Tuberous sclerosis: genes, brain, and behaviour.

Major conceptual advances in the area of paediatric neurosciences have been made in the last few years, mainly due to both molecular genetics, whereby the neurological phenotypes are now tentatively correlated with specific genotypes, and functional neuroimaging, whereby the neurological signs can be mapped to specific regions or circuits in the brain. Tuberous sclerosis (TSC), a common multisystem genetic disorder, continues to be an exciting area of research for all those interested in molecular genetic programming of brain development. TSC also provides an important model for investigating relationships between functions of genes, strategically located brain abnormalities, and mechanisms of cognition and behaviour. Gene mutations in either of the two TSC genes influence neural precursors between weeks 7 and 20 of gestation, disrupting the mTOR pathways, and resulting in abnormal cell differentiation and dysregulated control of cell size. These cells then migrate in an atypical fashion to the cortex to generate an abnormal collection of inappropriately positioned neurons. Characteristic giant cells are found in three types of brain lesions (cortical tubers, subependymal nodules, and giant-cell astrocytomas). However, in TSC there is evidence of widespread cortical disorganization and structural abnormalities throughout the brain, not just associated with tubers and nodules. Even areas that appear normal on magnetic resonance imaging may be microscopically affected. Individuals with TSC typically present a variety of neuropsychiatric features including epilepsy, cognitive impairment, and behavioural disorders.1 As the causal genes are recognized, and we are beginning to understand the functions of the proteins they encode, TSC appears to be a good model for the investigation of the relationship between the genotype and the different neurological phenotypes. Besides the overlap of many features of patients with TSC types 1 (TSC1) and 2 (TSC2), the mutation data accumulated provide evidence for specific clinical differences. Patients with sporadic TSC2 mutations had, on average, more severe disease in comparison with patients with sporadic TSC1 mutations, with an overall increased incidence of seizures including infantile spasms, more severe intellectual impairment, and a higher occurrence of autism. The various parts of TSC genes have diverse functions, and it is likely that different mutations have diverse physiological effects. This will open an avenue for child neurologists to study new correlations between the genotype and the phenotypes. Around 45% of individuals with TSC have some degree of cognitive impairment, ranging from profound disabilities to mild learning problems. In addition, around 50% of children with TSC show behavioural problems, in the form of autism and/or attention-deficit–hyperactivity disorder (ADHD). Autism and ADHD are behaviourally defined disorders of the brain that are under-recognized, underdiagnosed, and often untreated in TSC patients. The link between brain abnorm-