Neurofibromatosis type 1 is the most common autosomal dominant tumor predisposition syndrome, caused by pathogenic variants in the NF1 tumor suppressor gene that may be inherited or arise spontaneously. The gene encodes neurofibromin, a RAS GTPase-activating protein that acts as a brake on RAS signaling and on the downstream mitogen-activated protein kinase, or MAPK, pathway. When NF1 is inactivated, this brake is released, and persistent MAPK signaling drives the formation of tumors throughout the central and peripheral nervous systems, including cutaneous and plexiform neurofibromas, malignant peripheral nerve sheath tumors, and gliomas. Central nervous system gliomas occur in roughly 15 to 20 percent of people with NF1, and they span a wide clinical spectrum, from indolent low-grade tumors that may never require treatment to aggressive high-grade gliomas with poor outcomes.

The therapeutic logic behind MEK inhibitors rests directly on this biology. Because NF1 loss leaves the MAPK pathway constitutively active, drugs that block MEK, a kinase midway along the pathway, should in principle starve the tumor of one of its central growth signals. This reasoning has already translated into clinical practice for selected NF1-associated low-grade gliomas, where guideline-based frameworks include MEK inhibition, BRAF and MEK-directed therapy for certain BRAF-altered tumors, and mTOR inhibition with everolimus as options for patients needing adjuvant treatment or therapy for progressive disease. Preclinical glioblastoma models have also suggested that NF1 deficiency may confer sensitivity to a range of clinically available and experimental MEK inhibitors, including mirdametinib, which added plausibility to the idea that the approach could extend to high-grade disease.

High-grade gliomas, however, are biologically different from their low-grade counterparts in ways that complicate this strategy. They more frequently carry additional genomic alterations, including loss of the CDKN2A and CDKN2B genes and changes involving ATRX, TP53, and the TERT promoter. They also display greater epigenetic diversity, with many tumors classified as high-grade astrocytoma with piloid features, abbreviated HGAP, or as molecular subclasses of isocitrate dehydrogenase-wildtype glioblastoma. As tumors accumulate these additional alterations, MAPK signaling may become only one component of a broader oncogenic program rather than the dominant dependency, which could explain why blocking the pathway produces radiographic stability in many patients but rarely prolonged disease control. Standard management of these tumors has otherwise been adapted from typical high-grade glioma care: maximal safe resection, radiotherapy, and alkylator-based chemotherapy, with published MEK inhibitor experience limited to case reports and small series.

The MD Anderson team identified patients through the health record system using the terms glioma and neurofibromatosis under an institutional review board-approved protocol, screening for adults aged 18 to 80 with NF1-associated high-grade glioma who initiated a MEK inhibitor between December 1, 2019, and January 31, 2026. The initial search returned fourteen patients; two fourteen-year-olds were excluded because of age, and three adults were excluded because they never started MEK inhibitor therapy, in some cases due to prescription barriers or insurance rejections. Eligible patients had progressive or recurrent disease and tumor tissue analysis confirming World Health Organization grade 3 or 4 glioma. NF1 status was determined from clinical records and molecular testing, with tumor-only testing without matched normal confirmation not used to assign germline status. The final cohort comprised nine patients, four female and five male.

The tumors in the cohort reflected the heterogeneity that makes this disease so difficult. Six patients had high-grade astrocytoma with piloid features, two had IDH-wildtype glioblastoma, and one had IDH-wildtype high-grade glioma not otherwise specified. Among the HGAP cases, ATRX alteration was the most frequent additional molecular change, present in all six, followed by CDKN2A/B loss in two. The glioblastoma and not-otherwise-specified cases carried more varied findings, including BRAF alterations at positions p.G494V and p.D594G, along with changes in TERT, TP53, GFAP, OLIG2, MYCL, and NOTCH3. Seven of the nine patients had clinical NF1 syndrome, one with a confirmed germline variant, while the remaining two had somatic tumor NF1 alterations without a clinical NF1 phenotype. The median age at high-grade glioma onset was 34 years, with a range of 22 to 58, and the median Karnofsky Performance Status at the start of MEK inhibitor therapy was 60, indicating substantial functional impairment.

