Differences in Motor Features of C9orf72 , MAPT , or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration

• Published in: Neurology Vol. 99; no. 11; p. e1154
• Main Authors: Tipton, Philip Wade, Deutschlaender, Angela B, Savica, Rodolfo, Heckman, Michael G, Brushaber, Danielle E, Dickerson, Bradford C, Gavrilova, Ralitza H, Geschwind, Daniel H, Ghoshal, Nupur, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grossman, Murray, Hsiung, Ging-Yuek R, Huey, Edward D, Irwin, David John, Jones, David T, Knopman, David S, McGinnis, Scott M, Rademakers, Rosa, Ramos, Eliana Marisa, Forsberg, Leah K, Heuer, Hilary W, Onyike, Chiadi, Tartaglia, Carmela, Domoto-Reilly, Kimiko, Roberson, Erik D, Mendez, Mario F, Litvan, Irene, Appleby, Brian S, Grant, Ian, Kaufer, Daniel, Boxer, Adam L, Rosen, Howard J, Boeve, Brad F, Wszolek, Zbigniew K
• Format: Journal Article
• Language: English
• Published: United States 13.09.2022
• Subjects: C9orf72 Protein - genetics; Frontotemporal Dementia - diagnosis; Frontotemporal Dementia - genetics; Frontotemporal Lobar Degeneration - genetics; Granulins - genetics; Humans; Mutation - genetics; Progranulins - genetics; Quality of Life; Supranuclear Palsy, Progressive; tau Proteins - genetics
• ISSN: 1526-632X
• DOI: 10.1212/WNL.0000000000200860

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.