Clinical Characteristics of C9ORF72-Linked Frontotemporal Lobar Degeneration

The most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) has been linked to a hexanucleotide repeat expansion in the C9ORF72 gene. The frequency of the C9ORF72 expansion in Finland is among the highest in the world.

We assessed 73 Finnish patients with FTLD in order to examine the clinical characteristics associated with the expanded C9ORF72. Demographic and clinical features were evaluated. As a potential disease modifier, the apolipoprotein E (APOE) genotype was also assessed. Neuropathological analysis was available on 2 expansion carriers and 1 non-carrier.

The C9ORF72 expansion was present in 20 of 70 (29%) probands. Significant associations with the C9ORF72 expansion were observed for concomitant ALS and positive family history of dementia or ALS. Psychoses were detected in both carriers and non-carriers (21 vs. 10%, p = 0.25). The APOE ε4 allele did not cluster among expansion carriers. Numerous p62-positive neuronal inclusions were detected in the cerebellar cortex of the 2 expansion carriers.

In line with the suggested C9ORF72 core phenotype, we also detected a high frequency of neuropsychiatric symptoms; however, these symptoms seem not be specific to C9ORF72-associated FTLD. FTLD should be considered in cases of middle-age-onset psychosis.