Monogenic Causes of Mental Retardation

Advances in gene discovery methodologies and the analysis of samples from large cohorts of families have rapidly increased our knowledge of the number of genes that cause mental retardation. To date, over 80 genes on the X chromosome have been identified where a mutation results in a syndromic or non-syndromic form of the disease. Although the X chromosome may harbour a disproportionate number of genes for intellectual development, nonetheless, it is likely that more than 1400 genes on the autosomes also give rise to mental retardation. To date, more syndromic forms of MR have been identified compared to non-syndromic forms due to ascertainment bias but with the advent of high resolution aCGH and autozygosity mapping the number of identified autosomal genes that cause disease is likely to grow. The biological mechanism by which each gene causes disease is still poorly understood and examples of proteins that control chromatin remodeling, nonsense mediated decay, post-translational modification of proteins or intracellular trafficking have all been described. This suggests that a mental retardation phenotype may reflect a generalized dysfunction of neurons rather than abnormalities of a few specific pathways required for intellectual processing and thus the understanding of the biological basis of this disease remains a substantial challenge. Copyright © 2010 S. Karger AG, Basel Definition of Mental Retardation The definition of Mental Retardation (MR) is discussed in detail in chapter 2. Briefly, it requires a significant subaverage general intellectual functioning (criterion A) that is accompanied by limitations in adaptive functioning in at least 2 key skill areas (criterion B) and the onset must occur before age 18 years (criterion C). General intellectual functioning is defined by the intelligence quotient, IQ. Adaptive functioning refers to how effectively individuals cope with common life demands. In Europe, the ICD-10 Classification of Mental and Behavioural Disorders, World Health Organization (WHO), Geneva 1992 is used whilst in the USA the DSM-IV diagnostic classification is used which is broadly similar to the WHO classification [1, 2]. Evidence for Single Genes The observation that intellectual processing, as defined by the intelligence quotient (IQ) in humans, is affected by the genetic status of the individual has been recognized since establishing that Down syndrome is due to an additional chromosome complement [3]. Not until the 1970s was it recognized that in some families the intellectual impairment was not due simply to the side effect of a generalised metabolic abnormality, as seen in the paediatric metabolic abnormalities but rather that there may be specific genes in the genome that only manifest as intellectual impairment in