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.
Capillary malformation. Sturge-Weber Syndrome is characterized by a so-called port-wine stain, a capillary malformation of the face in combination with angiomas, i.e. abnormally formed capillaries of the leptomeninges, which are part of the capillary lining of the brain. The vascular malformation the leptomeninges may lead to epilepsy and intellectual disability that is frequently seen in patients with Sturge-Weber Syndrome. In addition, many patients have so-called isolated port-wine stains without an affection of the brain. The mechanism leading to Sturge-Weber Syndrome has been elusive, but one hypothesis stipulated that somatic mutations at different stages of embryonic development may lead to the spectrum of diseases ranging from isolated port-wine stains to the full picture of Sturge-Weber Syndrome.
Activating mutations. Shirley and collaborators performed whole genome sequencing in affected versus unaffected tissue of three individuals with Sturge-Weber Syndrome. In all three individuals, they identified the same c.548G->A mutation in GNAQ that results in an amino acid substitution p.Arg183Gln. In a larger sample of 26 patients with Sturge-Weber Syndrome, they identified the same mutation in 88% of individuals. Likewise, the mutation was found in affected biopsy tissue in 6/7 patients with isolated port-wine stains. In patients where the combination of affected and unaffected tissue was available, it could be shown that the mutation was somatic.
The role of GNAQ. The GNAQ gene codes for G-alpha-q, a G-protein subunit that is involved in intracellular downstream signaling of transmembrane proteins. Specifically, GNAQ is involved in signaling within the MAPK and Phospholipase C pathway. Many of the cellular signals implicated in cell growth operate through these pathways. Using a reporter assay for the MAPK pathway, the authors could show that the GNAQ mutation resulted in an activation of downstream signaling. This suggests that the GNAQ mutation results in an overactivity of this pathway. Other activating somatic mutations in GNAQ have been reported in uveal melanoma, a rare form of eye cancer. The underlying mutations, however, lead to a stronger activation of the MAPK pathway. This suggests that the degree of activation may influence the phenotype resulting from the somatic mutation.
Conclusions. The biological basis of Sturge-Weber Syndrome and port-wine stains are explained by a single publication. Nearly all patients have this mutation, suggesting that the same mechanisms are relevant to the patient population at large. With the recent finding by Shirley and collaborators, Sturge-Weber Syndrome joins a growing group of neurodevelopmental disorders due to somatic mutations such as hemimegalencephaly. Sturge-Weber syndrome is regularly encountered in the epilepsy clinic, even though the syndrome is very rare. To me, it is fascinating to see that one of the disorders that we are confronted with can be explained with such simplicity. It is good to be able to provide an answer for the parents’ questions, especially with respect to recurrence risk and a possible hereditary component. Future research will tell whether this finding can be translated into therapeutic strategies.
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