MCI, or PD-dementia.</p><p><strong>Discussion: </strong>Selected plasma biomarkers seem useful as prognosis and monitoring tools of longitudinal imaging changes within real-world populations of neurodegenerative and/or cerebrovascular diseases, and provide insight into overlap across diseases in shared pathologic burden.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e213438"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597044","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":"Neurodegeneration and Demyelination in the Multiple Sclerosis Spinal Cord: Clinical, Pathological, and 7T MRI Perspectives.","authors":"Kedar R Mahajan, Danielle Herman, Yufan Zheng, Caroline Androjna, Bhaskar Thoomukuntla, Daniel Ontaneda, Kunio Nakamura, Bruce D Trapp","doi":"10.1212/WNL.0000000000210259","DOIUrl":"10.1212/WNL.0000000000210259","url":null,"abstract":"<p><strong>Background and objectives: </strong>Key findings in people with multiple sclerosis (MS) with progressive motor disability are spinal cord (SC) atrophy signifying irreversible axonal loss and SC demyelinated lesions. This study aimed to identify neurodegenerative changes and assess the clinical impact and pathologic characteristics of SC lesions.</p><p><strong>Methods: </strong>A cross-sectional study was performed using postmortem cervical cord segments from the Cleveland Clinic MS Rapid Autopsy Program. Inclusion included proximity to our center, absence of transmissible infections, and lack of prolonged hypoxia. In situ MRIs were performed before tissue removal and fixation followed by 7T MRI and immunohistochemistry. Quantitative T2* relaxation times were correlated with myelin, axons, and activated microglia/macrophages (major histocompatibility complex II [MHCII]) using Tukey comparison of means and a linear mixed-effects model; T2* was correlated with clinical disease characteristics using Wilcoxon rank sum.</p><p><strong>Results: </strong>The study included 40 MS cases (median age 58, female 55%) and 9 controls (median age 69, female 89%). A T2* threshold reliably discriminated demyelination (accuracy 89.7%, sensitivity 95.5%, and specificity 87.0%). Myelin content (95% CI -0.82 to -0.58, estimate -0.70) was the only significant predictor of T2*. T2* hyperintensities within the segments ranged from 0% to 100% (median 33.6, interquartile range 12.9-64.3) with only 57.1% demyelinated. T2*-hyperintense/myelinated regions had increased T2* relaxation time (19.2 ms, 95% CI 9.97-28.4), reduced myelin content (-8.3%, 95% CI -12.1 to -4.4), increased MHCII (3.6%, 95% CI 0.45-6.7), reduced axonal counts (-349.8, 95% CI -565.4 to -134.1), and increased axonal area (2.0 µm², 95% CI 1.0-3.1) compared with normal-appearing MRI regions. These regions occurred adjacent to T2*-hyperintense/demyelinated lesions (periplaque) or along tracts (tract-based). 7T postmortem T2* hyperintensities were subtle on clinical 1.5T axial T2, and only 43% were detected sagittally. T2*-hyperintense/demyelinated lesions correlated with Expanded Disability Status Scale (EDSS) (rho = 0.61, <i>p</i> < 0.0001) and upper cervical cord area (rho = -0.64, <i>p</i> < 0.0001) while T2*-hyperintense/myelinated regions did not.</p><p><strong>Discussion: </strong>Thresholding 7T T2* postmortem MRI can effectively discriminate demyelinated lesions which correlate with clinical disability and cord atrophy. T2*-hyperintense/myelinated regions exhibit myelin and axonal pathology in periplaque or tract-based distributions suggestive of neurodegeneration. Limitations include sampling of 2-cm of SC across participants making conclusions about proximal and distal pathology difficult.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e210259"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625432","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":"Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures.","authors":"Luca Bergonzini, Sara Carli, Silvia Pelle, Ilaria Pettenuzzo, Silvia Bonetti, Erika Santi, Caterina Visconti, Monica Maffei, Marta Sheremet, Eleonora Lamantea, Andrea Marsala, Olena Klub, Valentina Gentile, Duccio Maria Cordelli, Caterina Garone","doi":"10.1212/WNL.0000000000213373","DOIUrl":"10.1212/WNL.0000000000213373","url":null,"abstract":"<p><strong>Objective: </strong>Recessive variants in the <i>TK2</i> gene cause thymidine kinase 2 deficiency (TK2d) presenting with infantile, childhood, or adult-onset myopathy. CNS involvement is reported in only 25% of the infantile form. Compassionate use of deoxynucleoside substrate enhancement therapy (dC/dT) has been demonstrated safe and effective in TK2d myopathy, but no data are available on the potential efficacy on the human brain disease.</p><p><strong>Methods: </strong>Here, we report for the first time a patient with infantile TK2d epileptic encephalomyopathy enrolled in an early access program with dC/dT treatment (MT1621).</p><p><strong>Results: </strong>At age 3 months, he presented progressive hypotonia, motor regression, failure to thrive, and respiratory failure. At age 8 months, he developed drug-resistant epilepsy with migrating focal seizures. Brain MRI showed progressive atrophy and bilateral subcortical lesions with lactate peak. Exome sequencing revealed 2 novel biallelic heterozygous variants in the <i>TK2</i> gene (c.182G>A, p.Ser61Asn, c.704 T>C, p.Ile235Thr) whose pathogenicity was confirmed with in vitro studies. Early access compassionate use of dC/dT at 400 mg/kg prolonged the survival and stabilized the muscle disease but was not effective on the brain.