Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)-like spectrum with a unique NRAS c.182A>G (p.Q61R) variant: a case report

Abstract

Background

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a recently recognized cortical malformation linked to epilepsy, characterized by subtle cortical and white matter (WM) abnormalities. Typical MOGHE is predominantly associated with somatic SLC35A2 variants, while the genetic and phenotypic spectrum of MOGHE-like cortical malformations remains incompletely understood, with diverse undetermined molecular mechanisms contributing to disease heterogeneity and epileptogenesis.

Case Description

We report an 8-year-old girl with early-onset, drug-resistant epilepsy localized to the right temporal lobe. Brain magnetic resonance imaging (MRI) revealed atypical enlargement and irregular morphological changes of the right temporal lobe with a disrupted gray-white matter (GM-WM) interface, presenting cyst-like malformative changes that deviate from classic MOGHE radiological features. Neuropathological examination demonstrated cortical architectural disturbance, dysoriented neuronal clusters, and mild oligodendroglial hyperplasia consistent with a MOGHE-like spectrum lesion, while no histopathological evidence of low-grade epilepsy-associated tumor or other neoplastic lesions was identified. Whole exome sequencing (WES) identified a heterozygous NRAS c.182A>G (p.Q61R) variant, which is predicted to be functionally deleterious and interpreted as a potentially pathogenic variant based on standard clinical and genetic criteria. The patient achieved favorable post-surgical seizure control, and the pathogenic contribution of this rare NRAS variant requires further validation.

Conclusions

This case characterizes a rare epileptogenic MOGHE-like cortical malformation driven by a unique NRAS c.182A>G (p.Q61R) variant, expanding the molecular genetic spectrum of MOGHE-spectrum lesions. The findings indicate that alternative RAS-pathway molecular alterations may participate in the development of atypical MOGHE-like malformations and related epileptogenesis. This study underscores the necessity of comprehensive integration of radiological, histopathological, and genetic evidence for accurate diagnosis of atypical cortical developmental lesions, and provides novel insights for future mechanistic exploration and precision therapeutic research in refractory epilepsy associated with cortical malformations.

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Key findings

• This case report identifies a rare NRAS c.182A>G (p.Q61R) variant in an 8-year-old girl with a mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)-like spectrum epileptogenic cortical malformation. The patient presented with atypical radiological manifestations including enlarged and irregular right temporal lobe and disrupted gray-white matter interface. Neuropathological evaluation revealed cortical architectural disturbance, mild oligodendroglial hyperplasia and dysoriented neuronal clusters, without sufficient findings to fulfill criteria for classic MOGHE, and no histological evidence of low-grade epilepsy-associated tumor.

What is known and what is new?

• Traditionally, classic MOGHE is predominantly associated with somatic SLC35A2 variants. A substantial subset of patients with MOGHE-like cortical malformations lack SLC35A2 alterations, and the full genetic spectrum of this heterogeneous disease continuum remains poorly defined.

• Herein, we report a rare NRAS c.182A>G (p.Q61R) variant identified in a patient with an atypical MOGHE-like spectrum lesion associated with refractory temporal lobe epilepsy. This observation expands the molecular landscape of MOGHE-spectrum malformations and suggests that RAS-pathway aberrations constitute an alternative disease mechanism.

What is the implication, and what should change now?

• This finding highlights that the genetic architecture of MOGHE-spectrum disorders is not limited to canonical SLC35A2 alterations and supports the involvement of alternative RAS-related molecular pathways in disease pathogenesis and phenotypic heterogeneity. It emphasizes the necessity of broad, unbiased genetic screening for clinically atypical epilepsy-associated cortical malformations, rather than restricting genetic analysis to conventional hotspot genes only. Future functional and cohort studies are warranted to elucidate the mechanistic roles of NRAS variants in cortical dysplasia and epileptogenesis, which may revise current diagnostic frameworks and inspire novel targeted therapeutic approaches for drug-resistant epilepsy secondary to developmental cortical anomalies.

