Thalamus, timing and TSC1 deletions

Tuberous Sclerosis. Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by lack of function of the TSC1 or TSC2 tumor suppressor gene. With respect to the Central Nervous System, this disease is characterized by so-called tubers, benign tumors consisting of dysplastic neurons that are highly epileptogenic. Accordingly, TSC is one of the most common causes of West Syndrome. However, there is also evidence for neurological dysfunction beyond tubers. Increasing evidence suggests that the mutations alone can result in abnormalities of neuronal networks, resulting in epilepsy, intellectual disability or autism. The thalamus appears to be a key structure that is affected by this dysfunction. Now, a recent study in Cell explores the effects of TSC1 deletions at different developmental stages with respect to neuronal development in the thalamus. Continue reading

Sturge-Weber syndrome explained – somatic mutations in GNAQ

Phakomatoses. There are a group of disorders that affect both the skin and the central nervous system. These disorders, called neurocutaneous disorders or phakomatoses, may result in epilepsy or intellectual disability, depending on the extent to which the brain is affected. While a genetic basis for some neurocutaneous disorders including Tuberous Sclerosis Complex (TSC) and neurofibromatosis is known, the etiology of other neurocutaneous diseases remains unknown. Now, a recent paper in the New England Journal of Medicine reports on the genetic alterations underlying one of the most common neurocutaneous disorders, Sturge-Weber syndrome. Continue reading

Somatic mutations affecting the mTOR pathway in hemimegalencephaly

Mutations, but not germline. Many of the genetic alterations that we aim to investigate within the EuroEPINOMICS projects are so-called germline mutations. In the case of de novo events, these mutations have occurred in the germ cells themselves or in very early development. In the case of autosomal dominant or recessive inheritance, the mutations have been transmitted from parents. In either case, the mutation can be found in every cell of the body. Cancer research is mainly focussed on somatic mutations, which give rise to malignant transformation in already differentiated tissues. In fact, many of the techniques that we currently use in neurogenetics were developed to study somatic genetic aberrations. Array comparative genomic hybridization for example, had initially been established for these purposes before expanding the focus to germline microdeletions and microduplications. While the role of somatic mutations in cancer research is well established, the role somatic rather than germline genetic alterations play in other disorders is mainly speculative. Some initial evidence for somatic point mutations has recently been found in Proteus syndrome, a rare overgrowth syndrome. Activating somatic mutations in AKT1 have recently been identified in this disorder. A recent paper by Lee and colleagues now identifies mutations in several genes in the mTOR pathway in patients with hemimegalencephaly, a severe form of brain malformation. Continue reading