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September 13, 2022; 99 (11) Research Articles

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

View ORCID ProfilePhilip Wade Tipton, Angela B. Deutschlaender, View ORCID ProfileRodolfo Savica, Michael G. Heckman, Danielle E. Brushaber, View ORCID ProfileBradford C. Dickerson, Ralitza H. Gavrilova, Daniel H. Geschwind, View ORCID ProfileNupur Ghoshal, Jonathan Graff-Radford, Neill R. Graff-Radford, Murray Grossman, View ORCID ProfileGing-Yuek R. Hsiung, Edward D. Huey, David John Irwin, View ORCID ProfileDavid T. Jones, David S. Knopman, Scott M. McGinnis, View ORCID ProfileRosa Rademakers, Eliana Marisa Ramos, Leah K. Forsberg, Hilary W. Heuer, View ORCID ProfileChiadi Onyike, Carmela Tartaglia, Kimiko Domoto-Reilly, View ORCID ProfileErik D. Roberson, Mario F. Mendez, View ORCID ProfileIrene Litvan, Brian S. Appleby, Ian Grant, Daniel Kaufer, Adam L. Boxer, Howard J. Rosen, View ORCID ProfileBrad F. Boeve, Zbigniew K. Wszolek, for the ALLFTD Consortium
First published July 5, 2022, DOI: https://doi.org/10.1212/WNL.0000000000200860
Philip Wade Tipton
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.
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Angela B. Deutschlaender
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Rodolfo Savica
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Michael G. Heckman
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Danielle E. Brushaber
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Bradford C. Dickerson
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Ralitza H. Gavrilova
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Daniel H. Geschwind
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Nupur Ghoshal
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Jonathan Graff-Radford
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Neill R. Graff-Radford
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Murray Grossman
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Ging-Yuek R. Hsiung
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Edward D. Huey
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David John Irwin
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David T. Jones
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David S. Knopman
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Scott M. McGinnis
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Rosa Rademakers
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Eliana Marisa Ramos
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Leah K. Forsberg
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Hilary W. Heuer
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Chiadi Onyike
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Carmela Tartaglia
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Kimiko Domoto-Reilly
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Erik D. Roberson
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Mario F. Mendez
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Irene Litvan
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Brian S. Appleby
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Ian Grant
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Daniel Kaufer
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Adam L. Boxer
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Howard J. Rosen
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Brad F. Boeve
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Zbigniew K. Wszolek
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Citation
Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration
Philip Wade Tipton, Angela B. Deutschlaender, Rodolfo Savica, Michael G. Heckman, Danielle E. Brushaber, Bradford C. Dickerson, Ralitza H. Gavrilova, Daniel H. Geschwind, Nupur Ghoshal, Jonathan Graff-Radford, Neill R. Graff-Radford, Murray Grossman, Ging-Yuek R. Hsiung, Edward D. Huey, David John Irwin, David T. Jones, David S. Knopman, Scott M. McGinnis, Rosa Rademakers, Eliana Marisa Ramos, Leah K. Forsberg, Hilary W. Heuer, Chiadi Onyike, Carmela Tartaglia, Kimiko Domoto-Reilly, Erik D. Roberson, Mario F. Mendez, Irene Litvan, Brian S. Appleby, Ian Grant, Daniel Kaufer, Adam L. Boxer, Howard J. Rosen, Brad F. Boeve, Zbigniew K. Wszolek, for the ALLFTD Consortium
Neurology Sep 2022, 99 (11) e1154-e1167; DOI: 10.1212/WNL.0000000000200860

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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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