Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, North PE, Marchuk DA, Comi AM, Pevsner J. N Engl J Med. 2013 May 23; 368(21):1971-9. doi: 10.1056/NEJMoa1213507. Epub 2013 May 8.
Biochemistry, Cellular and Molecular Biology Program, Johns Hopkins School of Medicine, and Department of Neurology and Developmental Medicine, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
This ground-breaking study has revolutionized our understanding of Sturge-Weber syndrome, allowing us for the first time to conceive of future targeted therapies.
BACKGROUND: The Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge-Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred. To date, no such mutation has been identified.
METHODS: We performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 persons with the Sturge-Weber syndrome. We tested for the presence of a somatic mosaic mutation in 97 samples from 50 persons with the Sturge-Weber syndrome, a port-wine stain, or neither (controls), using amplicon sequencing and SNaPshot assays, and investigated the effects of the mutation on downstream signaling, using phosphorylation-specific antibodies for relevant effectors and a luciferase reporter assay.
RESULTS: We identified a nonsynonymous single-nucleotide variant (c.548G→A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge-Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls. The prevalence of the mutant allele in affected tissues ranged from 1.0 to 18.1%. Extracellular signal-regulated kinase activity was modestly increased during transgenic expression of mutant Gαq.
CONCLUSIONS: The Sturge-Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ. This finding confirms a long-standing hypothesis. (Funded by the National Institutes of Health and Hunter's Dream for a Cure Foundation).
A needle in a haystack: Sturge-Weber syndrome gene discovery. Comi AM, Marchuk DA, Pevsner J. Pediatr Neurol. 2013 Dec; 49(6):391-2. doi: 10.1016/j.pediatrneurol.2013.07.009. Epub 2013 Sep 26.
Neurology and Pediatrics, Kennedy Krieger Institute and Johns Hopkins Medicine, Baltimore, Maryland. firstname.lastname@example.org
This manuscript summarizes the story behind the scientific discovery of the somatic mutation which causes Sturge-Weber syndrome.
Updates and future horizons on the understanding, diagnosis, and treatment of Sturge-Weber syndrome brain involvement. Lo W, Marchuk DA, Ball KL, Juhász C, Jordan LC, Ewen JB, Comi A; Brain Vascular Malformation Consortium National Sturge-Weber Syndrome Workgroup. Dev Med Child Neurol. 2012 Mar; 54(3):214-23. doi: 10.1111/j.1469-8749.2011.04169.x. Epub 2011 Dec 23.
Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
This review summarizes the efforts of the Brain Vascular Malformation Consortium over the last several years to make inroads into the understanding, diagnosis, and treatment of Sturge-Weber syndrome.
AIM: To review recent developments in the understanding, diagnosis, and treatment of Sturge-Weber syndrome (SWS)
METHOD: Members of the Brain Vascular Malformation Consortium Sturge-Weber Syndrome National Workgroup contributed their expertise to review the literature and present promising directions for research.
RESULTS: The increasing number of reports dealing with SWS over the last decade reflects progress in the diagnosis and understanding of the neurological involvement. The proliferation of centers and advocacy groups to care for patients with SWS and to stimulate research has aided the development of new insights into the clinical manifestations and the pathophysiology of neurological progression, and the development of novel hypotheses to direct future research. Many key questions remain, but the tools and networks to answer them are being developed.
INTERPRETATION: This review summarizes important new knowledge and presents new research directions that are likely to provide further insights, earlier diagnosis, improved treatments, and possibly, prevention of this syndrome.
Cell proliferation and oxidative stress pathways are modified in fibroblasts from Sturge-Weber syndrome patients. Kadam SD, Gucek M, Cole RN, Watkins PA, Comi AM. Arch Dermatol Res. 2012 Apr;304(3):229-35.
Employed isobaric tags for relative and absolute quantification (iTRAQ-8plex)-based liquid chromatography interfaced with tandem mass spectrometry (LC-MS/MS) approach to identify differentially expressed proteins between port-wine-derived and normal skin-derived fibroblasts of four individuals with SWS.
