CT Scan Data Analysis in Malformations of Cortical Development.

Malformations of cortical development (MCDs) are a diverse group of disorders that result from abnormal neuronal migration, proliferation, and differentiation during brain development. Head computed tomography (CT) has limited use in the diagnosis of MCDs and should be reserved for selected cases with specific indications or when magnetic resonance imaging is not available or contraindicated. CT can detect brain calcifications associated with MCDs, thus helping in the differential diagnosis between acquired and genetic MCDs or in the identification of different genetic patterns. Moreover, CT can provide high-resolution images of the skull and bones, thus identifying associated malformations, such as craniosynostosis, inner and middle ear malformations, and vertebral anomalies. In this chapter, we review the CT scan technique, data analysis, and indications in the investigation of MCDs.

MRI Data Analysis in Malformations of Cortical Development.

Brain magnetic resonance imaging (MRI) is a noninvasive imaging modality that utilizes powerful magnets and radio waves to generate detailed images of the brain, making it a valuable tool for investigating malformations of cortical development (MCD). Various MRI techniques, including 3D T1-weighted, multiplanar thin-sliced T2-weighted, and 3D fluid-attenuated inversion recovery (FLAIR) sequences, can provide high-resolution images with excellent spatial and contrast resolution, allowing for a detailed visualization of cortical anatomy and abnormalities. Almost all MCD can be detected and characterized using MRI. Advanced techniques, such as arterial spin labeling MR perfusion, diffusion tensor imaging (DTI), and functional MRI (fMRI), may be used to improve the detection rate of these malformations and to plan surgery in case of drug-resistant epilepsy. However, there are also limitations related to high cost, relatively low availability, need for sedation or anesthesia, and limited sensitivity for detecting subtle focal cortical malformations. Despite these limitations, brain MRI plays a crucial role in the investigation of MCD, providing valuable information for diagnosis, treatment planning, and patient management.

[Advances of pathological research and classification in malformations of cortical development associated with refractory epilepsy].

With rapid development of genetic testing techniques, neuroimaging and neuroelectrophysiological technologies, our understanding of malformations of cortical development continues to be deepened and updated. In particular, mutations in genes related to the mammalian target of rapamycin (mTOR) signaling pathway have been successively discovered in focal cortical dysplasia (FCD). At the same time, the classification consensus on FCD issued by the International League Against Epilepsy (ILAE) in 2011 has encountered problems and challenges in diagnostic practice. Therefore, in 2022, ILAE proposed an updated version of the FCD classification based on the progress in molecular genetics over the past decade. The main addition to the classification system is "white matter lesions, " and it is also suggested to integrate histopathological, neuroimaging, and molecular testing results for multi-level integrated diagnosis to achieve reliable, clinically relevant, and therapeutic targeted final diagnosis.

Pharmacological evaluation of E2730, a novel selective uncompetitive GAT1 inhibitor, on epileptiform activities in resected brain tissues from human focal cortical dysplasia ex vivo.

Focal cortical dysplasia (FCD) is an important etiology of focal epilepsy in children and adults. However, only a few preclinical models sufficiently reproduce the characteristic histopathologic features of FCD. To improve the success rate of clinical trials for antiseizure medications (ASMs) in patients with FCD, more human-relevant preclinical models are needed, and epileptic foci resected from patients are a powerful tool for this purpose. Here, we conducted ex vivo studies using epileptic foci resected from patients with FCD type II to evaluate the pharmacologic effects of the ASM candidate E2730, a selective uncompetitive inhibitor of γ-aminobutyric acid transporter 1. We used the same ex vivo assay system to assess carbamazepine (CBZ), an ASM often prescribed for focal epilepsy, as a reference. At the higher dose tested (200 µM), both E2730 and CBZ suppressed spontaneous epileptiform activities almost completely. At the lower dose (100 µM), CBZ reduced the area of brain tissue showing epileptiform activity, whereas E2730 significantly decreased the number of epileptiforms. These findings suggest that E2730-both as a single agent and in combination with CBZ-merits evaluation in clinical trials involving patients with FCD.

