Neurology-Genetics最新文献

{"title":"CGG/CCG Repeat Expansions in <i>LOC642361/NUTM2B-AS1</i> in Thai Patients With Oculopharyngodistal Myopathy.","authors":"Sunsanee Pongpakdee, Metha Apiwattanakul, Thanes Termglinchan, Rawiphan Witoonpanich, Charungthai Dejthevaporn, Theeraphong Lee, Supika Wansophonkul, Ai Yamanaka, Shunsuke Funaguma, Aritoshi Lida, Ichizo Nishino","doi":"10.1212/NXG.0000000000200170","DOIUrl":"10.1212/NXG.0000000000200170","url":null,"abstract":"<p><strong>Objectives: </strong>This study characterizes oculopharyngodistal myopathy in 4 Thai patients from 3 families with CGG/CCG repeat expansion in <i>LOC642361/NUTM2B-AS1</i>.</p><p><strong>Methods: </strong>Repeat-primed PCR analyzed CGG/CCG repeat size in <i>LOC642361/NUTM2B-AS1</i> in 4 Thai patients suspected of oculopharyngodistal myopathy (OPDM). Clinical records were reviewed for clinicopathologic features.</p><p><strong>Results: </strong>All patients exhibited strong somatic instabilities of the expanded CGG/CCG repeats, primarily manifesting as oculopharyngeal weakness. Patient 1 had mild finger extensor and intrinsic hand muscle weakness, and although patient 2 lacked limb weakness, both siblings showed electrophysiologic evidence of distal myopathy, indicative of OPDM. Patient 3, the daughter of a sibling with OPDM reported in 2004, lacked limb weakness or leukoencephalopathy on brain MRI. Patient 4, initially misdiagnosed with refractory myasthenia gravis, had generalized muscle weakness.</p><p><strong>Discussion: </strong>While initially characterized as oculopharyngeal myopathy with leukoencephalopathy (OPML) in a Japanese family, our study suggests a stronger association between CGG/CCG expansion in <i>LOC642361/NUTM2B-AS1</i> and oculopharyngodistal myopathy (OPDM) rather than OPML. The variable presence or absence of leukoencephalopathy further supports OPDM as the predominant clinical manifestation linked to CGG/CCG expansion in <i>LOC642361/NUTM2B-AS1</i>.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 4","pages":"e200170"},"PeriodicalIF":3.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142298995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Genetic Variant in <i>HUWE1</i>: Prenatal and Postnatal Neuroimaging Phenotype.","authors":"Mario Tortora, Elisa Cattaneo, Luigina Spaccini, Maria Iascone, Barbara Scelsa, Alessia Micalizzi, Antonio Novelli, Mariano Lanna, Andrea Righini, Pierangelo Veggiotti, Chiara Doneda","doi":"10.1212/NXG.0000000000200169","DOIUrl":"10.1212/NXG.0000000000200169","url":null,"abstract":"<p><strong>Objectives: </strong>To provide a comprehensive description of neuroradiologic findings in a patient with a probable pathogenic variant of <i>HUWE1</i>, particularly in relation to pontine and cerebellar hypoplasia.</p><p><strong>Methods: </strong>We first report prenatal and postnatal neuroradiologic phenotype of a female patient carrying a <i>HUWE1</i> likely pathogenic variant and discuss its function.</p><p><strong>Results: </strong>An ultrasound shows borderline ventriculomegaly, rotated cerebellar vermis, and dysgenetic corpus callosum. An MR study identify a short, thin corpus callosum, falcine sinus persistence, reduced cerebellar vermis size, wide inferior IV ventricle, and reduced pontine bulging.</p><p><strong>Discussion: </strong><i>HUWE1</i> is a gene encoding an E3 ubitiquine ligase protein involved in nervous system development, function, and disease. The mechanisms by which <i>HUWE1</i> gene affects nervous system are still largely unclear, but a growing body of literature described disease-causing variants in this gene. This report may help prenatal diagnostic experts in consider also this entity, especially when dealing with pontine and cerebellar hypoplasia findings.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 4","pages":"e200169"},"PeriodicalIF":3.