Introduction

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an emerging epileptogenic cortical malformation first described by Schurr et al. in 2017 (1). It was initially recognized from retrospective analyses of refractory epilepsy surgical specimens with inconspicuous or non-specific conventional imaging findings, accounting for approximately 3.7% of cryptogenic epilepsy surgical cases. Classic MOGHE is defined by a constellation of subtle neuropathological and radiological features, including blurred gray-white matter (GM-WM) interfaces, increased subcortical oligodendroglial cellular density, and ectopic neurons within 500 μm of the gray-white junction. This entity predominantly affects pediatric patients and preferentially involves the frontal lobe, while atypical temporal lobe-dominant presentations have also been documented, expanding its phenotypic spectrum.

Atypical MOGHE-spectrum lesions frequently exhibit divergent radiological and pathological features that do not fully match the rigid classic diagnostic criteria, which often leads to diagnostic ambiguity and differential diagnostic confusion with low-grade epilepsy-associated tumors and other malformations of cortical development. Given the subtle, heterogeneous, and sometimes atypical nature of MOGHE-like pathologies, accurate preoperative diagnosis and surgical planning remain challenging. Elucidating the diverse clinical, radiological, histopathological, and molecular characteristics of expanded MOGHE-spectrum disorders is critical to refine diagnostic frameworks and optimize individualized epilepsy management. Herein, we report a unique case of atypical MOGHE-like spectrum lesion with a rare somatic NRAS c.182A>G (p.Q61R) variant in a pediatric patient with drug-resistant temporal lobe epilepsy. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0595/rc).

Case presentation

This case report involves an 8-year-old girl who was admitted to the Children’s Hospital of Fudan University on December 28, 2024, with over 5 months of limb tremors. These episodes, occurring exclusively during sleep, typically around 6 a.m., involved limb trembling with closed eyes, without perioral twitching or drooling, each lasting about 10 seconds and resolving spontaneously. Upon waking, the patient reported nightmares, initially twice a week, increasing to 4–5 times weekly. She was a full-term cesarean delivery, with normal growth analogous to peers. Upon admission, physical examination showed that her height was 128 cm [50^th percentile by the World Health Organization (WHO) standard] and weight was 25 kg (50^th percentile). Neurocutaneous findings or other systemic abnormalities were absent. Her family, including grandparents, parents and an older brother, had no seizure history.

Electroencephalography (EEG) revealed abnormal interictal patterns, including epileptiform discharges in the right anterior mid-temporal region that increased during sleep, along with abnormal background activity characterized by heightened δ and θ waves predominantly in the right temporal region during wakefulness, and a focal onset seizure originating in the right temporal area during hyperventilation (Figure 1A). Magnetic resonance imaging (MRI) indicated enlargement of the right temporal lobe extending towards the cisterna ambiens and suprasellar cistern. This was accompanied by irregular morphology of the deep temporal gyri, hippocampus, and parahippocampal gyrus, coupled with high T2 fluid-attenuated inversion recovery (FLAIR) signals. Additionally, there was enlargement of the right temporal horn of the lateral ventricle accompanied by gray matter (GM) heterotopia (Figure 1B). Positron emission tomography/computed tomography (PET/CT) showed hypometabolism in the right temporal lobe and insula (Figure 1B). Near-infrared brain functional imaging during an eyes-closed resting state displayed robust functional connectivity throughout the brain, with tight interconnections and high interhemispheric connectivity; during tasks, increased brain activity intensity was noted. Despite treatment with lacosamide and perampanel, seizures persisted, leading to right temporo-occipital disconnection, standard anterior temporal lobectomy, and right insulectomy. During surgery, the demarcation between gray and WM was indistinct; no cysts or masses were observed.

Figure 1.

