Autism and intellectual disability

Abstract

Intellectual disability and autism spectrum disorders affect approximately 3 % of the population and are commonly encountered in general neurological practice as a result of co-morbidity with a range of other neurological disorders, and in particular with epilepsy. Adult neurologists might reasonably expect that the diagnosis and classification of individuals affected by these conditions will have been achieved in childhood and or adolescence; however, epidemiological data suggests that this is frequently not the case. Intellectual disability in childhood is usually first identified within a wider backdrop of developmental delay and precipitates a series of longitudinal assessments and standard investigations. However, even after searching for established aetiological factors such as birth asphyxia, perinatal or neonatal infection and associated genetic conditions, the underlying cause of intellectual disability frequently remains obscure. Improved recognition and characterisation of these conditions will not only provide clarity about prognosis, but may also facilitate access to appropriate support or genetic counselling, avoid the need for unnecessary investigation and may even allow specific treatment recommendations. In order to unravel the complex aetiology and pathophysiology of these conditions, researchers have chosen to employ increasingly complex research methodologies. As a result one of the challenges facing modern clinical neurologists is to develop acquaintance with these methods in order to understand implications for clinical practice. This is particularly relevant to the rapidly evolving fields of genetics and imaging as it seems likely that techniques similar to those currently used in research studies will emerge into the diagnostic arena before too long. Array based chromosomal analysis is already used in the diagnostic setting of intellectual disability to identify common causative duplications or deletions that are below the detection level of conventional karyotyping. Exome-wide sequencing, that enables sequencing of the entire coding portion of the genome, can now detect de novo mutations at relatively low cost. However, as with any unbiased genome-wide technique, relevant results must be extracted from a mass of irrelevant data. In particular a major challenge is to predict which de novo mutation is likely to be pathogenic, since any new born child will be expected to have acquired 50–100 de novo mutations in his or her genome. Similarly, functional MRI has a well established role in uncovering abnormal circuitry in neurological and psychiatric illness but also requires complex statistical analyses and careful interpretation. This is particularly the case when resting-state imaging is acquired to investigate the default mode of the brain. In this month’s journal club we review three papers that focus on autism spectrum disorders and intellectual disability. The first uses a novel functional MRI method to address the question of whether reduced connectivity in autism occurs at a regional or a whole-brain level. The second and third papers both use exome-wide sequencing to identify de novo, potentially pathogenic mutations in individuals with severe intellectual disability.