| Disease ID | Source | Name | Description |
| 105550 | OMIM | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1) | An autosomal dominant neurodegenerative disorder characterized by adult onset of frontotemporal dementia and/or amyotrophic lateral sclerosis in an affected individual. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. The disease is caused by variants affecting the gene represented in this entry. In the first intron of the gene, the expansion of a GGGGCC hexanucleotide that can vary from 10 to thousands of repeats, represents the most common genetic cause of both familial and sporadic FTDALS. The hexanucleotide repeat expansion (HRE) is structurally polymorphic and during transcription, is responsible for the formation of RNA and DNA G-quadruplexes resulting in the production of aborted transcripts at the expense of functional transcripts. The accumulation of those aborted transcripts may cause nucleolar stress and indirectly cell death (PubMed:24598541). The expanded GGGGCC repeats are bidirectionally transcribed into repetitive RNA, which forms sense and antisense RNA foci. Remarkably, despite being within a non-coding region, these repetitive RNAs can be translated in every reading frame to form five different dipeptide repeat proteins (DPRs) -- poly-GA, poly-GP, poly-GR, poly-PA and poly-PR -- via a non-canonical mechanism known as repeat-associated non-ATG (RAN) translation. These dipeptide repeat proteins (DPRs) co-aggregate in the characteristic SQSTM1-positive TARDBP negative inclusions found in FTLD/ALS patients with C9orf72 repeat expansion (PubMed:24132570). |