EEG and neuroimaging features of the atypical MOGHE-like spectrum lesion in the present patient with drug-resistant temporal lobe epilepsy. (A) The EEG shows slow wave activity in the right temporal region during wakefulness (= “awake”). Interictal phases reveal sharp and slow wave complexes as well as spike-and-slow wave patterns in the right temporal area. During seizures (= “Ictal”), there is rhythmic slow wave activity originating from the right temporal region. (B) MRI reveals enlargement of the right temporal lobe extending towards the cisterna ambiens and suprasellar cistern (white arrow). The deep temporal gyri, hippocampus, and parahippocampal gyrus exhibit irregular morphology, accompanied by high T2 FLAIR signals (red arrow). There is a cyst-like enlargement of the right temporal horn of the lateral ventricle with adjacent nodular GM signals (blue arrow). PET/CT shows hypometabolism in the right temporal lobe and insula (inside the circle). CT, computed tomography; EEG, electroencephalography; FLAIR, fluid-attenuated inversion recovery; GM, gray matter; MOGHE, mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy; MRI, magnetic resonance imaging; PET, positron emission tomography; T1, T1-weighted imaging; T2, T2-weighted imaging; WM, white matter.

Microscopic examination of surgically resected brain tissue demonstrated cortical architectural disorganization, increased oligodendroglial density near the GM-WM junction, and scattered dysoriented neuronal clusters within subcortical WM (Figure 2A-2C). Immunohistochemical staining revealed about 10 Olig2-positive oligodendroglial cells per microscopic field of 50×50 μm (Figure 2D). The Ki-67 proliferation index was quantitatively assessed as 4% (Figure 2E), reflecting low proliferative activity. Dysoriented neurons showed NeuN immunoreactivity (Figure 2F). No histological or immunohistochemical features supporting low-grade epilepsy-associated tumors or other glioneuronal neoplasms were identified.

Figure 2.

Histopathological and immunohistochemical features of the atypical MOGHE-like spectrum lesion. Microscopic examination shows cortical architectural disorganization with increased oligodendroglial density at the WM junction (A,B) and scattered dysoriented neuronal clusters within the subcortical WM (C). Immunohistochemistry demonstrates abundant Olig2-positive oligodendroglial cells (D). The Ki-67 proliferation index was quantitatively evaluated and indicates low proliferative activity (E). Dysoriented neurons exhibit NeuN immunoreactivity (F). Scale bars are indicated in each panel. GM, gray matter; MOGHE, mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy; WM, white matter.

Whole exome sequencing (WES) at a depth of 1,000× of the surgically resected brain tissue identified a heterozygous [c.182(exon3)A>G/p.(Q61R) (NM_002524)] variant in the NRAS gene (Figure 3A), with a variant allele frequency of 28.45%. The mutation [PS2_VeryStrong + PS3_Supporting (protein_function) + PS4 + PM1 + PM2_Supporting + PP3_Moderate (REVEL_Mis)] was evaluated to be pathogenic according to the guideline of the ACMG (2). The variant interpretation was additionally provided in Table 1. This site is conserved across species (Figure 3B). In the PyMOL modeling, the Q61R substitution does not alter the polar contacts with surrounding amino acids (Figure 3C). Meanwhile, WES and Sanger sequencing (Figure 3D) of the patient’s and her parents’ peripheral blood were performed, and the results confirmed that the mutation was somatic rather than germline.

Figure 3.

Molecular genetic characterization of the atypical MOGHE-like spectrum lesion harboring the NRAS c.182A>G (p.Q61R) variant. (A) WES identifies a heterozygous NRAS c.182A>G (p.Q61R) variant in the resected brain tissue. (B) The affected amino acid residue at position 61 is highly conserved across different vertebrate species. (C) Structural modeling using PyMOL suggests that the Q61R substitution does not abolish polar interactions with Tyr64. (D) Sanger sequencing of peripheral blood DNA from the patient and her parents confirms the variant is not present in the germline. MOGHE, mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy; WES, whole exome sequencing.

Table 1. The evidence for the pathogenicity of the identified NRAS variant.