Sturge-Weber syndrome: altered blood vessel fibronectin expression and morphology. Comi AM, Weisz CJ, Highet BH, Skolasky RL, Pardo CA, Hess EJ. J Child Neuro. 2005 July; 20(7):572-7.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. email@example.com
This research studied how the extracellular matrix molecule fibronectin is expressed in the brain and skin tissue of individuals with SWS. It showed evidenced of abnormal expression in the brain. Fibronectin has important roles in the blood brain barrier, in blood vessel function and in the innervation of blood vessels. This papers discusses new hypotheses regarding the pathogenensis of SWS.
Sturge-Weber syndrome presents with vascular malformations of the brain, skin, and eye. Fibronectin has potent effects on angiogenesis, vessel remodeling, and vessel innervation density. To determine fibronectin expression in the blood vessels of Sturge-Weber syndrome brain and skin tissue and to quantify the density and circumference of Sturge-Weber syndrome blood vessels by type compared with controls, we performed in situ hybridization for fibronectin messenger ribonucleic acid (RNA) expression on six Sturge-Weber syndrome cortical brain samples, six epilepsy brain samples, skin from two port-wine stain skin lesions, and two normal skin samples from two subjects with Sturge-Weber syndrome. Fibronectin messenger RNA was expressed in blood vessels and endothelial cells in the parenchyma of both Sturge-Weber syndrome and control brain tissues and in skin samples. Fibronectin expression was significantly reduced by 23% in the Sturge-Weber syndrome meningeal vessels compared with the epilepsy controls (P < .01). Fibronectin expression was significantly increased by 19% in the Sturge-Weber syndrome parenchymal vessels compared with the epilepsy controls (P < .05). No difference was found in the expression of fibronectin in port-wine stain skin blood vessels. The density of leptomeningeal blood vessels in the Sturge-Weber syndrome brain tissue samples was 45% greater than in the epilepsy samples (P < .05). Blood vessel circumference was significantly decreased in the Sturge-Weber syndrome meningeal vessels compared with the controls (27%; P < .05). When blood vessels from different brain regions were compared, fibronectin expression was decreased in Sturge-Weber syndrome meningeal vessels and was increased in the parenchymal vessels. Altered blood vessel fibronectin expression in Sturge-Weber syndrome could contribute to abnormal vascular structure and function in this disorder.
Sturge-Weber syndrome associated with other abnormalities: a medical record and literature review. Comi AM, Mehta P, Hatfield LA, Dowling MM. Arch Neurol. 2005 Dec;62(12):1924-7.
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. firstname.lastname@example.org
This paper reported a series of patients with SWS and other malformations, tumors or abnormal conditions. This information was used to search databases and suggest a gene locus that may have some role in the eitiology of SWS.
OBJECTIVE: To develop hypotheses regarding the relationship between Sturge-Weber syndrome (SWS) and other abnormalities in a subset of patients. DESIGN: We retrospectively reviewed medical records in a group of 28 patients with SWS, noting the main features of SWS and accompanying unexpected abnormalities. We also conducted a literature review of abnormalities associated with SWS. RESULTS: Twenty-eight medical records of patients with SWS were reviewed. Of this number, we found 8 (29%, 2 female) patients who manifested other abnormalities. Our review of the literature uncovered 15 additional cases with associated abnormalities. CONCLUSIONS: We hypothesize that the abnormalities associated with SWS suggest testable insights regarding pathogenesis and that chromosome 17p1-p13 may be a candidate region for genes involved with SWS. We also propose that some patients with SWS may have disorders of cholesterol biosynthesis or carbohydrate glycosylation.
This review summarized the literature with regards to hypotheses and possible eitiologies of SWS and synthesized the data one the pathagenesis of the neurodegeneration in SWS.
