Neurogenetic syndromes with behavioural phenotypes

Particular patterns of behaviour, temperament, and psychopathology may be associated with specific chromosomal and genetic disorders. (256) The term 'behavioural phenotype' was introduced by Nyhan in 1972(7) to describe patterns of unusual behaviour that are so characteristic that they suggest a specific neurogenetic disorder. He described stereotypical patterns of behaviour occurring in syndromic fashion in sizeable numbers of affected individuals with a given syndrome, and observed that these patterns seemed self-programmed. In these children, he proposed that it is reasonable to hypothesize that their behaviours are associated with an abnormal neuroanatomy and that such stereotypical patterns of unusual behaviour could reflect the presence of structural deficits in the central nervous system. Recent developments in the neurosciences provide a means to investigate the biological bases of behavioural phenotypes. Behavioural assessments, neuropsychological testing, and neuroimaging procedures, carried out in well-characterized genetic syndromes, are being utilized to understand pathways from genes to cognition and complex behaviours in these conditions.

Comprehensive study of children with different neurogenetic disorders may increase our appreciation for the relative contribution of genetic variables in the pathogenesis of specific affective and behavioural disorders. Behavioural phenotypes have been studied most extensively in Down syndrome (mimicry), (8) fragile X syndrome (gaze aversion, hyperkinesia, autistic-like behaviour),(9) Williams syndrome (sociability, hyperverbal behaviour, and visuospatial deficits), fy0,,11 Lesch-Nyhan syndrome (compulsive self-injury and aggression), (!2.,13 and 14 and Prader-Willi syndrome (hyperphagia, obsessive-compulsive behaviour). ^l6 The number of identifiable behavioural phenotypes is growing with careful observations of behaviours in neurogenetic disorders. (5) Besides behaviours, particular temperamental features have also been considered in these disorders. However, when studying temperament, the appropriate measures must be chosen. For example, when Down syndrome, proposed to be linked to a particular temperament, was studied using temperamental clusters of easy temperament, slow to warm up, and difficult temperament, Gunn et alS1) demonstrated both easy and difficult temperament in children with Down syndrome; therefore, a typical temperamental pattern among these three categories was not demonstrated. However, when a more comprehensive assessment was carried out in other syndromes^.8 (that included the personality factors of extraversion, agreeableness, conscientiousness, emotional stability, and openness, along with motor activity and irritability), specific personality phenotypes were identified. These were differentially related to parental behaviours and family context in Prader-Willi, fragile X, and Williams syndromes. Moreover, isolated special abilities, as in calculation and in music, (19) are recognizable that might be considered as phenotypes and linked to the proposed modular organization of the central nervous system. Finally, physical and behavioural phenotypes are not only identified in neurogenetic syndromes but also in those caused by environmental events, such as intrauterine exposure to alcohol: namely, the fetal alcohol syndrome. Because alcoholism is a familial disorder, there may vulnerability to its effects resulting in a more severe presentation in some individuals. (29

Both traditional Mendelian laws of inheritance (Lesch-Nyhan syndrome) and non-traditional inheritance have been identified in conditions with behavioural phenotypes. Among the non-traditional forms of inheritance are triplet repeat amplification (fragile X syndrome), microdeletion or contiguous gene deletion (Williams syndrome), imprinting (Prader-Willi syndrome), and excessive gene dosage (Down syndrome). A key finding is the recognition that mutations of single genes can lead to complex behavioural symptoms, especially if the affected protein is essential for the expression or processing of multiple 'downstream' genes.

Behavioural phenotypes are also discussed in relation to mental retardation in Cha,P.t§.L.10.5.:1.

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