Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p

Abstract

Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.

Fig. 1

Neuropathological features in patients with the C9ORF72 mutation. All cases with a clinical diagnosis of amyotrophic lateral sclerosis had TDP-43 immunoreactive cytoplasmic inclusions in lower motor neurons that were filamentous (a), granular or compact (b). All cases, both with and without clinical frontotemporal dementia, had small TDP-43 immunoreactive neuronal cytoplasmic inclusions in the extramotor neocortex (c) and the hippocampal dentate granule cells (d). A consistent feature was small neuronal cytoplasmic inclusions and short neurites in the granule cell layer of the cerebellar cortex that were immunoreactive for ubiquitin and p62, but negative for TDP-43 (e). Immunohistochemistry from C9ORF72 showed increased cytoplasmic staining of some lower motor neurons in cases of ALS, both with and without the C9ORF72 mutation (f). Immunohistochemistry for TDP-43 (a – d), ubiquitin (e) and C9ORF72 (f). Scale bar 25 μm (a, b, d), 15 μm (c), 12 μm (e), 60 μm (f).