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRI Insights in Hypomyelinating Disorders With Early Myelination Disturbances.","authors":"Prateek Malik, Bidkar Sayli U, Benjamin B Mathew, Maya Thomas, Sangeetha Yoganathan","doi":"10.1212/NXG.0000000000200165","DOIUrl":"10.1212/NXG.0000000000200165","url":null,"abstract":"","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 4","pages":"e200165"},"PeriodicalIF":3.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease Progression and Multiparametric Imaging Characteristics of Spinocerebellar Ataxia Type 3 With Spastic Paraplegia.","authors":"Zhi-Xian Ye, Hao-Ling Xu, Na-Ping Chen, Xin-Yuan Chen, Meng-Cheng Li, Ru-Ying Yuan, Wei Lin, Liangliang Qiu, Minting Lin, Wan-Jin Chen, Ning Wang, Jian-Ping Hu, Ying Fu, Shi-Rui Gan","doi":"10.1212/NXG.0000000000200162","DOIUrl":"10.1212/NXG.0000000000200162","url":null,"abstract":"<p><strong>Background and objectives: </strong>Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia that occurs worldwide. Clinical patterns were observed, including the one characterized by marked spastic paraplegia. This study investigated the clinical features, disease progression, and multiparametric imaging aspects of patients with SCA3.</p><p><strong>Methods: </strong>We retrospectively analyzed 249 patients with SCA3 recruited from the Organization for Southeast China for cerebellar ataxia research between October 2014 and December 2020. Of the 249 patients, 145 were selected and assigned to 2 groups based on neurologic examination: SCA3 patients with spastic paraplegia (SCA3-SP) and SCA3 patients with nonspastic paraplegia (SCA3-NSP). Participants underwent 3.0-T brain MRI examinations, and voxel-wise and volume-of-interest-based approaches were used for the resulting images. A tract-based spatial statistical approach was used to investigate the white matter (WM) alterations using diffusion tensor imaging, neurite orientation dispersion, and density imaging metrics. Multiple linear regression analyses were performed to compare the clinical and imaging parameters between the 2 groups. The longitudinal data were evaluated using a linear mixed-effects model.</p><p><strong>Results: </strong>Forty-three patients with SCA3-SP (mean age, 37.58years ± 11.72 [SD]; 18 women) and 102 patients with SCA3-NSP (mean age, 47.42years ± 12.50 [SD]; 39 women) were analyzed. Patients with SCA3-SP were younger and had a lower onset age but a larger cytosine-adenine-guanine repeat number, as well as higher clinical severity scores (all corrected <i>p</i> < 0.05). The estimated progression rates of the Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale scores were higher in the SCA3-SP subgroup than in the SCA3-NSP subgroup (SARA, 2.136 vs 1.218 points; ICARS, 5.576 vs 3.480 points; both <i>p</i> < 0.001). In addition, patients with SCA3-SP showed gray matter volume loss in the precentral gyrus with a decreased neurite density index in the WM of the corticospinal tract and cerebellar peduncles compared with patients with SCA3-NSP.</p><p><strong>Discussion: </strong>SCA3-SP differs from SCA3-NSP in clinical features, multiparametric brain imaging findings, and longitudinal follow-up progression.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 3","pages":"e200162"},"PeriodicalIF":3.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11152645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>TARDBP</i> Mutations in Facial-Onset Sensory and Motor Neuronopathy.","authors":"Vincent Picher-Martel, Suma Babu, Anthony A Amato","doi":"10.1212/NXG.0000000000200160","DOIUrl":"10.1212/NXG.0000000000200160","url":null,"abstract":"<p><strong>Objectives: </strong>Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined.</p><p><strong>Methods: </strong>A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel.</p><p><strong>Results: </strong>The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/<i>TARDBP</i>). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that <i>TARDBP</i> mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including <i>C9ORF72</i> or <i>SOD1</i>, are respectively absent or rare in FOSMN.