Item	Content
Gene	NRAS
Chromosome location	Chr1:115256529
Exon	Exon 3
Nucleotide alteration	c.182 A>G
Transcript	NM_002524.5
Amino acid alterations	p.Q61R(Gln61Arg)
RS number	rs11554290
Variant allele frequency	28.45%
GnomAD	<0.0005
REVEL predicted value	[0.773, 0.932]
Pathogenic basis	PS2_VeryStrong + PS3_Supporting (protein_function) + PS4 + PM1 + PM2_Supporting + PP3_Moderate (REVEL_Mis)
ACMG grade	Pathogenic

ACMG, American College of Medical Genetics and Genomics; GnomAD, Genome Aggregation Database; RS, reference single nucleotide polymorphism.

The patient recovered well postoperatively, with no seizures reported at the 1-year follow-up. The patient and her family expressed satisfaction with the treatment process as well as the outcome.

All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the Children’s Hospital of Fudan University (No. FELL-2024-401). Written informed consent was obtained from the patient’s guardian for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Clinically, classic MOGHE is characterized by early-onset seizures, generally emerging before 3 years of age, with epileptic spasms reported as the most frequent initial manifestation (3). The patient described herein presented with recurrent nocturnal tremors and progressively more frequent awake seizures, reflecting the broad heterogeneity of seizure phenotypes observed across the MOGHE spectrum. EEG detected epileptiform discharges over the right anterior mid-temporal region together with abnormal background activity during wakefulness, consistent with interictal patterns that have prognostic relevance for epilepsy surgery. Typical MRI signatures of classic MOGHE consist of blurred GM-WM junctions and elevated T2/FLAIR signal, features frequently overlapping with focal cortical dysplasia (1,4). Beyond these conventional imaging alterations, our case demonstrated atypical cyst-like temporal lobe expansion alongside architectural distortion; importantly, no histopathological evidence of neoplasia was identified to support a low-grade epilepsy-associated tumor. PET/CT demonstrated focal hypometabolism within the lesion, a finding consistent with previous published observations (5,6). Although the patient’s epilepsy proved refractory to antiseizure medications, surgical resection achieved seizure freedom, an outcome comparable to that reported in other patients with MOGHE-spectrum epileptogenic malformations (5,6).

MOGHE constitutes a distinct epileptogenic malformation within the broader spectrum of cortical developmental anomalies and was formally recognized as a WM abnormality in the updated 2022 International League Against Epilepsy (ILAE) classification system (7). Strict classic MOGHE diagnostic criteria emphasize characteristic oligodendroglial proliferation and subcortical neuronal heterotopia; however, accumulating evidence indicates substantial phenotypic heterogeneity across the MOGHE disease spectrum (8). The histopathological diagnosis of MOGHE was made if the density of oligodendroglial cells at the GM-WM junction was above 2,200/mm² and that of heterotopic neurons in the subcortical WM was above 30/mm². The density of Olig2-immunoreactive cells above 2,200/mm² was determined based on the analysis of at least randomly selected microscopic fields of 50×50 μm, where more than 10 cells were counted per field (8). In the present atypical case, histopathological examination revealed increased oligodendroglial density at the WM junction and scattered dysoriented neuronal clusters within the subcortical WM, consistent with an atypical MOGHE-like spectrum lesion rather than a fully typical, canonical MOGHE entity. Notably, this lesion presents diagnostic challenges due to overlapping radiological features with low-grade epilepsy-associated tumors. Nevertheless, no histopathological signs of neoplasia, tumorous mass formation, or infiltrative growth were detected in the resected specimen, which definitively excludes low-grade glioneuronal tumors, such as dysembryoplastic neuroepithelial tumor. Although the Olig2-positive cellular density in this lesion resembles that observed in low-grade oligodendroglial lesions, the Ki67 proliferation index remained really low, consistent with a malformative, non-neoplastic etiology. Collectively, the absence of tumor architecture, lack of cellular atypia, and presence of cortical developmental disorganization support the diagnosis of an atypical MOGHE-spectrum malformation rather than a neoplastic process, further highlighting the heterogeneous neuropathological continuum of MOGHE-related epilepsy-associated cortical lesions.

