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Abstract
Background and Objectives 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 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). 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.
Methods 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 C9orf72, MAPT, or GRN. 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.
Results We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants.
Discussion We present a large comparative study of motor features in C9orf72, MAPT, and GRN 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.
Trial Registration Information NCT02365922, NCT02372773, and NCT04363684.
Glossary
- AAO=
- age at onset;
- ALS=
- amyotrophic lateral sclerosis;
- ARTFL=
- Advancing Research and Treatment in Frontotemporal Lobar Degeneration;
- ALLFTD=
- ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium;
- ALSFRS=
- Amyotrophic Lateral Sclerosis Rating Scale;
- bvFTD=
- behavioral variant FTD;
- C9orf72=
- chromosome 9 open reading frame 72;
- CBS=
- corticobasal syndrome;
- FTD=
- frontotemporal dementia;
- FTLD=
- frontotemporal lobar degeneration;
- GRN=
- granulin;
- HRE=
- hexanucleotide repeat expansion;
- LEFFTDS=
- Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects;
- MAPT=
- microtubule-associated protein tau;
- NACC=
- National Alzheimer's Coordinating Center;
- nfvPPA=
- nonfluent/agrammatic variant PPA;
- PD=
- Parkinson disease;
- PPA=
- primary progressive aphasia;
- PSP=
- progressive supranuclear palsy;
- PSP-QoL=
- Progressive Supranuclear Palsy–Quality of Life Rating Scale;
- PSPRS=
- Progressive Supranuclear Palsy Rating Scale;
- svPPA=
- semantic PPA;
- UPDRS=
- Unified Parkinson's Disease Rating Scale
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
Coinvestigators are listed at links.lww.com/WNL/C317
Submitted and externally peer reviewed. The handling editors were Rawan Tarawneh, MD, and Brad Worrall, MD, MSc, FAAN.
- Received November 2, 2021.
- Accepted in final form May 2, 2022.
- © 2022 American Academy of Neurology
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