</p><p><strong>Discussion: </strong>FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically <i>TARDBP</i> should be considered in patients with FOSMN.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 3","pages":"e200160"},"PeriodicalIF":3.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11152643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting the Shared Genetic Architecture of Common Epilepsies With Cortical Brain Morphology.","authors":"Naz Karadag, Espen Hagen, Alexey A Shadrin, Dennis van der Meer, Kevin S O'Connell, Zillur Rahman, Gleda Kutrolli, Nadine Parker, Shahram Bahrami, Vera Fominykh, Kjell Heuser, Erik Taubøll, Nils Eiel Steen, Srdjan Djurovic, Anders M Dale, Oleksandr Frei, Ole A Andreassen, Olav B Smeland","doi":"10.1212/NXG.0000000000200143","DOIUrl":"10.1212/NXG.0000000000200143","url":null,"abstract":"<p><strong>Background and objectives: </strong>Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We investigated the extent to which these phenotypes share genetic influences.</p><p><strong>Methods: </strong>We analyzed genome-wide association study data on common epilepsies (n = 69,995) and TH and SA (n = 32,877) using Gaussian mixture modeling MiXeR and conjunctional false discovery rate (conjFDR) analysis to quantify their shared genetic architecture and identify overlapping loci. We biologically interrogated the loci using a variety of resources and validated in independent samples.</p><p><strong>Results: </strong>The epilepsies (2.4 k-2.9 k variants) were more polygenic than both SA (1.8 k variants) and TH (1.3 k variants). Despite absent genome-wide genetic correlations, there was a substantial genetic overlap between SA and genetic generalized epilepsy (GGE) (1.1 k), all epilepsies (1.1 k), and juvenile myoclonic epilepsy (JME) (0.7 k), as well as between TH and GGE (0.8 k), all epilepsies (0.7 k), and JME (0.8 k), estimated with MiXeR. Furthermore, conjFDR analysis identified 15 GGE loci jointly associated with SA and 15 with TH, 3 loci shared between SA and childhood absence epilepsy, and 6 loci overlapping between SA and JME. 23 loci were novel for epilepsies and 11 for cortical morphology. We observed a high degree of sign concordance in the independent samples.</p><p><strong>Discussion: </strong>Our findings show extensive genetic overlap between generalized epilepsies and cortical morphology, indicating a complex genetic relationship with mixed-effect directions. The results suggest that shared genetic influences may contribute to cortical abnormalities in epilepsies.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 3","pages":"e200143"},"PeriodicalIF":3.1,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptive and Innate Immunity Are Key Drivers of Age at Onset of Multiple Sclerosis.","authors":"Elina Misicka, Yunfeng Huang, Stephanie Loomis, Nilanjana Sadhu, Elizabeth Fisher, Arie Gafson, Heiko Runz, Ellen Tsai, Xiaoming Jia, Ann Herman, Paola G Bronson, Tushar Bhangale, Farren B Briggs","doi":"10.1212/NXG.0000000000200159","DOIUrl":"10.1212/NXG.0000000000200159","url":null,"abstract":"<p><strong>Background and objectives: </strong>Multiple sclerosis (MS) age at onset (AAO) is a clinical predictor of long-term disease outcomes, independent of disease duration. Little is known about the genetic and biological mechanisms underlying age of first symptoms. We conducted a genome-wide association study (GWAS) to investigate associations between individual genetic variation and the MS AAO phenotype.</p><p><strong>Methods: </strong>The study population was comprised participants with MS in 6 clinical trials: ADVANCE (N = 655; relapsing-remitting [RR] MS), ASCEND (N = 555; secondary-progressive [SP] MS), DECIDE (N = 1,017; RRMS), OPERA1 (N = 581; RRMS), OPERA2 (N = 577; RRMS), and ORATORIO (N = 529; primary-progressive [PP] MS). Altogether, 3,905 persons with MS of European ancestry were analyzed. GWAS were conducted for MS AAO in each trial using linear additive models controlling for sex and 10 principal components. Resultant summary statistics across the 6 trials were then meta-analyzed, for a total of 8.3 × 10^-6 single nucleotide polymorphisms (SNPs) across all trials after quality control and filtering for heterogeneity. Gene-based tests of associations, pathway enrichment analyses, and Mendelian randomization analyses for select exposures were also performed.