Previous molecular studies have demonstrated that somatic SLC35A2 pathogenic variants account for approximately 45% of classic MOGHE cases, highlighting the pivotal role of mosaic somatic mutations in neuroglial progenitor cells during cortical development (8). Rare variants in DEPDC5 and EGFR have also been sporadically documented in individual MOGHE-spectrum cases, further indicating the genetic heterogeneity of this disease entity (9,10). In the present case of atypical MOGHE-like cortical malformation, WES successfully identified a somatic heterozygous NRAS c.182A>G (p.Q61R) variant, while no canonical SLC35A2 mutation was detected. The altered amino acid residue at position 61 is highly conserved across species, implying its functional importance for normal NRAS protein activity. Multiple in silico functional prediction tools, including CADD, PolyPhen-2, and SIFT, consistently classified this NRAS c.182A>G variant as functionally deleterious. Physiologically, the wild-type glutamine at position 61 possesses a neutral side chain, whereas the substituted arginine carries a positively charged hydrophilic side chain that tends to localize to the protein surface. Despite no obvious disruption of polar interactions with tyrosine 64 (Y64) observed in PyMOL structural modeling, the Q61 residue constitutes a core catalytic site of NRAS protein; therefore, the Q61R substitution is highly likely to perturb normal protein function and downstream signaling cascades.

Pathogenic NRAS variants are well-established to drive neurodevelopmental disorders via aberrant activation of the RAS/MAPK pathway, which impairs neural progenitor cell differentiation, migration, and cortical maturation, ultimately leading to structural brain anomalies (11,12). Somatic NRAS Q61 hotspot mutations have been repeatedly detected in various malformations of cortical development, which are closely associated with intractable focal epilepsy (9). Combined with our case findings, NRAS pathogenic variants may represent an alternative genetic driver for atypical MOGHE-spectrum lesions, expanding the molecular spectrum beyond the canonical SLC35A2-driven pathogenesis. We hypothesize that aberrant NRAS-mediated signaling may contribute to cortical architectural disorganization and increased neuronal excitability, thereby promoting epileptogenesis in this atypical malformation.

Further functional validation and animal model studies are urgently required to elucidate the exact mechanistic link between NRAS mutations, cortical dysplasia, and seizure susceptibility, which may facilitate the development of targeted therapeutic strategies for refractory epilepsy secondary to RAS-pathway-related cortical malformations. Additionally, recent research has reported mosaic Y-chromosome alterations in a subset of MOGHE patients of both sexes, suggesting a potential extra-autosomal pathogenic mechanism for this disorder (13). Since Y-chromosome analysis was not performed in the present case, the potential involvement of sex-chromosome mosaicism in this atypical MOGHE-like lesion cannot be excluded and requires further exploration in future studies.

Conclusions

In this study, we describe an atypical case of a MOGHE-like spectrum cortical malformation harboring a somatic NRAS c.182A>G (p.Q61R) variant in a pediatric patient with drug-resistant temporal lobe epilepsy. This finding expands the heterogeneous phenotypic and genetic spectrum of MOGHE-related developmental lesions, which were previously dominated by canonical SLC35A2 alterations. The present case further highlights the diagnostic challenge of atypical MOGHE-like lesions, which may radiologically mimic low-grade epilepsy-associated tumors but exhibit purely malformative, non-neoplastic histopathological features. Our results emphasize the necessity of comprehensive integration of neuroimaging, detailed histopathological evaluation, and unbiased molecular genetic testing for precise diagnosis of atypical cortical developmental anomalies. The identification of the pathogenic NRAS variant provides novel insight into the alternative RAS-pathway mechanisms underlying epileptogenesis in MOGHE-spectrum malformations, improves our understanding of genetically heterogeneous focal epilepsy, and may facilitate future precision medicine strategies and targeted therapeutic development for refractory epilepsy secondary to cortical malformations.

Supplementary

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the Children’s Hospital of Fudan University (No. FELL-2024-401). Written informed consent was obtained from the patient’s guardian for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.