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更新于：2025-05-07

Leukodystrophy, Demyelinating, Adult-Onset, Autosomal Dominant

常染色体显性遗传性成人脱髓鞘性脑白质病变

更新于：2025-05-07

基本信息

别名

ADLD、Adult-onset autosomal dominant demyelinating leukodystrophy、Adult-onset autosomal dominant leukodystrophy

+ [6]

简介

A rare, slowly progressive neurological disorder involving central nervous system demyelination, leading to autonomic dysfunction, ataxia and mild cognitive impairment.

关联

项与常染色体显性遗传性成人脱髓鞘性脑白质病变相关的药物

nL-LMNB1-001

靶点

LMNB1

作用机制

LMNB1 modulators

在研机构

n-Lorem Foundation

原研机构

n-Lorem Foundation

在研适应症

常染色体显性遗传性成人脱髓鞘性脑白质病变

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

项与常染色体显性遗传性成人脱髓鞘性脑白质病变相关的临床试验

NCT06816498

/ Enrolling by invitation临床1/2期IIT

An Open-label, Single-center, Single-participant Study of an Experimental Antisense Oligonucleotide Treatment for a Patient with LMNB1 Mutation Associated Autosomal Dominant Leukodystrophy (ADLD)

This research project entails delivery of a personalized antisense oligonucleotide (ASO) drug designed for a single participant with Autosomal Dominant Leukodystrophy (ADLD) due to LMNB1 mutation

开始日期2025-02-01

申办/合作机构

n-Lorem Foundation

[+1]

NCT02699190

/ CompletedN/A

LeukoSEQ: Whole Genome Sequencing As a First-Line Diagnostic Tool for Leukodystrophies

Leukodystrophies, and other heritable disorders of the white matter of the brain, were previously resistant to genetic characterization, largely due to the extreme genetic heterogeneity of molecular causes. While recent work has demonstrated that whole genome sequencing (WGS), has the potential to dramatically increase diagnostic efficiency, significant questions remain around the impact on downstream clinical management approaches versus standard diagnostic approaches.

开始日期2017-01-06

申办/合作机构

The Children's Hospital of Philadelphia

NCT03047369

/ RecruitingN/A

The Myelin Disorders Biorepository Project and Global Leukodystrophy Initiative Clinical Trials Network

The Myelin Disorders Biorepository Project (MDBP) seeks to collect and analyze clinical data and biological samples from leukodystrophy patients worldwide to support ongoing and future research projects. The MDBP is one of the world's largest leukodystrophy biorepositories, having enrolled nearly 2,000 affected individuals since it was launched over a decade ago.
Researchers working in the biorepository hope to use these materials to uncover new genetic etiologies for various leukodystrophies, develop biomarkers for use in future clinical trials, and better understand the natural history of these disorders. The knowledge gained from these efforts may help improve the diagnostic tools and treatment options available to patients in the future.

开始日期2016-12-08

申办/合作机构

The Children's Hospital of Philadelphia

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100 项与常染色体显性遗传性成人脱髓鞘性脑白质病变相关的临床结果

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100 项与常染色体显性遗传性成人脱髓鞘性脑白质病变相关的转化医学

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0 项与常染色体显性遗传性成人脱髓鞘性脑白质病变相关的专利（医药）

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283

项与常染色体显性遗传性成人脱髓鞘性脑白质病变相关的文献（医药）

2025-03-01·Journal of Voice

Symptom Expression Across Voiced Speech Sounds in Adductor Laryngeal Dystonia

Article

作者: Doyle, Philip C ; Marks, Katherine L ; Stepp, Cara E ; Frankford, Saul A ; Feaster, Taylor F

OBJECTIVESDifferential diagnosis for adductor laryngeal dystonia (AdLD) is often carried out by comparing symptom expression during sentences with either all voiced or voiced and voiceless consonants. However, empirical research examining the effects of phonetic context on symptoms is sparse. The purpose of this study was to examine whether symptom probabilities varied across voiced speech segments in an all-voiced sentence, and whether this variability was systematic with respect to phonetic features.METHODSEighteen speakers with AdLD read aloud a sentence comprised entirely of voiced speech sounds. Speech segment boundaries and AdLD symptoms (phonatory breaks, frequency shifts, and creak) were labeled separately, and speech segments were coded as symptomatic or asymptomatic based on their temporal overlap. Generalized linear mixed effects models with a binomial outcome variable were used to compare the probability of symptom expression across: 1) all speech segments in the sentence, and 2) four speech sound classes (vowels, approximants, nasals, and obstruents).RESULTSSignificant symptom variability was found across voiced speech segments in the sentence. Furthermore, the estimated probability of a symptom occurring on vowels and approximants was significantly greater than that of nasals and obstruents.CONCLUSIONThese results indicate that AdLD symptoms are not uniformly distributed across voiced speech segments with systematic variation across speech sound classes.To explain these findings, future work should investigate how the complex interactions between the vocal tract articulators and glottal configurations may influence symptom expression in this population.

