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Individuals from a 6-octapeptide repeat insertion (6-OPRI) mutation inherited prion disease kindred, with over 100 affected patients, exhibit severe emotional and behavioural difficulties starting in childhood, distinct from the adult-onset prion dementia (Collinge et al, Brain 1992). The direct effects of the PRNP mutation on brain development versus indirect social influences remain unclear. Thematic analysis of 21 6-OPRI recent carriers identified five symptom dimensions: behavioural disturbances(43%), emotional dysregulation(33%), educational challenges(52%), substance use(33%), and motivational abnormalities(10%). Compared to controls, carriers were significantly more likely to exhibit these symptoms (p < 0.001). A case vignette describes an individual with a severe mental disorder of this type, who was adopted from a young age, suggesting neuropsychiatric symptoms may stem directly from the mutation. Plasma neurofilament light levels, a neurodegeneration marker, differed significantly between asymptomatic carriers and symptomatic patients (p = 0.005). We illustrate how biomarkers and MRI brain can help distinguish the kindred’s premorbid syndrome from features of early dementia. Exome sequencing of three related 6-OPRI carriers confirmed the pathogenic mutation but identified no confounding deleterious variants. These findings support the concept of a premorbid neuropsychiatric syndrome linked to the neurodevelopmental effects of 6-OPRI (and by extension other large insertional mutations of PRNP).l.farakish@nhs.net