Clinical Heterogeneity in Familial Frontotemporal Dementia and Amyotrophic Lateral Sclerosis Caused by C9ORF72 Mutation (IN9-1.001)

Abstract

Objective: To recognize the variable presentation of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) due to C9ORF72 mutation. Background FTD and ALS are closely related syndromes with common pathological substrates. Recent identification of mutations in the C9ORF72 gene as a cause of both familial FTD and ALS further highlights their relationships. In this study we analyzed the clinical presentation from 16 unrelated families with proven mutation in the C9ORF72 gene. Design/Methods: Subjects were recruited from families with proven FTLD-TDP pathology for longitudinal assessment. Clinical charts were also retrospectively reviewed in deceased subjects. The GGGGCC hexanucleotide repeats were detected by repeat-primed PCR reaction and RNA-FISH confirmation. Clinical diagnosis of FTD was based on Neary criteria and ALS diagnosis was based on El Escorial criteria. The presence of clinical features was scored using a semiquantitative grading system (0, absent; 1, mild; 2, moderate; 3, severe). Results: Thirty subjects (70% male) from 16 unrelated families with proven C9ORF72 mutation were identified. Age of onset ranged from 34 to 74. Initial diagnoses included 15 bvFTD, 9 ALS, 1 FTD-ALS, 2 alcoholic dementia, 1 mild cognitive impairment, 1 psychosis/schizophrenia, and 1 atypical Alzheimer disease. The common presenting symptoms are behavioural (47%) and language (47%), followed by executive dysfunction (40%), affective changes (40%), motor weakness (33%), memory problems (30%), and extrapyramidal symptoms (10%). ALS increased to 50% of the subjects in longitudinal follow up, and had a negative impact on survival (2.8 yrs +/- 1.5 with ALS vs. 8.4 +/- 3.8 without ALS). Conclusions: While patients with FTD and ALS associated with C9ORF72 hexanucleotide expansion have a common molecular mechanism and typical pathology, their initial clinical presentations can be quite variable and may overlap with other clinical syndromes. Early recognition requires a high clinical acumen. Other genetic or environmental factors may influence the presentation of clinical phenotype. Supported by: Canadian Institutes of Health Research [operating grants #179009, #74580] and the Pacific Alzheimer Research Foundation [center grant C06-01]. Disclosure: Dr. Hsiung has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Feldman has received personal compensation for activities with Bristol-Myers Squibb Company as an employee. Dr. Feldman holds stock and/or stock options in Bristol-Myers Squibb Company. Dr. Sengdy has nothing to disclose. Dr. Bouchard-Kerr has nothing to disclose. Dr. Dwosh has nothing to disclose. Dr. Leung has nothing to disclose. Dr. Fok has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Mackenzie has nothing to disclose.