</p><p><strong>Results: </strong>Four lead SNPs within 2 loci were identified (<i>p</i> < 5 × 10^-8), including a) 3 SNPs in the major histocompatibility complex and their effects were independent of <i>HLA-DRB1*15:01</i> and b) a <i>LOC105375167</i> variant on chromosome 7. At the gene level, the top association was <i>HLA-C</i> (<i>p</i> = 1.2 × 10^-7), which plays an important role in antiviral immunity. Functional annotation revealed the enrichment of pathways related to T-cell receptor signaling, autoimmunity, and the complement cascade. Mendelian randomization analyses suggested a link between both earlier age at puberty and shorter telomere length and earlier AAO, while there was no evidence for a role for either body mass index or vitamin D levels.</p><p><strong>Discussion: </strong>Two genetic loci associated with MS AAO were identified, and functional annotation demonstrated an enrichment of genes involved in adaptive and complement immunity. There was also evidence supporting a link with age at puberty and telomere length. The findings suggest that AAO in MS is multifactorial, and the factors driving onset of symptoms overlap with those influencing MS risk.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 3","pages":"e200159"},"PeriodicalIF":3.1,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and Characterization of <i>NOTCH2NLC</i> GGC Repeat Expansions in Koreans: From a Hospital Cohort Analysis to a Population-Wide Study.","authors":"Seungbok Lee, Jihoon G Yoon, Juhyeon Hong, Taekeun Kim, Narae Kim, Jana Vandrovcova, Wai Yan Yau, Jaeso Cho, Sheehyun Kim, Man Jin Kim, Soo Yeon Kim, Soon-Tae Lee, Kon Chu, Sang Kun Lee, Han-Joon Kim, Jungmin Choi, Jangsup Moon, Jong-Hee Chae","doi":"10.1212/NXG.0000000000200147","DOIUrl":"10.1212/NXG.0000000000200147","url":null,"abstract":"<p><strong>Background and objectives: </strong>GGC repeat expansions in the <i>NOTCH2NLC</i> gene are associated with a broad spectrum of progressive neurologic disorders, notably, neuronal intranuclear inclusion disease (NIID). We aimed to investigate the population-wide prevalence and clinical manifestations of <i>NOTCH2NLC</i>-related disorders in Koreans.</p><p><strong>Methods: </strong>We conducted a study using 2 different cohorts from the Korean population. Patients with available brain MRI scans from Seoul National University Hospital (SNUH) were thoroughly reviewed, and NIID-suspected patients presenting the zigzag edging signs underwent genetic evaluation for <i>NOTCH2NLC</i> repeats by Cas9-mediated nanopore sequencing. In addition, we analyzed whole-genome sequencing data from 3,887 individuals in the Korea Biobank cohort to estimate the distribution of the repeat counts in Koreans and to identify putative patients with expanded alleles and neurologic phenotypes.</p><p><strong>Results: </strong>In the SNUH cohort, among 90 adult-onset leukoencephalopathy patients with unknown etiologies, we found 20 patients with zigzag edging signs. Except for 2 diagnosed with fragile X-associated tremor/ataxia syndrome and 2 with unavailable samples, all 16 patients (17.8%) were diagnosed with NIID (repeat range: 87-217). By analyzing the Korea Biobank cohort, we estimated the distribution of repeat counts and threshold (>64) for Koreans, identifying 6 potential patients with NIID. Furthermore, long-read sequencing enabled the elucidation of transmission and epigenetic patterns of <i>NOTCH2NLC</i> repeats within a family affected by pediatric-onset NIID.</p><p><strong>Discussion: </strong>This study presents the population-wide distribution of <i>NOTCH2NLC</i> repeats and the estimated prevalence of NIID in Koreans, providing valuable insights into the association between repeat counts and disease manifestations in diverse neurologic disorders.