Landmark Meta-Analysis Maps the Hidden Psychiatric Burden of Neurofibromatosis Type 1

Neurofibromatosis type 1 has long been recognised as a disorder of the skin, nerves and tumours, but a sweeping new synthesis of global evidence suggests that its most disabling consequences may lie in the mind. A systematic review and meta-analysis published in the Journal of Neurology has pooled data from fifty studies spanning four continents to deliver the most precise estimates yet of how often people with NF1 experience intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, depression, anxiety, seizures and epilepsy. The findings quantify a neuropsychiatric burden far exceeding that of the general population and reinforce calls for routine developmental and mental health screening in everyone diagnosed with the condition.

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