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Abstract
Objective To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies.
Methods We prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non–amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS.
Results The mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was −1.8 ± 1.7 for ALS Functional Rating Scale–Revised and −1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives.
Conclusions We present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.
Glossary
- ADNI=
- Alzheimer's Disease Neuroimaging Initiative;
- ALS=
- amyotrophic lateral sclerosis;
- ALS-CBS=
- ALS Cognitive Behavioral Screen;
- ALSCBQ=
- ALS Caregiver Behavioral Questionnaire;
- ALSFRS-R=
- ALS Functional Rating Scale–Revised;
- ASO=
- antisense oligonucleotide;
- C9ALS=
- individuals with amyotrophic lateral sclerosis with chromosome 9 open reading frame 72 expansion mutations;
- C9orf72=
- chromosome 9 open reading frame 72;
- DPR=
- dipeptide repeat protein;
- FTLD=
- frontotemporal lobar degeneration;
- MGH=
- Massachusetts General Hospital;
- NCRI=
- Neurologic Clinical Research Institute;
- NEALS=
- Northeast Amyotrophic Lateral Sclerosis Consortium;
- RAN=
- repeat associated, non-ATG;
- rpPCR=
- repeat primed PCR;
- SALS=
- singleton amyotrophic lateral sclerosis;
- SDS=
- sodium dodecyl sulfate;
- SEC=
- size exclusion chromatography;
- SMA=
- spinal muscular atrophy;
- SNP=
- single nucleotide polymorphism;
- SVC=
- slow vital capacity;
- WU=
- Washington University
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.
Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at links.lww.com/WNL/A999.
- Received December 18, 2018.
- Accepted in final form May 20, 2019.
- © 2019 American Academy of Neurology
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