Treatment exposure varied widely. Six patients received MEK inhibitors after progression following prior radiotherapy, and most had undergone other local or systemic treatments beforehand, including resection in six patients, radiotherapy in seven, and chemotherapy or biologic agents such as temozolomide, lomustine, carboplatin, bevacizumab, and an ERK inhibitor. Six patients received selumetinib for one to seven cycles, one received dabrafenib plus trametinib for two cycles, and three received mirdametinib, with overall exposure ranging from one to fourteen cycles. By Response Assessment in Neuro-Oncology criteria, the best radiographic response was partial response in two patients, stable disease in six, and not evaluable in one. Both partial responses occurred in the mirdametinib-treated group, and both met RANO criteria confirmed on imaging at least four weeks apart.

The durability of those responses diverged sharply. One of the two responding patients remained on mirdametinib without progression at last follow-up, the only patient in the cohort still on active MEK inhibitor-based therapy. The other developed radiographic progression after 4.9 months, roughly five cycles, discontinued the drug, and transitioned to lomustine. Toxicity also shaped the outcomes: one patient could not tolerate MEK inhibitor therapy at all and later progressed; one experienced a transient decline in left ventricular ejection fraction that required a treatment hold of less than a month before resumption; one developed a cutaneous rash that forced a dose reduction and ultimately prevented completion of a third cycle; and four patients discontinued therapy in the setting of complications not clearly attributed to treatment. One patient was lost to follow-up after three cycles of selumetinib, with death recorded 6.4 months after starting therapy. By Kaplan-Meier analysis, median overall survival from high-grade glioma diagnosis was 35.6 months, while median progression-free survival and overall survival from MEK inhibitor initiation were 2.9 and 9.4 months respectively. Three patients were alive at last follow-up.

The authors frame the mirdametinib responses as a clinically notable but hypothesis-generating signal rather than proof of efficacy. They suggest that the drug’s central nervous system pharmacodynamic profile and its preclinical activity in NF1-deficient glioblastoma models may account for its ability to reach intracranial NF1-driven tumors, and they argue that the observed responses justify prospective evaluation. At the same time, they acknowledge that response attribution is constrained by the retrospective design, heterogeneous prior therapy, and the possible effects of earlier radiotherapy or concurrent systemic treatment. The exclusion of the two pediatric patients cuts both ways: it reduced potential confounding from age-related differences in pharmacokinetics and dosing, but both children experienced early progression or intolerance, so their exclusion may have biased the results toward more favorable estimates.

What the study ultimately delivers is a carefully documented baseline for a disease where almost no systematic data existed. It is, to the authors’ knowledge, the first clinical report of mirdametinib in NF1-associated high-grade glioma and the largest single-center cohort of MEK inhibitor use in this population published to date, spanning HGAP, glioblastoma, and not-otherwise-specified tumors. The partial responses suggest that at least some of these tumors may retain sensitivity to MAPK pathway blockade even at high grade, although the authors caution that MAPK signaling may be only one component of a broader oncogenic program in these tumors, and the short median progression-free survival and the spectrum of toxicities underline that single-agent MEK inhibition did not produce durable disease control for most patients. The authors conclude that larger, multi-institutional prospective studies with standardized response assessment and molecular correlates are needed to define which patients are most likely to benefit, the optimal timing of therapy, and whether MEK inhibition can improve survival in this rare and underserved population.

Subject of Research: MEK inhibitor treatment outcomes in NF1-associated high-grade glioma

Article Title: MEK inhibitors in NF1-associated high-grade glioma: partial responses and outcomes from a single-institution cohort and literature review

Article References: Yu, M.-C., Hsi, A. H., Adnan, A., Knight, S. R., McCutcheon, I. E., Slopis, J. M., & Kamiya-Matsuoka, C. (2026). MEK inhibitors in NF1-associated high-grade glioma: partial responses and outcomes from a single-institution cohort and literature review. Journal of Neuro-Oncology, 180(2), Article 30. https://doi.org/10.1007/s11060-026-05835-6

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05835-6

Keywords: NF1, high-grade glioma, MEK inhibitors, mirdametinib, selumetinib, glioblastoma, RAS/MAPK pathway, RANO criteria, retrospective cohort, targeted therapy, neuro-oncology, progression-free survival

Noonan syndrome and related genetic disorders, collectively known as RASopathies, involve changes in the RAS-MAPK signaling pathway, which has an important role in cell growth and development. Cardiovascular abnormalities occur in 80% to 90% of people with Noonan syndrome, and hypertrophic cardiomyopathy is present in approximately 20%. The condition causes the heart muscle to become abnormally thick, and some infants develop severe disease and heart failure early in life.

BabyMERIT focuses on this severe infantile presentation rather than on the full spectrum of Noonan syndrome or all forms of hypertrophic cardiomyopathy. The trial addresses an urgent need for prospective evidence on treatment options for infants with RASopathy-associated hypertrophic cardiomyopathy. Investigators said the study builds on evidence that targeting the RAS-MAPK pathway may improve the cardiac condition, while emphasizing that the new study is needed to evaluate both potential benefits and risks.

The project is also intended to establish clinical and data-coordination infrastructure for examining a condition that can make affected infants critically ill very early in life. Standardized collection of cardiac imaging, biomarker data and clinical outcomes across participating centers will allow investigators to study the disease systematically. Mount Sinai will serve as the BabyMERIT Clinical Coordinating Center, while Carelon Research/New England Research Institutes will serve as the Data Coordinating Center.

The latter organization has received NIH funding totaling more than $4.43 million over six years. Together, the awards provide more than $8.5 million for the trial’s clinical and data-coordination infrastructure. Bruce D. Gelb, MD, of Mount Sinai, and Jane W. Newburger, MD, MPH, of Boston Children’s Hospital, are the Clinical Coordinating Center principal investigators.

Their work with the Pediatric Heart Network will support collaboration among centers across the United States and coordinated collection of data on treatment effects and safety. Researchers plan to enroll 25 infants in the prospective treatment arm. Eligible participants must be older than 28 days and younger than six months and must have Noonan syndrome or a closely related RASopathy, hypertrophic cardiomyopathy and severe heart failure requiring hospitalization.

The small planned sample reflects the specialized nature of the group being studied, and the investigators will document adverse events as well as potential changes in heart function and disease-related outcomes. BabyMERIT will use a single-arm, open-label design, meaning that all 25 enrolled infants will receive trametinib and both participants and clinicians will know the treatment being given. Researchers will compare the prospective treatment arm with a real-world evidence cohort of approximately 100 infants who received standard-of-care treatment between 2015 and the study period.

The comparison group is not described as a randomized control group. Although the design can provide structured prospective information about treated infants, the absence of concurrent randomization and the use of an open-label regimen will be important considerations when interpreting differences between the treatment arm and the historical real-world cohort. Infants in the treatment arm will receive trametinib for 12 months and then enter observation for up to 12 additional months to monitor for relapse.

Infants whose disease relapses may be eligible for retreatment for up to another 12 months. The primary endpoint is a composite of death, heart transplantation or septal myectomy by 12 months. Septal myectomy is open-heart surgery used to treat hypertrophic cardiomyopathy.

The composite therefore combines three outcomes—mortality, the need for a heart transplant and the need for surgery—rather than providing a single continuous measure of cardiac function. The planned observation period will also show whether cardiac disease returns after the initial treatment course and how infants respond if they are treated again. In addition to the primary endpoint, researchers will assess heart function, heart failure, biomarkers, relapse, response to retreatment and adverse events.

Cardiac imaging and biomarker testing will receive centralized review through Pediatric Heart Network core laboratories, supporting consistent evaluation across participating sites. Participants will also be monitored closely for potential adverse effects involving the skin, eyes and heart, as well as changes in blood counts and kidney, liver or thyroid function. This surveillance will provide information about both the course of the heart condition and the broader safety profile of trametinib in infants younger than six months.

The scientific question is whether inhibiting signaling in the molecular pathway implicated in RASopathies can change the course of severe hypertrophic cardiomyopathy in infancy. BabyMERIT is a test of a precision-medicine approach, not an established treatment, and the announcement does not report enrollment results, treatment responses, survival data or evidence of efficacy. Its small treatment arm and nonrandomized historical comparison will limit the strength of conclusions that can be drawn if the groups differ in ways beyond treatment.

Results will depend on completion of treatment, follow-up and analysis of the specified endpoints. Even so, the trial will provide prospective clinical and safety data intended to guide future research and care for infants with this rare RASopathy-associated condition.

Subject of Research: A national single-arm trial of trametinib for severe hypertrophic cardiomyopathy in infants with Noonan syndrome and related RASopathies

Article Title: Mount Sinai to lead national trial of targeted therapy for infants with noonan syndrome and severe hypertrophic cardiomyopathy

Article References: Mount Sinai to lead national trial of targeted therapy for infants with noonan syndrome and severe hypertrophic cardiomyopathy. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: BabyMERIT trial, trametinib, Noonan syndrome, RASopathies, hypertrophic cardiomyopathy, infant heart failure, RAS-MAPK pathway, Pediatric Heart Network, precision medicine, clinical trial, Mount, Sinai

NF1 is an autosomal dominant genetic disorder caused by germline mutations in the NF1 gene, which encodes neurofibromin, a critical negative regulator of the RAS/MAPK signalling pathway. With an estimated incidence of one in 2500 to 3000 live births, it is classified among the RASopathies and shows strikingly variable clinical expression. When neurofibromin function is lost, RAS signalling runs unchecked, driving peripheral nerve sheath tumours, skeletal dysplasias and alterations in brain architecture. But the pathway also governs processes central to cognition: neuroplasticity, myelination and the delicate excitatory–inhibitory balance within specific synaptic circuits. Dysregulation of these mechanisms is thought to underlie the cognitive and behavioural deficits that emerge from an early age and shape socio-cognitive development and academic performance.

The research team, led by Elena Moreno-Charco and Carlos Pascual-Morena of the University of Castilla-La Mancha in Spain, searched MEDLINE, Scopus and Web of Science from inception to April 2026, following PRISMA and MOOSE guidelines with a protocol registered in PROSPERO. From 4932 identified records, fifty studies were ultimately included, covering populations in the Americas, Europe, Asia and Oceania. Sample sizes ranged from 24 to 8579 participants, with mean ages between 4.5 and 43.3 years and an approximately equal sex distribution. Crucially, the investigators separated, where possible, studies of the general NF1 population from those focusing exclusively on patients carrying NF1 microdeletions, a genetically distinct subgroup in which a larger chunk of chromosome 17 is lost.

The headline numbers are striking. Pooled prevalence of intellectual disability in the general NF1 population was 8 percent, roughly four to sixteen times higher than general population figures of 0.5 percent in adults and 1.8 percent in children. In the microdeletion subgroup, that figure leapt to 41 percent. Autism spectrum disorder affected an estimated 11 percent of people with NF1, compared with roughly 0.76 percent in the general population. ADHD emerged as the single most common neuropsychiatric comorbidity, with a pooled prevalence of 33 percent against a general population estimate of 3.4 percent, and 45 percent among microdeletion carriers. Seizures affected 11 percent and epilepsy 9 percent, several-fold above the roughly 0.64 percent of people affected by active epilepsy worldwide. Depression and anxiety each affected around 12 to 13 percent.

The fivefold elevation of intellectual disability risk in microdeletion carriers has a well-characterised biological basis. Whereas most patients with NF1 carry point mutations affecting only the NF1 gene itself, NF1 microdeletions involve the simultaneous loss of up to 14 contiguous functional genes in chromosomal region 17q11.2, generating extensive haploinsufficiency with disproportionate cognitive impact. Among the co-deleted genes, two have been specifically implicated in the intellectual phenotype: OMG, which encodes an oligodendrocyte myelin glycoprotein involved in regulating synaptic plasticity, and RNF135, an E3 ubiquitin ligase whose deficiency is associated with intellectual disability and neurodevelopmental deficits. The co-deletion of both genes may explain why microdeletion cohorts consistently report the highest rates of cognitive impairment.

The molecular story is more nuanced for seizures. Loss of neurofibromin and the resulting RAS hyperactivation can alter brain architecture, disrupt myelination and, crucially, disturb the excitatory–inhibitory balance in synaptic circuits, creating intrinsic susceptibility to seizure activity. Yet the authors caution that this mechanism does not account for the full clinical picture. NF1-associated epilepsy is heterogeneous and frequently secondary to demonstrable structural pathology, including brain tumours, mesial temporal sclerosis and cortical malformations, the latter identified as independent predictors of persistent, drug-resistant seizures. Intrinsic molecular causes and clinically visible structural lesions should therefore be regarded as distinct contributors to the seizure burden.

Methodological rigour was a defining feature of the analysis. The team used random-effects meta-analyses with the Hartung–Knapp–Sidik–Jonkman model, assessed heterogeneity with the I-squared statistic, and calculated 95 percent prediction intervals to describe the range of prevalence a future comparable study might expect. Forty-three of the fifty studies, or 86 percent, were rated high quality on the Joanna Briggs Institute checklist, with none rated low quality. Sensitivity analyses excluding one study at a time did not materially alter any pooled estimate, and results were consistent between untransformed and Freeman–Tukey double-arcsine analyses. Meta-regression identified one intriguing moderator: for every 1 percent increase in the proportion of females in a cohort, the prevalence of depression rose by approximately 1.1 percent, a finding consistent with well-documented sex differences in depression in the general population, driven by a combination of biological, psychological and social factors.

The authors are candid about the limits of their synthesis. Heterogeneity was substantial for most outcomes, with individual study estimates ranging from 3 to 23 percent for intellectual disability, 2 to 26 percent for autism, and 3 to 72 percent for ADHD. Prediction intervals were correspondingly wide, particularly for ADHD, spanning 2 to 73 percent. Much of this variability reflects genuine methodological differences: studies relying on administrative records or parental report systematically underestimate prevalence by missing mild or subthreshold cases, while screening scales, whose cut-offs are calibrated for sensitivity, tend to overestimate depression in particular. Tertiary referral centres concentrate the most severe cases, inflating estimates, and diagnostic criteria have shifted considerably across the decades the included studies span. Funnel-plot asymmetry suggestive of small-study effects was detected for several outcomes, though the authors stress this cannot be equated with publication bias. As a single-arm meta-analysis, the study also provides contextual comparisons rather than matched estimates of relative risk.

Despite these caveats, the clinical message is unambiguous. The quantified burden of neuropsychiatric and seizure disorders in NF1 reinforces existing guideline recommendations for developmental and neuropsychiatric surveillance, aligning NF1 care with approaches already applied across other RASopathies. Early detection enables timely pharmacological, psychoeducational and behavioural intervention, with meaningful gains in quality of life and long-term functional outcomes. At the same time, the analysis exposes a significant gap in knowledge: the neuropsychiatric profile of microdeletion carriers rests on only a handful of small studies, and whether contiguous-gene deletion modifies the attentional or autistic burden, as it clearly does for intellectual disability, remains unresolved. The authors call for larger prospective studies that integrate molecular and genetic data alongside clinical variables, so that genotype–phenotype associations can be established with confidence and screening strategies tailored to the specific genetic subtype each patient carries.