</p><p><strong>Discussion: </strong>Our report highlights the importance of deep-phenotyping infantile TK2d before dC/dT supplementation to stratify disease severity further and suggests a limited tissue-specific brain efficacy.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e213373"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557402","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":"Case of Pure Agraphia in Kana and Romaji Without Sensorimotor Deficits After a Small Infarct of the Posterior Limb of the Internal Capsule.","authors":"Kazuto Katsuse, Akatsuki Kubota, Kazuo Kakinuma, Shoko Ota, Shigenori Kanno, Toshiyuki Kakumoto, Yuichiro Shirota, Masashi Hamada, Tatsushi Toda, Kyoko Suzuki","doi":"10.1212/WNL.0000000000210254","DOIUrl":"10.1212/WNL.0000000000210254","url":null,"abstract":"<p><strong>Objectives: </strong>Infarctions of the posterior limb of the internal capsule (plIC) typically cause contralateral motor deficits. Cases with pure agraphia, writing impairments alone, are rare. We present a case of agraphia as the sole symptom after a small infarction in the anterior portion of the left plIC, which facilitates understanding of the interplay between the subcortical and cortical networks controlling writing.</p><p><strong>Methods: </strong>This study evaluated a 62-year-old right-handed Japanese man presenting with difficulties in typing and writing. In addition to neuropsychological assessments, diffusion tensor tractography and brain perfusion scintigraphy were used to analyze subcortical-cortical network disruptions.</p><p><strong>Results: </strong>Neuropsychological tests revealed selective agraphia in Kana and Romaji, characterized by phonological errors, but intact Kanji writing. Neuroimaging revealed disrupted neural fibers connecting the thalamus to the superior and middle frontal gyri and mild hypoperfusion in the middle frontal cortex.</p><p><strong>Discussion: </strong>Selective impairment of thalamic radiation projecting to the left frontal cortex due to the plIC infarction can result in pure agraphia. Our findings suggest a specific role of the left anterior plIC in writing Kana and Romaji, specifically in sound-to-letter conversion and postorthographic processes. This case underscores the importance of evaluating writing ability in patients with plIC infarctions to avoid overlooking agraphia.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e210254"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11902897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605850","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":"Ictal Hyperperfusion Highlights the Right Mesial Parietal Heading Direction System in Roller Coaster Reflex Epilepsy.","authors":"David N Vaughan, Chris Tailby, Marty Bryant, Alexander Berry-Noronha, John S Archer, Graeme D Jackson","doi":"10.1212/WNL.0000000000213494","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213494","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e213494"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597285","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":"Teaching NeuroImage: Use of Intraoperative Indocyanine Green Angiography to Demonstrate Multiple Spinal Dural Arteriovenous Fistulas.","authors":"Xiaodong Niu, Si Cai, Jin Li","doi":"10.1212/WNL.0000000000213452","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213452","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e213452"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605907","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":"To Kill Time: A Bold Step Toward Simplifying Multiple Sclerosis Diagnosis.","authors":"Angela Vidal-Jordana, Daniel Ontaneda","doi":"10.1212/WNL.0000000000213416","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213416","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e213416"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557424","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":"Risk of Ischemic and Hemorrhagic Stroke in Individuals With Type 1 and Type 2 Diabetes: A Nationwide Cohort Study in Sweden.","authors":"Anastasios Mavridis, Adam Viktorisson, Björn Eliasson, Mia von Euler, Katharina S Sunnerhagen","doi":"10.1212/WNL.0000000000213480","DOIUrl":"10.1212/WNL.0000000000213480","url":null,"abstract":"<p><strong>Background and objectives: </strong>Diabetes significantly increases the risk of cardiovascular events, including stroke. Although the association with ischemic stroke is well established, the relationship with hemorrhagic stroke remains unclear. This study aimed to evaluate the risk of ischemic and hemorrhagic stroke in individuals with type 1 and type 2 diabetes compared with diabetes-free controls from the general population.</p><p><strong>Methods: </strong>This cohort study included individuals with type 1 or type 2 diabetes from the Swedish National Diabetes Register between 2005 and 2019, matched to diabetes-free controls by age and sex. Data on baseline characteristics, comorbidities, medications, and outcomes were collected from multiple national registers. Stroke incidence rates and adjusted hazard ratios were estimated using Cox proportional hazard models, stratified by diabetes type, for ischemic and hemorrhagic stroke.