2025-03-01·Journal of Voice

Study of Glottal Attack Time and Glottal Offset Time in Neurogenic Voice Disorders During Sustained Phonation

Article

作者: Naghibolhosseini, Maryam ; Zayernouri, Mohsen ; Deliyski, Dimitar D ; Henry, Trent M ; Zacharias, Stephanie R C

OBJECTIVENeurogenic voice disorders like adductor laryngeal dystonia (AdLD), vocal tremor, and vocal paresis/paralysis impact the neuromuscular control of the phonatory system, which might lead to an impaired phonation onset/offset. Utilizing laryngeal high-speed videoendoscopy (HSV), this study investigates the glottal attack time (GAT) and glottal offset time (GOT) during soft, habitual, and hard glottal attack modalities in sustained phonation for several neurogenic voice disorders.METHODSHSV data and audio recordings were obtained simultaneously from 14 participants with neurogenic voice disorders and 14 normophonic participants during two productions of the /i/ vowel at soft, habitual, and hard glottal attacks. Using HSV, GAT, defined as the time interval between the first oscillation and the first contact of the vocal folds at phonation onset, and GOT, the time interval between the last oscillation and the last contact of the vocal folds at phonation offset, were measured. GAT and GOT for different glottal attack modalities were compared within each group, also among the different disorders and normophonic participants. Additionally, these values were compared between sustained phonation and connected speech for the normophonic participants and those with AdLD.RESULTSThe neurogenic disorders group exhibited significantly higher GAT values than the normophonic participants during the hard glottal attack modality. Habitual GOTs for vocal tremor were significantly different than those of unilateral vocal fold paralysis and AdLD. Moreover, the normophonic participants shared similar trends between connected speech and sustained phonation across glottal attack modalities for GAT, while the AdLD group did not. AdLD participants shared the same trend for GOT, while normophonic participants did not.CONCLUSIONSThis study provides evidence of differences in GAT and GOT values during sustained phonation across different neurogenic voice disorders, contributing to the understanding of their pathophysiology. These findings may inform the development of strategies and speech tasks for clinical assessment of neurogenic voice disorders.

2024-12-01·Neurobiology of Disease

The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology

Article

作者: Irvine, Katharine M ; Pal, Reiss ; Irvine, Katharine M. ; Summers, Kim M. ; Mabbott, Neil A ; Bradford, Barry M ; Hume, David A ; Woodruff, Trent M. ; Woodruff, Trent M ; Carter-Cusack, Dylan ; Mabbott, Neil A. ; Khan, Nemat ; Pridans, Clare ; Stables, Jennifer ; Summers, Kim M ; Hume, David A. ; Bradford, Barry M. ; Taylor, Isis

Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Previous analysis demonstrated that heterozygous mutation (Csf1r^E631K/+) had a dominant inhibitory effect on CSF1R signaling in vitro and in vivo but did not recapitulate human disease pathology. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the Csf1r^E631K/+ mutation impact on microglial phenotype, postnatal brain development, age-related changes in gene expression and on prion disease and experimental autoimmune encephalitis (EAE), two pathologies in which microgliosis is a prominent feature. The Csf1r^E631K/+ mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 and 43 weeks of age. There was no selective effect on homeostatic markers e.g. P2ry12, or age-related changes in gene expression in striatum and hippocampus. An epistatic interaction was demonstrated between Csf1r^E631K/+ and Cx3cr1^EGFP/+ genotypes leading to dysregulated microglial and neuronal gene expression in hippocampus and striatum. Heterozygous Csf1r^E631K mutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, inflammation-associated transcripts in the hippocampus and striatum were suppressed in parallel with microglia-specific transcripts. The results support a dominant inhibitory model of CSF1R-related leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology.