Anne M Comi’s research while affiliated with Johns Hopkins Medicine and other places

Sturge–Weber syndrome (SWS) is a rare congenital neurovascular disorder that initially presents with a facial port-wine birthmark (PWB) and most commonly associated with a R183Q somatic mosaic mutation in the gene GNAQ. This mutation is enriched in endothelial cells. Contrast-enhanced magnetic resonance imaging (MRI) diagnoses brain abnormalities including leptomeningeal vascular malformation, an enlarged choroid plexus, and abnormal cortical and subcortical blood vessels. Mouse SWS models identify dysregulated proteins important for abnormal vasculogenesis and blood brain barrier permeability. Recent clinical research has focused on early diagnosis, biomarker development, presymptomatic treatment, and development of novel treatment strategies. Prospective pilot clinical drug trials with cannabidiol (Epidiolex) or with sirolimus, an mTOR inhibitor, indicate possible reductions in seizure frequency and improved cognitive outcome. This review connects the most recent molecular research in SWS cell culture and animal models to developing new treatment methods and identifies future areas of research.

Sturge–Weber syndrome (SWS) is a rare congenital neurocutaneous disorder typically caused by a somatic mosaic mutation in R183Q GNAQ. At-risk children present at birth with a capillary malformation port-wine birthmark. The primary diagnostic characteristic of the disorder includes leptomeningeal enhancement of the brain, which demonstrates abnormal blood vessels and results in impaired venous drainage and impaired local cerebral perfusion. Impaired cerebral blood flow is complicated by seizures resulting in strokes, hemiparesis and visual field deficits, hormonal deficiencies, behavioral impairments, and intellectual disability. Therefore, anti-seizure medication in combination with low-dose aspirin is a common therapeutic treatment strategy. Recently published data indicate that the underlying mutation in endothelial cells results in the hyperactivation of downstream pathways and impairment of the blood–brain barrier. Cannabidiol (CBD) has been used to treat medically refractory seizures in SWS due to its anti-seizure, anti-inflammatory, and neuroprotective properties. Pilot research suggests that CBD improves cognitive impairment, emotional regulation, and quality of life in patients with SWS. Recent preclinical studies also suggest overlapping molecular pathways in SWS and in CBD, suggesting that CBD may be uniquely effective for SWS brain involvement. This review aims to summarize early data on CBD’s efficacy for preventing and treating epilepsy and neuro-cognitive impairments in patients with SWS, likely molecular pathways impacted, and provide insights for future translational research to improve clinical treatment for patients with SWS.

Objectives To identify potential risk factors influencing Sturge–Weber Syndrome (SWS) and neurological outcomes in individuals with SWS and port-wine birthmarks from paternal, maternal, and familial factors. Methods This study follows a retrospective cross-sectional design. Clinical visits took place at the Kennedy Krieger Institute, a tertiary care center. Participants were individuals with SWS or port-wine birthmarks. Results Higher paternal age at conception was associated with a range of cognitive dysfunctions in offspring with SWS brain involvement. Indeed, paternal age was associated with low intelligence quotient (n = 25, P = .004), strokes or stroke-like episodes (n = 34, P = .030), gross and/or fine motor delay (n = 34, P = .036), delays in ability to perform activities of daily living (n = 30, P = .012), and delayed learning compared to peers (n = 31, P = .027). Furthermore, paternal age was correlated with worse cognitive outcomes, as measured by cognitive Neuroscore ( r s = 0.575, P < .001, n = 32). When maternal thyroid disease and hypertension were present during pregnancy, offspring were more likely to experience low intelligence quotient (n = 30, P = .041) and regression of any abilities (n = 37, P = .045), respectively. Logistic regression confirmed the association between paternal age and severe cognitive Neuroscore ( β = .580, P = .033, odds ratio: 1.79, 95% confidence interval: 1.05–3.04), even when controlling for the effects of seizures and strokes or stroke-like episodes. Conclusions Prenatal factors were associated with neurological symptoms in subjects with SWS. Older paternal age, in particular, may predict worse neurocognitive outcomes. Further research is needed in larger cohorts to determine the value of the identified prenatal factors as prognostic tools. Likewise, animal models may be used to determine the impact of prenatal factors on the severity of outcome.

Objective(s) Sturge–Weber syndrome (SWS), a rare neurovascular malformation disorder, is usually caused by the R183Q GNAQ somatic mosaic mutation enriched in brain endothelial cells. A developmental mouse model of SWS brain involvement is needed to investigate mutation impact upon brain vascular development and to facilitate preclinical drug studies. Methods A new Tet-ON R183Q GNAQ transgenic mouse line was paired with rtTA tet transactivator mice under the Tie2 promoter to generate mice expressing endothelial R183Q GNAQ in the presence of doxycycline. Litters were perfused at P14-17; half received a subseizure dose (1.5 mg/kg; intraperitoneal) of kainate an hour before perfusion. A subset was perfused with Evans blue. Fixed mouse brains were stained with X-gal, DAPI, and antibodies for Gαq, Tie2, phosphorylated-S6, and claudin-5. Images were scored for vessel staining intensity. Results X-gal staining was seen only in mutant mice; leptomeningeal endothelial X-gal staining was more frequent in kainate-treated mice ( P < 0.001). When perfused with Evans blue, only mutant brains showed severe staining ( P = 0.028). Median phosphorylated-S6 vessel scores were significantly higher in the leptomeninges of mutant mice ( P = 0.035). Mutant cortical microvessels demonstrated discontinuous claudin-5 and phosphorylated-S6 staining as well as increased vessel length in kainate-treated mice ( P = 0.024). Conclusions The new R183Q GNAQ Tet-ON developmental mouse brain model of SWS demonstrates endothelial expression of mutant Gαq associated with blood–brain barrier breakdown, altered vascular mammalian target of rapamycin activity, and abnormal cortical microvessel structure. This new translational model can be used to develop new drug targets and treatments for SWS.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

This commentary is on the original article by Mankel et al. on pages 111–118 of this issue.

Objective This study identified biomarkers of neurological outcome in Sturge‐Weber syndrome (SWS) via urine angiogenic factors and captured longitudinally derived natural history data within an SWS cohort. Methods This longitudinal, prospective, multicentered study of 61 people with SWS aged 0.4–55 years reports port‐wine birthmark score, Neuroscore, Neuro‐Quality of Life, and urine angiogenic factors over a two‐year period. Results Cognitive Neuroscore worsened over time for children aged 0–2 years. Male sex was associated with worsening Cognitive Function Neuroscore during the study. Age of seizure onset before 2 years was strongly associated with worse Neuroscore. Children with SWS had low Neuro‐Quality of Life related to cognitive function. Seizure severity, male sex, and earlier age of seizure onset were associated with worse Neuro‐Quality of Life in school‐aged children. Children with SWS have elevated basic fibroblast growth factor in their urine compared with controls, whereas higher vascular endothelial growth factor was associated with better Neuroscore. Interpretation This study is the first multicenter, prospective, and longitudinal study of people with SWS. It identifies significant clinical prognostic factors such as age of seizure onset and male sex, informs symptom progression over time by age group, and suggests that further study of angiogenic mechanisms and potential biomarkers are needed.

Background Ninety percent of infants with Sturge–Weber syndrome (SWS) brain involvement have seizure onset before 2 years of age; early‐onset seizures are associated with worse neurological outcome. Presymptomatic treatment before seizure onset may delay seizure onset and improve outcome, as has been shown in other conditions with a high risk of developing epilepsy, such as tuberous sclerosis complex. The electroencephalogram (EEG) may be a biomarker to predict seizure onset. This retrospective clinical data analysis aims to assess the impact of presymptomatic treatment in SWS. Methods This two‐center, Institutional Review Board–approved, retrospective study analyzed records from patients with SWS brain involvement. Clinical data recorded included demographics, age of seizure onset (if present), brain involvement extent (unilateral versus bilateral), port‐wine birthmark (PWB) extent, family history of seizures, presymptomatic treatment if received, Neuroscore, and antiseizure medications. EEG reports prior to seizure onset were analyzed. Results Ninety‐two patients were included (48 females), and 32 received presymptomatic treatment outside of a formal protocol (five aspirin, 16 aspirin and levetiracetam; nine aspirin and oxcarbazepine, two valproic acid). Presymptomatically treated patients were more likely to be seizure‐free at 2 years (15 of 32, 47% versus 7 of 60, 12%; p < 0.001). A greater percentage of presymptomatically treated patients had bilateral brain involvement (38% treated versus 17% untreated; p = 0.026). Median hemiparesis Neuroscore at 2 years was better in presymptomatically treated patients. In EEG reports prior to seizure onset, the presence of slowing, epileptiform discharges, or EEG‐identified seizures was associated with seizure onset by 2 years (p = 0.001). Conclusion Presymptomatic treatment is a promising approach to children diagnosed with SWS prior to seizure onset. Further study is needed, including prospective drug trials, long‐term neuropsychological outcome, and prospective EEG analysis, to assess this approach and determine biomarkers for presymptomatic treatment.

Objectives We summarize the current knowledge of Sturge–Weber syndrome (SWS) including genetic involvement, difficulties in diagnosis, symptoms caused by the vascular malformations, treatments, and future areas of research. Methods PubMed searches were completed between October and December of 2022 including the following search terms: Sturge–Weber neuroimaging, Sturge–Weber ocular involvement, Sturge–Weber G‐protein alpha q subunit (GNAQ), Sturge–Weber presymptomatic treatment, and Sturge–Weber quantitative EEG. Clinically relevant articles and case reports were reviewed and summarized, with emphasis placed on reports from the last 20 years. Results Literature suggests that early identification of brain involvement is essential for optimal medical care. Infants with a port‐wine birthmark on the forehead, temple, or eyelids are at risk for SWS brain and eye involvement. Neuroimaging findings include leptomeningeal enhancements, cortical calcifications, and brain atrophy, and diagnosis requires magnetic resonance imaging with and without contrast. Before 1 year of age, neuroimaging has low sensitivity and may underestimate the extent of involvement; imaging after 1 year of age is needed to exclude brain involvement. The most common underlying cause for SWS is a somatic mosaic mutation in GNAQ. Neurological symptoms include seizures, stroke or stroke‐like episodes, headaches, and cognitive deficits. Recommended treatment for SWS brain involvement includes aggressive seizure control with antiepileptic medications; low‐dose aspirin is also frequently but not universally utilized. Current literature suggests that children with SWS may benefit from presymptomatic treatment; further study of this approach is ongoing. Conclusions SWS is a rare neurovascular disorder usually signaled by a facial port‐wine birthmark. Early diagnosis and appropriate treatment may improve outcomes.