</p><p><strong>Results: </strong>The study included 47,720 individuals with type 1 diabetes (mean age 34.4, 44.8% female) and 686,158 with type 2 diabetes (mean age 65.3, 43.3% female), matched to 143,160 and 2,058,474 controls, respectively. In individuals with type 1 diabetes, the ischemic stroke risk was 2.54 times higher (95% CI 2.36-2.73) and the hemorrhagic stroke risk was 1.88 times higher (95% CI 1.57-2.26) compared with controls. In individuals with type 2 diabetes, the ischemic stroke risk was 1.37 times higher (95% CI 1.35-1.38) while the hemorrhagic stroke risk was not significantly increased (HR: 0.99, 95% CI 0.96-1.02). Higher HbA1c levels were associated with increased ischemic stroke risk for both diabetes types. For hemorrhagic stroke, individuals with type 1 diabetes had significantly higher risk starting at HbA1c > 52 mmol/mol while in those with type 2 diabetes, a modest risk increase was observed only at HbA1c > 72 mmol/mol.</p><p><strong>Discussion: </strong>The risk of ischemic stroke was higher for both diabetes types. Individuals with type 1 diabetes also exhibited a higher risk of hemorrhagic stroke compared with diabetes-free controls while type 2 diabetes was significantly associated with risk of hemorrhagic stroke only when HbA1c was higher than 72 mmol/mol. These findings highlight the increased stroke risk in diabetes, with distinct patterns by stroke subtype and diabetes type. Tailored prevention strategies are essential to address these differences.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e213480"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625435","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":"Editors' Note: Domestic Violence and Abuse in People Living With Multiple Sclerosis.","authors":"Aravind Ganesh, Steven L Galetta","doi":"10.1212/WNL.0000000000213407","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213407","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e213407"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573568","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-Phenotype Landscape of <i>NALCN</i> and <i>UNC80</i>-Related Disorders.","authors":"Paloma Parra-Díaz, Arnaud Monteil, Daniel Calame, Nawale Hadouiri, Luca Soliani, Egidio Spinelli, Elena Jabbour Caron, Klaus Dieterich, Amy Kritzer, Kacie Riley, Jose M Serratosa Fernández, Jeremy A Tanner, Hélène Tevissen, Christel Thauvin, Rafael Vera-Medialdea, Stephan M Waltz, Álvaro Beltrán-Corbellini, Irene García Morales, Irene Sánchez-Miranda Román, Rafael Toledano, Adrián Valls-Carbó, Antonio Gil-Nagel","doi":"10.1212/WNL.0000000000213429","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213429","url":null,"abstract":"<p><strong>Background and objectives: </strong>The NALCN channelosome regulates the resting membrane potential through sodium leak currents, influencing cellular excitability. Genetic variants in <i>NALCN</i> and <i>UNC80</i>, a subunit of the NALCN channelosome, cause ultra-rare and severe neurodevelopmental disorders. Autosomal dominant congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome is associated with gain-of-function (GOF) variants in <i>NALCN</i>. Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) 1 syndrome is associated with biallelic variants in <i>NALCN</i> and IHPRF 2 syndrome with biallelic variants in <i>UNC80</i>, both resulting in a loss-of-function (LOF). This study aims to expand the phenotypes associated with these syndromes, exploring potential genotype-phenotype associations.</p><p><strong>Methods: </strong>This is a cross-sectional study including patients with pathogenic or likely pathogenic variants in <i>NALCN</i> and <i>UNC80</i>. Phenotypes were evaluated through a structured interview, questionnaires, and review of medical records. Associations between variants, clinical features, and syndromes were analyzed.</p><p><strong>Results: </strong>Fifty-one patients were included (34 with CLIFAHDD, 9 with IHPRF 1, 8 with IHPRF 2; 3 months-27 years; 37.3% female). All exhibited neurodevelopmental delay, more severe in patients with LOF variants (<i>p</i> = 0.019). Neurodevelopmental regression was observed in 29.4% of patients with CLIFAHDD syndrome, associated with the onset of ataxia (70%). Patients with CLIFAHDD had more severe respiratory symptoms at birth (11.7% orotracheal intubation). Distal arthrogryposis (76.5%), episodic ataxia (41.2% of ambulatory patients), and paroxysmal dystonia (11.7%) were exclusively diagnosed in patients with CLIFAHDD. Patients with LOF variants presented more frequently with failure to thrive (88.2%, <i>p</i> = 0.001), central sleep apnea (CSA, 64.7%, <i>p</i> < 0.001), and epilepsy (70.6%, <i>p</i> < 0.001). Epilepsy was associated with more severe cognitive delays (<i>p</i> = 0.016) and was refractory in 58.8% of patients. Earlier seizure onset was associated with refractory epilepsy (<i>p</i> = 0.014). Patients with CLIFAHDD and premature death, epilepsy, or paroxysmal dystonia carried variants within NALCN pore domains.</p><p><strong>Discussion: </strong>This study provides an in-depth clinical characterization of <i>NALCN</i>-related and <i>UNC80</i>-related disorders. Distal arthrogryposis, episodic ataxia, and paroxysmal dystonia were diagnosed in patients with CLIFAHDD while failure to thrive, CSA, and epilepsy were associated with LOF variants. We suggest potential genotype-phenotype associations, formulating hypotheses for validation in future studies with larger cohorts.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"104 7","pages":"e213429"},"PeriodicalIF":7.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573574","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}