Abstract
Objective: To understand phenotypic and molecular characteristics of patients with clinically “definite” primary lateral sclerosis (PLS) in a prospective study.
Methods: Six sites enrolled 41 patients who had pure upper motor neuron dysfunction, bulbar symptoms, a normal EMG done within 12 months of enrollment, and onset of symptoms ≥5 years before enrollment. For phenotypic analyses, 27 demographic, clinical, and cognitive variables were analyzed using the k-means clustering method. For molecular studies, 34 available DNA samples were tested for the C9ORF72 mutation, and exome sequencing was performed to exclude other neurologic diseases with known genetic cause.
Results: K-means clustering using the 25 patients with complete datasets suggested that patients with PLS can be classified into 2 groups based on clinical variables, namely dysphagia, objective bulbar signs, and urinary urgency. Secondary analyses performed in all 41 patients and including only variables with complete data corroborated the results from the primary analysis. We found no evidence that neurocognitive variables are important in classifying patients with PLS. Molecular studies identified C9ORF72 expansion in one patient. Well-characterized pathogenic mutations were identified in SPG7, DCTN1, and PARK2. Most cases showed no known relevant mutations.
Conclusions: Cluster analyses based on clinical variables indicated at least 2 subgroups of clinically definite PLS. Molecular analyses further identified 4 cases with mutations associated with amyotrophic lateral sclerosis, Parkinson disease, and possibly hereditary spastic paraplegia. Phenotypic and molecular characterization is the first step in investigating biological clues toward the definition of PLS. Further studies with larger numbers of patients are essential.
GLOSSARY
- ALS=
- amyotrophic lateral sclerosis;
- ALS-CBS=
- Amyotrophic Lateral Sclerosis-Cognitive Behavioral Screen;
- COWAT=
- Controlled Oral Word Association Test;
- HSP=
- hereditary spastic paraplegia;
- IRB=
- Institutional Review Board;
- LMN=
- lower motor neuron;
- LPGM=
- Laboratory of Personalized Genomic Medicine;
- MND=
- motor neuron disease;
- PD=
- Parkinson disease;
- PLS=
- primary lateral sclerosis;
- SNP=
- single nucleotide polymorphism;
- UMN=
- upper motor neuron
Footnotes
PLS Study COSMOS Group coinvestigators are listed at Neurology.org/ng
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by Columbia University.
Supplemental data at Neurology.org/ng
- Received February 9, 2015.
- Accepted in final form March 17, 2015.
- © 2015 American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
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