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 3","pages":"e200147"},"PeriodicalIF":3.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic <i>HK1</i> Variants.","authors":"Saskia B Wortmann, Rene G Feichtinger, Lucia Abela, Loes A van Gemert, Mélodie Aubart, Claire-Marine Dufeu-Berat, Nathalie Boddaert, Rene de Coo, Lara Stühn, Jasmijn Hebbink, Wolfram Heinritz, Julia Hildebrandt, Nastassja Himmelreich, Christoph Korenke, Anna Lehman, Thomas Leyland, Christine Makowski, Rafael Jenaro Martinez Marin, Pauline Marzin, Chris Mühlhausen, Marlène Rio, Agnes Rotig, Charles-Joris Roux, Manuel Schiff, Tobias B Haack, Steffen Syrbe, Stas A Zylicz, Christian Thiel, Maria Veiga da Cunha, Emile van Schaftingen, Matias Wagner, Johannes A Mayr, Ron A Wevers, Eugen Boltshauser, Michel A Willemsen","doi":"10.1212/NXG.0000000000200146","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200146","url":null,"abstract":"<p><strong>Background and objectives: </strong>Hexokinase 1 (encoded by <i>HK1</i>) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic <i>HK1</i> variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals.</p><p><strong>Methods: </strong>We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic <i>HK1</i> variants and an NDD phenotype.</p><p><strong>Results: </strong>All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile.</p><p><strong>Discussion: </strong>Genotype-phenotype correlations appear to exist for <i>HK1</i> variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic <i>HK1</i> variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 2","pages":"e200146"},"PeriodicalIF":3.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11010246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140872970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Review of Phenotypic Heterogeneity of Neuronal Intranuclear Inclusion Disease and <i>NOTCH2NLC</i>-Related GGC Repeat Expansion Disorders.","authors":"Tao Zhang, Lei Bao, Hao Chen","doi":"10.1212/NXG.0000000000200132","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200132","url":null,"abstract":"<p><p>Neuronal intranuclear inclusion disease (NIID) is an underdiagnosed neurodegenerative disorder caused by pathogenic GGC expansions in <i>NOTCH2NLC</i>. However, an increasing number of reports of <i>NOTCH2NLC</i> GGC expansions in patients with Alzheimer disease, essential tremor, Parkinson disease, amyotrophic lateral sclerosis, and oculopharyngodistal myopathy have led to the proposal of a new concept known as <i>NOTCH2NLC</i>-related GGC repeat expansion disorders (NREDs). The majority of studies have mainly focused on screening for <i>NOTCH2NLC</i> GGC repeat variation in populations previously diagnosed with the associated disease, subsequently presenting it as a novel causative gene for the condition. These studies appear to be clinically relevant but do have their limitations because they may incorrectly regard the lack of MRI abnormalities as an exclusion criterion for NIID or overlook concomitant clinical presentations not typically observed in the associated diseases. Besides, in many instances within these reports, patients lack pathologic evidence or undergo long-term follow-up to conclusively rule out NIID. In this review, we will systematically review the research on <i>NOTCH2NLC</i> 5' untranslated region GGC repeat expansions and their association with related neurologic disorders, explaining the limitations of the relevant reports. Furthermore, we will integrate subsequent studies to further demonstrate that these patients actually experienced distinct clinical phenotypes of NIID.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 2","pages":"e200132"},"PeriodicalIF":3.1,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10997217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140872981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}