Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort
| العنوان: | Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort |
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| المؤلفون: | Margaret Fink, Carsten G. Bönnemann, Gina Norato, Diana Bharucha-Goebel, Sandra Donkervoort, A. Reghan Foley, G. Averion, Victoria Biancavilla, Sarah Debs, Dimah Saade, Eduardo Paredes, Ying Hu, Minal S. Jain, Rupleen Kaur, Wadih M. Zein, Diane Armao, M. Waite, Steven J. Gray, Tanya J. Lehky |
| المصدر: | Brain |
| بيانات النشر: | Oxford University Press (OUP), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Pathology, medicine.medical_specialty, Adolescent, Cross-sectional study, Disease, Cohort Studies, Young Adult, medicine, Humans, Child, Giant axonal neuropathy, Clinical pathology, business.industry, Gigaxonin, Original Articles, medicine.disease, Natural history, Cross-Sectional Studies, Giant Axonal Neuropathy, Child, Preschool, Cohort, Female, Neurology (clinical), business, Natural history study |
| الوصف: | Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the peripheral nervous system and central nervous system. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed giant axonal neuropathy to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with giant axonal neuropathy of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross correlation analysis of measures of strength, motor function, and electrophysiologic markers of disease severity, we identified the Motor Function Measure 32 (MFM-32) to have the strongest correlation across measures and age in individuals with giant axonal neuropathy. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a sub cohort of individuals with a milder form of giant axonal neuropathy and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of giant axonal neuropathy, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in giant axonal neuropathy as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed giant axonal neuropathy is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of giant axonal neuropathy in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with giant axonal neuropathy. |
| تدمد: | 1460-2156 0006-8950 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd1db4ed000f65c170b9dd66f4963050Test https://doi.org/10.1093/brain/awab179Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cd1db4ed000f65c170b9dd66f4963050 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602156 00068950 |
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