Lost in (clinical) translation: A case report of psychosis in a C9orf72 mutation carrier

Background

The pathogenic hexanucleotide repeat expansion in chromosome 9, the C9orf72 mutation, represents the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Psychiatric symptoms, especially psychosis, are common in FTD secondary to C9orf72 mutation, and cases of psychosis have been reported in expansion carriers before the onset of prototypical cognitive symptoms. This can create diagnostic challenges due to their homology to primary psychiatric disorders. Although the mechanisms underlying the presence of psychotic symptoms in pre-symptomatic C9orf72 mutation-carriers are unclear, there is potential for the mutation to play a role in the development of prodromal psychiatric symptoms in ALS-FTD spectrum disorders.

Case report

We report the case of a 39-years old patient admitted to a psychiatric inpatient unit due to an inaugural atypical psychotic syndrome, with persecutory delusions, auditory hallucinations, prominent critical judgement impairment and behavioural symptoms. The patient had a previous history of an anxiety disorder and had severe extrapyramidal symptoms associated with dopamine D2-receptor antagonists. The family history was remarkable for a first-degree relative with C9orf72-positive FTD. Cognitive impairment was not detected in bedside screening tests and brain computed tomography showed no major abnormalities. We ordered genetic testing, which confirmed a heterozygous pathogenic expansion of C9orf72. The patient was treated with oral aripiprazole, with partial response. Follow-up and further neuropsychological assessment could not be obtained as the patient suddenly died, 10 days after discharge.

Discussion

This case highlights the need of addressing the current literature gaps on the clinical significance of C9orf72 pathological repeat expansion in patients with a positive family history of ALS-FTD who present with psychosis but have no cognitive or neuroimaging abnormalities. The threshold to order a genetic test or the implications of a positive test in terms of risk stratification and follow-up remain unsolved. Although no specific treatment for psychosis in C9orf72 carriers is currently available, a correct diagnosis can have prognostic and intervention implications and may contribute to the understanding of different disease trajectories and distinct clinical phenotypes, ultimately leading to the development of more accurate tools for disease staging and therapeutic strategies.