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Neurogenetic markers may influence behavioural phenotypes, far away from the disease onset

Genetic endophenotypes mark the onset, clinical characteristics and disease severity in neurodegenerative diseases. The C9orf72 hexanucleotide repeat expansion (C9orf72RE) is the most common genetic cause of behavioural variant of frontal–temporal dementia (bvFTD). Dysfunctions in executive processes and social cognition represent the core symptoms of bvFTD, essential for clinical diagnosis. The presence of an extensive symptomatic overlap with psychiatric disorders, particularly for impaired social cognition is responsible for frequent misdiagnosis in the early phase of disease. Of relevance, bvFTD and psychiatric brain disorders share involvement of frontal–subcortical neuronal circuits, as confirmed by functional imaging studies. It is conceivable that C9orf72RE, and the related development of bvFTD, may be characterised by a disorganisation of molecular and functional brain architecture at microlevel and mesolevel, leading to a lifelong neuropsychiatric vulnerability. The hypothesis that C9orf72RE may cause lifelong behavioural and personality changes dating back to early life was tested by Gossink and colleagues. To do so the authors examined 20 C9orf72RE bvFTD positive and 23 C9orf72RE negative individuals diagnosed with bvFTD, by collecting detailed biographical interviews from patients and their relatives. The data were analysed with quantitative and qualitative methods. Personality traits, such as fixed behavioural patterns in daily life, limited empathy, compulsive shopping and physical exercise were present since early in life, supporting the existence of a premorbid neuropsychiatric phenotype. Of note, this was not influenced by environmental factors or cognitive proxies such as education, occupation and professional careers, and was not related to the lifelong number of intimate partners that did not differ between carriers and noncarriers. The existence of links between neurodevelopmental and neurodegenerative diseases has been reported in the case of other neurodegenerative conditions. In particular, the presence of a family history of developmental language disorders, such as dyslexia, is a possible risk factor for primary progressive aphasia syndromes. This has led to the hypothesis that a geneticallybased language network vulnerability, interfering with language and literacy acquisition, might represent a ‘locus of least resistance’ to the effects of independently arising neurodegenerative disease in later life. This conceptual model may contribute to the explanation of a central conundrum of neurodegeneration research, that is, why does the same neurodegenerative disease selectively target different vulnerable networks, causing specific phenotypes, involving memory, language, social cognition of other cognitive and behavioural functions? The present study is compatible with different mechanisms. That is, a lifelong effect of the genetic abnormality resulting in early onset neuropsychiatric manifestations in individuals, who in later life developed the full clinical picture of bvFTD. Both conceptual frameworks are crucial in supporting the emerging hypothesis that adultonset neurodegenerative diseases might have their roots in early developmental disadjustments. As suggested by the authors, large prospective followup studies into the early life aspects of C9orf72RE and other bvFTDrelated mutations may strengthen the hypothesis of a specific social cognition genetic endophenotype.