From the Department of Neurology (P.W.T., A.B.D., N.R.G.-R., Z.K.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.S., D.E.B., R.H.G., J.G.-R., D.T.J., D.S.K., L.K.F., B.F.B.), Mayo Clinic, Rochester, MN; Division of Clinical Trials and Biostatistics (M.G.H.), Mayo Clinic, Jacksonville, FL; Massachusetts General Hospital (B.C.D., S.M.M.), Harvard University, Boston; University of California, Los Angeles (UCLA) (D.H.G., E.M.R., M.F.M.); Washington University (N.G.), St. Louis, MO; University of Pennsylvania (M.G., D.J.I.), Philadelphia; University of British Columbia (G.-Y.R.H.), Vancouver, Canada; Columbia University (E.D.H.), New York; Department of Neuroscience (R.R.), Mayo Clinic, Jacksonville, FL; University of California, San Francisco (UCSF) (H.W.H., A.L.B., H.J.R.); Johns Hopkins University School of Medicine (C.O.), Baltimore, MD; University of Toronto (C.T.), Ontario, Canada; University of Washington (K.D.-R.), Seattle; University of Alabama at Birmingham (E.D.R.); University of California, San Diego (UCSD) (I.L.); Case Western Reserve University (B.S.A.), Cleveland, OH; Northwestern University (I.G.), Evanston, IL; and University of North Carolina (D.K.), Chapel Hill.
Neurology. 2022 Sep 13;99(11):e1154-e1167. doi: 10.1212/WNL.0000000000200860. Epub 2022 Jul 5.
Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (), microtubule-associated protein tau (), or granulin (). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes.
We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in , , or . We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test.
We identified 184 symptomatic participants who had a single pathogenic variant in (n = 88), (n = 53), or (n = 43). Motor symptom age at onset was earliest in the participants followed by , whereas the pathogenic variant carriers developed symptoms later. participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the cohort, whereas apraxia and focal limb dystonia occurred more often in participants with variants.
We present a large comparative study of motor features in , , and pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders.
NCT02365922, NCT02372773, and NCT04363684.
家族性额颞叶变性（f-FTLD）是一种表型异质性的神经退行性疾病谱，最常由 9 号染色体开放阅读框 72（）、微管相关蛋白 tau（）或颗粒蛋白（）内的变异引起。这些基因与每种表型的关联尚未完全理解。我们假设特定临床特征的频率将与不同的基因相对应。
我们对 Advancing Research and Treatment in Frontotemporal Lobar Degeneration（ARTFL）/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects（LEFFTDS）/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration 联盟中，携带致病性变异的症状携带者进行筛查，这些变异位于、或。我们根据详细神经检查、进行性核上性麻痹评分量表、进行性核上性麻痹生活质量评分量表、统一帕金森病评定量表第三部分（运动项目）和肌萎缩侧索硬化功能评定量表修订版记录的数据，评估这 3 组之间的临床差异。数据采用 Kruskal-Wallis 和 Wilcoxon 秩和检验和 Fisher 确切检验进行分析。
我们确定了 184 名具有单一致病性变异的有症状参与者，其中位于（n = 88）、（n = 53）或（n = 43）。运动症状发病年龄最早见于组，其次是组，而组携带者发病较晚。组参与者更常出现肌束颤动、肌肉萎缩和无力，而帕金森病较少见。垂直眼球运动异常在组中更为常见，而失用症和局灶性肢体肌张力障碍在携带变异的参与者中更为常见。
我们进行了一项大型的、针对、和携带者的运动特征的比较研究，这些携带者患有有症状的 f-FTLD。我们的发现表明，与特定基因变异相对应的特征性表型差异增加了我们对这一复杂神经退行性疾病谱中基因型-表型关系的理解。
NCT02365922、NCT02372773 和 NCT04363684。