For the estimated one in 2500 to 3000 people born with NF1, and the families and clinicians who care for them, this synthesis transforms scattered, often contradictory prevalence figures into a coherent evidence base. It confirms that the brain is not a bystander in this disease but one of its principal battlegrounds, and that a multidisciplinary approach, pairing tumour surveillance with systematic neuropsychiatric screening, is not optional but essential. As research moves toward haploinsufficiency-restoring therapies and precision genotyping, the hope is that the cognitive and emotional toll of NF1 will shift from an accepted inevitability to a treatable target.

Subject of Research: Prevalence of neuropsychiatric and seizure disorders in neurofibromatosis type 1

Article Title: Prevalence of neuropsychiatric and seizure disorders in neurofibromatosis type 1: a systematic review and meta-analysis

Article References: Moreno-Charco, E., Pascual-Morena, C., Álvarez-Bueno, C., Zuheros-Lara, B., Martínez-García, I., Martínez-Sánchez, P., Contreras-Molina, M., & Patiño-Cardona, S. (2026). Prevalence of neuropsychiatric and seizure disorders in neurofibromatosis type 1: a systematic review and meta-analysis. Journal of Neurology, 273(10), Article 603. https://doi.org/10.1007/s00415-026-14143-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14143-y

Keywords: neurofibromatosis type 1, NF1, meta-analysis, ADHD, autism spectrum disorder, intellectual disability, epilepsy, depression, anxiety, RAS/MAPK pathway, NF1 microdeletion, neurodevelopmental disorders

Using clinical follow-up and genotype-focused analysis, researchers assessed how cardiomyopathy evolves soon after diagnosis. The central question was whether the RASopathy subtype itself acts as a prognostic marker for cardiac outcomes, rather than HCM being driven by uniform mechanisms across all cases. By stratifying patients according to subtype, the team evaluated the timing and intensity of disease progression in relation to underlying molecular causes.

The findings suggest that early HCM course is not “one-size-fits-all.” Patients with certain RASopathy subtypes showed signs consistent with a more aggressive early cardiac phenotype, including earlier manifestation and more pronounced echocardiographic features. Other subtypes appeared to progress more slowly, implying that the severity of signaling dysregulation translates into measurable differences in cardiac remodeling.

Genetically, the study emphasizes that specific variants within the RAS/MAPK network may influence not only the probability of developing HCM, but also the speed at which cardiac hypertrophy emerges. This points to a mechanistic gradient: upstream molecular disruptions can change how cardiomyocytes respond to growth cues, potentially altering hypertrophic pathways and downstream cardiac stress responses.

From a clinical perspective, the work supports subtype-aware risk stratification. Rather than relying solely on baseline cardiac imaging, clinicians may benefit from incorporating genetic information to anticipate which children require closer surveillance. Early identification could improve timing of intervention decisions, such as managing symptoms, monitoring arrhythmia risk, and guiding care intensity.

The study’s “early course” focus is particularly important because pediatric cardiomyopathy trajectories can shift rapidly during growth. Detecting higher-risk patterns early may help clinicians tailor follow-up intervals and reduce the chance of delayed recognition of worsening disease.

Beyond immediate care, the results offer a roadmap for translational research. If genotype predicts phenotype, targeted therapies that modulate RAS/MAPK activity or related growth signaling could be tested with stratification, improving the likelihood of detecting subtype-specific benefits.

Overall, this viral science news highlights a move toward precision cardiology in rare genetic disorders—where the RASopathy label is not merely descriptive, but predictive of how the heart will behave early in life.

Subject of Research: RASopathies and early disease course in RASopathy-associated hypertrophic cardiomyopathy
Article Title: Impact of RASopathy subtype on the early disease course of RASopathy-associated hypertrophic cardiomyopathy: clinical outcomes and genetic insights
Article References: López-Guillén, J.L., Carcavilla, A., Díez-Sebastián, J. et al. (2026) Pediatr Res. https://doi.org/10.1038/s41390-026-05152-8
Image Credits: AI Generated
DOI: 10.1038/s41390-026-05152-8
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