PL‐05‐02: Clinical, pathological and genetic aspects of C9ORF72 mutations

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with autosomal dominant inheritance in which members affected by FTD, ALS or both; showing genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as a massively expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). Review of published and unpublished data. Studies from many centers have now shown the C9ORF72 mutation to be the most common genetic cause of familial and sporadic forms of both FTD and of ALS and the basis of most families in which both conditions occur. The associated phenotype is heterogeneous with wide variation in age of onset and survival. FTD is more often the behavioral variant than progressive non-fluent aphasia and the motor features are usually typical of ALS but with more frequent bulbar onset. Memory problems, psychosis and a wide range of other motor symptoms have also been reported. There may be striking clinical variability within families and some evidence for genetic anticipation. The underlying neuropathology is a characterized by TDP-43 immunoreactive inclusions in a wide range of neuroanatomical regions including the cerebral cortex (FTLD-TDP) and lower motor neurons (ALS-TDP). In addition, the presence of ubiquitin-positive, TDP-43-negative inclusions in the cerebellum and hippocampus is a consistent and unique feature that indicates abnormal metabolism of some unidentified protein(s). The hexanucleotide repeat is located between two alternately spliced first exons and abnormal expansion results in loss of one alternatively spliced C9ORF72 transcript and the formation of nuclear RNA foci, suggesting multiple pathogenic mechanisms. The C9ORF72 mutation is a major cause of familial and sporadic FTD and ALS, and likely accounts for the majority of families with combined FTD and ALS. This further supports the concept that FTD and ALS represent a clinicopathological spectrum of disease and highlights the role of RNA mis-metabolism in the pathogenesis of these conditions.

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