Sturge-Weber syndrome is a neurocutaneous disorder classically presenting with a facial port-wine birthmark, vascular eye abnormalities, and an ipsilateral occipital leptomeningeal angioma. Children with Sturge-Weber syndrome often develop progressive neurologic problems. Data on the pathophysiology of Sturge-Weber syndrome are briefly reviewed. The embryologic, genetic, and pathologic considerations are discussed, as are theories regarding the mechanisms of the degenerative brain changes. Sturge-Weber syndrome likely results from an early embryologic malformation of vascular development affecting the development of the nearby skin, eye, and brain structures. Studies suggest that complex molecular interactions contribute to the abnormal development and function of blood vessels in Sturge-Weber syndrome. Neurologic deterioration in Sturge-Weber syndrome is likely secondary to impaired blood flow to the brain and is worsened by the presence of seizures. Insights from related areas are discussed, and future research studies are suggested.
Encephalofacial angiomatosis sparing the occipital lobe and without facial nevus: on the spectrum of Sturge-Weber syndrome variants? Comi AM, Fischer R, Kossoff EH. J Child Neurol. 2003 Jan;18(1):35-8.
This case series highlighted patients with brain involvement but without skin involvement of SWS and discusses why the somatic mutation hypothesis explains these clinical variations.
We report two cases of leptomeningeal angiomatosis in atypical frontoparietotemporal locations without an associated facial port-wine birthmark. Evidence of a leptomeningeal angioma was found in each when they were evaluated for headaches and seizures. The diagnosis of a leptomeningeal angioma was suggested by calcifications noted on computed tomographic scan of the head and confirmed with contrast-enhanced magnetic resonance images of the brain. We hypothesize that given the lack of occipital involvement with the angioma, and therefore the noncontiguous nature of this lesion with the developing upper facial ectoderm, the failure to develop a facial angioma would be expected. We found that the use of an anticonvulsant along with a migraine prophylactic medication appeared to have the greatest efficacy in these two cases, whereas anticonvulsants alone were less helpful. This diagnosis should be considered in any child presenting with seizures or complicated migraines and intracranial calcifications.
Increased fibronectin expression in Sturge-Weber syndrome fibroblasts and brain tissue. Comi AM, Hunt P, Vawter MP, Pardo CA, Becker KG, Pevsner J. Pediatr Res. 2003 May;53(5):762-9.
This study utilized state-of-the-art technique to identify fibronectin as an abnormally regulated protein in SWS. Fibronectin has important roles in blood vessel development and function.
Sturge-Weber syndrome (SWS) is a neurocutaneous disorder that presents with a facial port-wine birthmark and a leptomeningeal angioma. Fibronectin expression regulates angiogenesis and vasculogenesis and participates in brain tissue responses to ischemia and seizures. We therefore hypothesized that abnormal gene expression of fibronectin and other extracellular matrix genes would be found in SWS brain tissue and SWS port-wine skin fibroblasts. Fibronectin gene and protein expression from port-wine-derived fibroblasts were compared with that from normal skin-derived fibroblasts of four individuals with SWS using microarrays, reverse transcriptase-PCR, Western analysis, and immunocytochemistry. Fibronectin gene and/or protein expression from eight SWS surgical brain samples was compared with that in two surgical epilepsy brain samples and six postmortem brain samples using microarrays, reverse transcriptase-PCR, and Western analysis. The gene expression of fibronectin was significantly increased (p < 0.05) in the SWS port-wine-derived fibroblasts compared with that of fibroblasts from SWS normal skin. A trend for increased protein levels of fibronectin in port-wine fibroblasts was found by Western analysis. No difference in the pattern of fibronectin staining was detected. The gene expression of fibronectin was significantly increased (p < 0.05), and a trend for increased fibronectin protein expression was found in the SWS surgical brain samples compared with the postmortem controls. These results suggest a potential role for fibronectin in the pathogenesis of SWS and in the brain's response to chronic ischemic injury in SWS. The reproducible differences in fibronectin gene expression between the SWS port-wine-derived fibroblasts and the SWS normal skin-derived fibroblasts are consistent with the presence of a hypothesized somatic mutation underlying SWS.
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