Development and prospective clinical validation of a convolutional neural network for automated detection and segmentation of focal cortical dysplasias.

PURPOSE: Focal cortical dysplasias (FCDs) are a leading cause of drug-resistant epilepsy. Early detection and resection of FCDs have favorable prognostic implications for postoperative seizure freedom. Despite advancements in imaging methods, FCD detection remains challenging. House et al. (2021) introduced a convolutional neural network (CNN) for automated FCD detection and segmentation, achieving a sensitivity of 77.8%. However, its clinical applicability was limited due to a low specificity of 5.5%. The objective of this study was to improve the CNN's performance through data-driven training and algorithm optimization, followed by a prospective validation on daily-routine MRIs. MATERIAL AND METHODS: A dataset of 300 3 T MRIs from daily clinical practice, including 3D T1 and FLAIR sequences, was prospectively compiled. The MRIs were visually evaluated by two neuroradiologists and underwent morphometric assessment by two epileptologists. The dataset included 30 FCD cases (11 female, mean age: 28.1 ± 10.1 years) and a control group of 150 normal cases (97 female, mean age: 32.8 ± 14.9 years), along with 120 non-FCD pathological cases (64 female, mean age: 38.4 ± 18.4 years). The dataset was divided into three subsets, each analyzed by the CNN. Subsequently, the CNN underwent a two-phase-training process, incorporating subset MRIs and expert-labeled FCD maps. This training employed both classical and continual learning techniques. The CNN's performance was validated by comparing the baseline model with the trained models at two training levels. RESULTS: In prospective validation, the best model trained using continual learning achieved a sensitivity of 90.0%, specificity of 70.0%, and accuracy of 72.0%, with an average of 0.41 false positive clusters detected per MRI. For FCD segmentation, an average Dice coefficient of 0.56 was attained. The model's performance improved in each training phase while maintaining a high level of sensitivity. Continual learning outperformed classical learning in this regard. CONCLUSIONS: Our study presents a promising CNN for FCD detection and segmentation, exhibiting both high sensitivity and specificity. Furthermore, the model demonstrates continuous improvement with the inclusion of more clinical MRI data. We consider our CNN a valuable tool for automated, examiner-independent FCD detection in daily clinical practice, potentially addressing the underutilization of epilepsy surgery in drug-resistant focal epilepsy and thereby improving patient outcomes.

Detection of somatic and germline pathogenic variants in adult cohort of drug-resistant focal epilepsies.

OBJECTIVE: This study investigates the prevalence of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway in surgical specimens of malformations of cortical development (MCDs) and cases with negative histology. The study also aims to evaluate the predictive value of genotype-histotype findings on the surgical outcome. METHODS: The study included patients with drug-resistant focal epilepsy who underwent epilepsy surgery. Cases were selected based on histopathological diagnosis, focusing on MCDs and negative findings. We included brain tissues both as formalin-fixed, paraffin-embedded (FFPE) or fresh frozen (FF) samples. Single-molecule molecular inversion probes (smMIPs) analysis was conducted, targeting the MTOR gene in FFPE samples and 10 genes within the mTOR pathway in FF samples. Correlations between genotype-histotype and surgical outcome were examined. RESULTS: We included 78 patients for whom we obtained 28 FFPE samples and 50 FF tissues. Seventeen pathogenic variants (22 %) were identified and validated, with 13 being somatic within the MTOR gene and 4 germlines (2 DEPDC5, 1 TSC1, 1 TSC2). Pathogenic variants in mTOR pathway genes were exclusively found in FCDII and TSC cases, with a significant association between FCD type IIb and MTOR genotype (P = 0.003). Patients carrying mutations had a slightly better surgical outcome than the overall cohort, however it results not significant. The FCDII diagnosed cases more frequently had normal neuropsychological test, a higher incidence of auras, fewer multiple seizure types, lower occurrence of seizures with awareness impairment, less ictal automatisms, fewer Stereo-EEG investigations, and a longer period long-life of seizure freedom before surgery. SIGNIFICANCE: This study confirms that somatic MTOR variants represent the primary genetic alteration detected in brain specimens from FCDII/TSC cases, while germline DEPDC5, TSC1/TSC2 variants are relatively rare. Systematic screening for these mutations in surgically treated patients' brain specimens can aid histopathological diagnoses and serve as a biomarker for positive surgical outcomes. Certain clinical features associated with pathogenic variants in mTOR pathway genes may suggest a genetic etiology in FCDII patients.

Reprint of: Recessive APC2 missense variants associated with epilepsies without neurodevelopmental disorders.

OBJECTIVES: The APC2 gene, encoding adenomatous polyposis coli protein-2, is involved in cytoskeletal regulation in neurons responding to endogenous extracellular signals and plays an important role in brain development. Previously, the APC2 variants have been reported to be associated with cortical dysplasia and intellectual disability. This study aims to explore the association between APC2 variants and epilepsy. METHODS: Whole-exome sequencing (WES) was performed in cases (trios) with epilepsies of unknown causes. The damaging effects of variants were predicted by protein modeling and in silico tools. Previously reported APC2 variants were reviewed to analyze the genotype-phenotype correlations. RESULTS: Four pairs of compound heterozygous missense variants were identified in four unrelated patients with epilepsy without brain malformation/intellectual disability. All variants presented no or low allele frequencies in the controls. The missense variants were predicted to be damaging by silico tools, and affect hydrogen bonding with surrounding amino acids or decreased protein stability. Patients with variants that resulted in significant changes in protein stability exhibited more severe and intractable epilepsy, whereas patients with variants that had minor effect on protein stability exhibited relatively mild phenotypes. The previously reported APC2 variants in patients with complex cortical dysplasia with other brain malformations-10 (CDCBM10; MIM: 618677) were all truncating variants; in contrast, the variants identified in epilepsy in this study were all missense variants, suggesting a potential genotype-phenotype correlation. SIGNIFICANCE: This study suggests that APC2 is potentially associated with epilepsy without brain malformation/intellectual disability. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic heterogeneity.

Early developmental changes in a rat model of malformations of cortical development: Abnormal neuronal migration and altered response to NMDA-induced excitotoxic injury.

Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental changes in the brain of the MCD rat model, which exhibits increased seizure susceptibility during infancy (P12-15), we analyzed the pathological changes in the brains of MCD model rats during the neonatal period and tested NMDA-induced seizure susceptibility. Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8. In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p < 0.001). Golgi staining and immunofluorescence revealed abnormal neuronal migration, with a reduced number of neuronal cell populations and less dendritic arborization at P8. Furthermore, MCD rats exhibited a significant reduction in the expression of NMDA receptors and AMPAR4, along with an increase in AMPAR3 expression (p < 0.05). Although there was no difference in the latency to seizure onset between MCD rats and controls, the MCD rats survived significantly longer than the controls. These results provide insights into the early developmental changes in the cortex of a MCD rat model and suggest that delayed and abnormal neuronal development in the immature brain is associated with a blunted response to NMDA-induced excitotoxic injury. These developmental changes may be involved in the sudden onset of epilepsy in patients with MCD or prenatal brain injury.

Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.

Automated detection of focal cortical dysplasia based on magnetic resonance imaging and positron emission tomography.

