From the Guidelines
The C9orf72 gene mutation is the most common genetic cause of frontotemporal dementia (FTD) and is associated with a high risk of developing dementia, with almost complete penetrance, but some carriers may not show symptoms until 80 years of age 1.
Key Points
- The C9orf72 mutation involves an abnormal expansion of a specific DNA sequence (GGGGCC) that disrupts normal cellular function, with the exact pathogenic threshold not yet definitively established, but 530 repeats is considered pathogenic 1.
- This mutation typically causes earlier onset of dementia symptoms (often before age 65) and may produce distinctive symptoms including behavioral changes, language difficulties, and motor neuron problems, with a long disease duration of up to 22 years in a proportion of patients possible 1.
- The mutation is inherited in an autosomal dominant pattern, meaning a person needs only one copy of the mutated gene to develop the condition, giving affected individuals a 50% chance of passing it to each child.
- Genetic testing for this mutation is available and recommended for individuals with a family history of FTD or ALS, with genetic counseling strongly advised before and after testing to help individuals understand the implications of results for themselves and family members.
Clinical Presentation
- The most common clinical presentations include behavioral variant frontotemporal dementia (bvFTD), amyotrophic lateral sclerosis (ALS), or the combination of both, but also prodromal psychiatric syndromes, with reports of bipolar disorder, obsessive compulsive disorder, and schizophrenia occurring in patients in the years preceding FTD 1.
- Delusions and hallucinations, mostly auditory, were reported in 21-56% of C9orf72 repeat expansions carriers, with delusion subtypes including persecutory, jealousy, grandiosity, religiosity, and somatic, and these may precede the classical presentation of bvFTD symptoms by up to a decade 1.
Diagnosis and Management
- Neuroimaging usually shows symmetric atrophy of frontal, temporal, and parietal lobes, as well as cerebellum and thalamus, but MRI and even FDG-PET can be normal during initial assessment 1.
- Currently, there are no specific medications that target the C9orf72 mutation itself, though symptomatic treatments like selective serotonin reuptake inhibitors for behavioral symptoms or speech therapy for language difficulties may help manage symptoms.
From the Research
C9ORF72 Gene and Dementia
- The C9ORF72 gene has been identified as a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) 2, 3, 4, 5, 6.
- The mutation in the C9ORF72 gene leads to a repeat expansion, which can cause both haploinsufficiency and gain-of-function effects, resulting in the accumulation of toxic proteins and RNA foci 2, 5.
- Studies have shown that the C9ORF72 mutation is associated with a unique clinical profile, including executive dysfunction, memory impairment, language deficits, and behavioral changes such as disinhibition, apathy, and psychosis 3, 4, 6.
Clinical Features of C9ORF72 Mutation Carriers
- Psychotic symptoms, including delusions and hallucinations, are common in C9ORF72 mutation carriers, and may be a discriminating feature between carriers and non-carriers 3, 6.
- Family history of ALS or psychiatric illness is also more common in C9ORF72 mutation carriers 6.
- Brain atrophy is often less pronounced in C9ORF72 mutation carriers, and the progression of the disease may be slower than in non-carriers 6.
Diagnostic Implications
- The C9ORF72 mutation is a common cause of FTD, and genetic testing may be considered in patients with a family history of ALS or psychiatric illness, or in those with psychotic symptoms 3, 6.
- Clinicians should be aware of the unique clinical profile associated with the C9ORF72 mutation, and consider genetic testing in patients who do not meet the typical diagnostic criteria for FTD 6.