PURPOSE: Focal cortical dysplasia (FCD) is a common etiology of drug-resistant focal epilepsy. Visual identification of FCD is usually time-consuming and depends on personal experience. Herein, we propose an automated type II FCD detection approach utilizing multi-modal data and 3D convolutional neural network (CNN). METHODS: MRI and positron emission tomography (PET) data of 82 patients with FCD were collected, including 55 (67.1%) histopathologically, and 27 (32.9%) radiologically diagnosed patients. Three types of morphometric feature maps and three types of tissue maps were extracted from the T1-weighted images. These maps, T1, and PET images formed the inputs for CNN. Five-fold cross-validations were carried out on the training set containing 62 patients, and the model behaving best was chosen to detect FCD on the test set of 20 patients. Furthermore, ablation experiments were performed to estimate the value of PET data and CNN. RESULTS: On the validation set, FCD was detected in 90.3% of the cases, with an average of 1.7 possible lesions per patient. The sensitivity on the test set was 90.0%, with 1.85 possible lesions per patient. Without the PET data, the sensitivity decreased to 80.0%, and the average lesion number increased to 2.05 on the test set. If an artificial neural network replaced the CNN, the sensitivity decreased to 85.0%, and the average lesion number increased to 4.65. SIGNIFICANCE: Automated detection of FCD with high sensitivity and few false-positive findings is feasible based on multi-modal data. PET data and CNN could improve the performance of automated detection.

A genetic variant in the MAST1 gene is associated with mega-corpus-callosum syndrome with hypoplastic cerebellar vermis, in a fetus.

BACKGROUND: Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations is a rare neurological disorder that is associated with typical clinical and imaging features. The syndrome is caused by pathogenic variants in the MAST1 gene, which encodes a microtubule-associated protein that is predominantly expressed in postmitotic neurons in the developing nervous system. METHODS: Fetal DNA from umbilical cord blood samples and genomic DNA from peripheral blood lymphocytes were subjected to whole-exome sequencing. The potential causative variants were verified by Sanger sequencing. RESULTS: A 26-year-old primigravid woman was referred to our prenatal center at 25 weeks of gestation due to abnormal ultrasound findings in the brain of the fetus. The brain abnormalities included wide cavum septum pellucidum, shallow and incomplete bilateral lateral fissure cistern, bilateral dilated lateral ventricles, hyperplastic corpus callosum, lissencephaly, and cortical dysplasia. No obvious abnormalities were observed in the brainstem or cerebellum hemispheres, but the cerebellum vermis was small. Whole-exome sequencing identified a de novo, heterozygous missense variant, c.695T>C(p.Leu232Pro), in the MAST1 gene and a genetic diagnosis of mega-corpus-callosum syndrome was considered. CONCLUSION: This study is the first prenatal case of MAST1-related disorder reported in the Chinese population and has expanded the mutation spectrum of the MAST1 gene.

Low prevalence of neural autoantibodies in perioperative cerebrospinal fluid samples of epilepsy surgery patients: A multicenter prospective study.

OBJECTIVE: Refractory epilepsy may have an underlying autoimmune etiology. Our aim was to assess the prevalence of neural autoantibodies in a multicenter national prospective cohort of patients with drug-resistant epilepsy undergoing epilepsy surgery utilizing comprehensive clinical, serologic, and histopathological analyses. METHODS: We prospectively recruited patients undergoing epilepsy surgery for refractory focal epilepsy not caused by a brain tumor from epilepsy surgery centers in the Czech Republic. Perioperatively, we collected cerebrospinal fluid (CSF) and/or serum samples and performed comprehensive commercial and in-house assays for neural autoantibodies. Clinical data were obtained from the patients' medical records, and histopathological analysis of resected brain tissue was performed. RESULTS: Seventy-six patients were included, mostly magnetic resonance imaging (MRI)-lesional cases (74%). Mean time from diagnosis to surgery was 21 ± 13 years. Only one patient (1.3%) had antibodies in the CSF and serum (antibodies against glutamic acid decarboxylase 65) in relevant titers; histology revealed focal cortical dysplasia (FCD) III (FCD associated with hippocampal sclerosis [HS]). Five patients' samples displayed CSF-restricted oligoclonal bands (OCBs; 6.6%): three cases with FCD (one with FCD II and two with FCD I), one with HS, and one with negative histology. Importantly, eight patients (one of them with CSF-restricted OCBs) had findings on antibody testing in individual serum and/or CSF tests that could not be confirmed by complementary tests and were thus classified as nonspecific, yet could have been considered specific without confirmatory testing. Of these, two had FCD, two gliosis, and four HS. No inflammatory changes or lymphocyte cuffing was observed histopathologically in any of the 76 patients. SIGNIFICANCE: Neural autoantibodies are a rare finding in perioperatively collected serum and CSF of our cohort of mostly MRI-lesional epilepsy surgery patients. Confirmatory testing is essential to avoid overinterpretation of autoantibody-positive findings.

Epileptogenesis and drug-resistant in focal cortical dysplasias: Update on clinical, cellular, and molecular markers.

Focal cortical dysplasia (FCD) is a cortical malformation in brain development and is considered as one of the major causes of drug-resistant epilepsiesin children and adults. The pathogenesis of FCD is yet to be fully understood. Imaging markers such as MRI are currently the surgeons major obstacle due to the difficulty in delimiting the precise dysplasic area and a mosaic brain where there is epileptogenic tissue invisible to MRI. Also increased gene expression and activity may be responsible for the alterations in cell proliferation, migration, growth, and survival. Altered expressions were found, particularly in the PI3K/AKT/mTOR pathway. Surgery is still considered the most effective treatment option, due to drug-resistance, and up to 60 % of patients experience complete seizure control, varying according to the type and location of FCD. Both genetic and epigenetic factors may be involved in the pathogenesis of FCD, and there is no conclusive evidence whether these alterations are inherited or have an environmental origin.

The clinical, imaging, pathological and genetic landscape of bottom-of-sulcus dysplasia.

Bottom-of-sulcus dysplasia (BOSD) is increasingly recognized as a cause of drug-resistant, surgically-remediable, focal epilepsy, often in seemingly MRI-negative patients. We describe the clinical manifestations, morphological features, localization patterns and genetics of BOSD, with the aims of improving management and understanding pathogenesis. We studied 85 patients with BOSD diagnosed between 2005-2022. Presenting seizure and EEG characteristics, clinical course, genetic findings and treatment response were obtained from medical records. MRI (3 T) and 18F-FDG-PET scans were reviewed systematically for BOSD morphology and metabolism. Histopathological analysis and tissue genetic testing were performed in 64 operated patients. BOSD locations were transposed to common imaging space to study anatomical location, functional network localization and relationship to normal MTOR gene expression. All patients presented with stereotyped focal seizures with rapidly escalating frequency, prompting hospitalization in 48%. Despite 42% patients having seizure remissions, usually with sodium channel blocking medications, most eventually became drug-resistant and underwent surgery (86% seizure-free). Prior developmental delay was uncommon but intellectual, language and executive dysfunction were present in 24%, 48% and 29% when assessed preoperatively, low intellect being associated with greater epilepsy duration. BOSDs were missed on initial MRI in 68%, being ultimately recognized following repeat MRI, 18F-FDG-PET or image postprocessing. MRI features were grey-white junction blurring (100%), cortical thickening (91%), transmantle band (62%), increased cortical T1 signal (46%) and increased subcortical FLAIR signal (26%). BOSD hypometabolism was present on 18F-FDG-PET in 99%. Additional areas of cortical malformation or grey matter heterotopia were present in eight patients. BOSDs predominated in frontal and pericentral cortex and related functional networks, mostly sparing temporal and occipital cortex, and limbic and visual networks. Genetic testing yielded pathogenic mTOR pathway variants in 63% patients, including somatic MTOR variants in 47% operated patients and germline DEPDC5 or NPRL3 variants in 73% patients with familial focal epilepsy. BOSDs tended to occur in regions where the healthy brain normally shows lower MTOR expression, suggesting these regions may be more vulnerable to upregulation of MTOR activity. Consistent with the existing literature, these results highlight (i) clinical features raising suspicion of BOSD; (ii) the role of somatic and germline mTOR pathway variants in patients with sporadic and familial focal epilepsy associated with BOSD; and (iii) the role of 18F-FDG-PET alongside high-field MRI in detecting subtle BOSD. The anatomical and functional distribution of BOSDs likely explain their seizure, EEG and cognitive manifestations and may relate to relative MTOR expression.

A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria.

Bilateral perisylvian polymicrogyria (BPP) is a structural malformation of the cerebral cortex that can be caused by several genetic abnormalities. The most common clinical manifestations of BPP include intellectual disability and epilepsy. Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a protein that interacts with the fragile X mental retardation protein (FMRP). CYFIP2 variants can cause various brain structural abnormalities with the most common clinical manifestations of intellectual disability, epileptic encephalopathy and dysmorphic features. We present a girl with multiple disabilities and BPP caused by a heterozygous, novel, likely pathogenic variant (c.1651G>C: p.(Val551Leu) in the CYFIP2 gene. Our case report broadens the spectrum of genetic diversity associated with BPP by incorporating CYFIP2.

Focal cortical dysplasia is a frequent coexistent pathology in patients with Rasmussen's encephalitis.

INTRODUCTION: Rasmussen's encephalitis (RE) is a rare, predominantly pediatric epilepsy disorder of unknown etiology. It classically affects one of the cerebral hemispheres and histologically shows cortical chronic inflammation, gliosis, and neuronal loss. The etiopathogenesis of RE remains unknown, with genetic, infectious, and autoimmune factors all speculated to play a role. Although the histologic findings in RE are well described, few studies have investigated a large cohort of cases looking for the coexistence of RE with focal cortical dysplasia (FCD). DESIGN: The study is a retrospective review of RE patients who underwent surgical resection of brain tissue between 1979 and 2021. Relevant patient history was retrieved, and available histologic slides were reviewed. The histologic severity of RE was described according to the Pardo criteria. In cases where FCD was present, the observed patterns of FCD (namely Ia, Ib, IIa, IIb, etc.) were described using the International League Against Epilepsy (ILAE) classification. RESULTS: Thirty-eight resection specimens from 31 patients formed the study cohort. Seventeen patients (54.8 %) were male; average age at surgery was 8 years (range: 2-28 years). Twenty-seven resection specimens (71.1 %) from 23 patients (74 %) showed evidence of coexistent FCD. Most cases with FCD resembled the ILAE type Ib (n = 23) pattern. Cases of RE that did not show FCD were either Pardo stage 1 (n = 5) or 4 (n = 6), with all Pardo stage 2 and 3 cases demonstrating FCD. CONCLUSIONS: FCD was found in most patients with RE (74 %). The most observed pattern of FCD was ILAE Ib.

Prenatal Ultrasound Diagnosis of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome with Persistent Hyperplastic Primary Vitreous: A Case Report.

INTRODUCTION: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare autosomal dominant disorder characterized by megalencephaly (i.e., overgrowth of the brain), polymicrogyria, focal hypoplasia of the cerebral cortex, and polydactyly. Persistent hyperplastic primary vitreous (PHPV) involves a spectrum of congenital ocular abnormalities that are characterized by the presence of a vascular membrane behind the lens. CASE PRESENTATION: Here, we present a case of foetal MPPH with PHPV that was diagnosed using prenatal ultrasound. Ultrasound revealed the presence of megalencephaly, multiple cerebellar gyri, and hydrocephalus. Whole-exome sequencing confirmed the mutation of the AKT3 gene, which led to the consideration of MPPH syndrome. Moreover, an echogenic band with an irregular surface was observed between the lens and the posterior wall of the left eye; therefore, MPPH with PHPV was suspected. CONCLUSION: MPPH syndrome with PHPV can be diagnosed prenatally.