FLNA regulates neuronal maturation by modulating RAC1-Cofilin activity in the developing cortex.

Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene - encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive. It has been hypothesized that dysfunctional cortical circuitry, rather than ectopic neurons, may explain the clinical manifestations. To address this issue, we depleted FLNA from cortical pyramidal neurons of a conditional Flnaflox/flox mice by timed in utero electroporation of Cre recombinase. We found that FLNA regulates dendritogenesis and spinogenesis thus promoting an appropriate excitatory/inhibitory inputs balance. We demonstrated that FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein 24 (ARHGAP24). Collectively, we disclose an uncharacterized role of FLNA and provide strong support for neural circuit dysfunction being a consequence of FLNA mutations.

Stereo-EEG-based ictal functional connectivity in patients with periventricular nodular heterotopia-related epilepsy.

Nodular heterotopia (NH)-related drug-resistant epilepsy is challenging due to the deep location of the NH and the complexity of the underlying epileptogenic network. Using ictal stereo-electroencephalography (SEEG) and functional connectivity (FC) analyses in 14 patients with NH-related drug-resistant epilepsy, we aimed to determine the leading structure during seizures. For this purpose, we compared node IN and OUT strength between bipolar channels inside the heterotopia and inside gray matter, at the group level and at the individual level. At seizure onset, the channels within NH belonging to the epileptogenic and/or propagation network showed higher node OUT-strength than the channels within the gray matter (p = .03), with higher node OUT-strength than node IN-strength (p = .03). These results are in favor of a "leading" role of NH during seizure onset when involved in the epileptogenic- or propagation-zone network (50% of patients). However, when looking at the individual level, no significant difference between NH and gray matter was found, except for one patient (in two of three seizures). This result confirms the heterogeneity and the complexity of the epileptogenic network organization in NH and the need for SEEG exploration to characterize more precisely patient-specific epileptogenic network organization.

Periventricular nodular heterotopia is coupled with the neocortex during resting and task states.

Periventricular nodular heterotopia (PVNH) is a well-defined developmental disorder characterized by failed neuronal migration, which forms ectopic neuronal nodules along the ventricular walls. Previous studies mainly focus on clinical symptoms caused by the PVNH tissue, such as seizures. However, little is known about whether and how neurons in the PVNH tissue functionally communicate with neurons in the neocortex. To probe this, we applied magnetoencephalography (MEG) and stereo-electroencephalography (sEEG) recordings to patients with PVNH during resting and task states. By estimating frequency-resolved phase coupling strength of the source-reconstructed neural activities, we found that the PVNH tissue was spontaneously coupled with the neocortex in the α-ß frequency range, which was consistent with the synchronization pattern within the neocortical network. Furthermore, the coupling strength between PVNH and sensory areas effectively modulated the local neural activity in sensory areas. In both MEG and sEEG visual experiments, the PVNH tissue exhibited visual-evoked responses, with a similar pattern and latency as the ipsilateral visual cortex. These findings demonstrate that PVNH is functionally integrated into cognition-related cortical circuits, suggesting a co-development perspective of ectopic neurons after their migration failure.

Diffuse interstitial lung disease in a male fetus with periventricular nodular heterotopia and filamin A mosaic variant.

BACKGROUND: Most periventricular nodular heterotopias (PNHs) are associated with a mutation in the filamin A (FLNA) gene in Xq28. This condition is associated with cardiovascular malformations, connective tissue abnormalities, epilepsy, and intellectual deficiency of varying severity. MATERIALS AND METHODS: We report a new FLNA gene mutation in a male patient associated with PNH and diffuse interstitial lung disease. RESULTS: A 23-year-old woman was referred at 31 gestational weeks to evaluate a suspected mega cisterna magna and ventricular septal defect with atrioventricular valve alignment in a male fetus. The fetal magnetic resonance imaging showed PNH associated with corpus callosum dysgenesis and a mega cisterna magna. At 2 months of age, the infant was diagnosed with severe respiratory distress with hypoxemia. A chest CT scan demonstrated a diffuse interstitial lung pattern with emphysema, multiple atelectasis foci, and signs of pulmonary hypertension. Rapid worsening led to his death at 4 months. Targeted sequencing of the FLNA gene identified a de novo hemizygous variant in 75% mosaic in lymphocyte cells, resulting in incomplete FLNA function loss. DISCUSSION & CONCLUSION: On the diagnosis of antenatal PNH, the possibility of such lung involvement should be considered in the prognostic evaluation during prenatal counseling.

ARF1-related disorder: phenotypic and molecular spectrum.

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Periventricular nodular heterotopia in patients with a prenatal diagnosis of myelomeningocele/myeloschisis: associations with seizures and neurodevelopmental outcomes during early childhood.

PURPOSE: Historically, the presence of gray matter heterotopia was a concern for adverse postnatal neurocognitive status in patients undergoing fetal closure of open spinal dysraphism. The purpose of this study was to evaluate neurodevelopmental outcomes and the onset of seizures during early childhood in patients with a prenatal diagnosis of myelomeningocele/myeloschisis (MMC) and periventricular nodular heterotopia (PVNH). METHODS: All patients evaluated at the Center for Fetal Diagnosis and Treatment with a diagnosis of MMC between June 2016 to March 2023 were identified. PVNH was determined from prenatal and/or postnatal MRI. The Bayley Scales of Infant and Toddler Development (edition III or IV) were used for neurodevelopmental assessments. Patients were screened for seizures/epilepsy. RESULTS: Of 497 patients evaluated with a prenatal diagnosis of MMC, 99 were found to have PVNH on prenatal MRI, of which 35 had confirmed PVNH on postnatal imaging. From the 497 patients, 398 initially did not exhibit heterotopia on prenatal MRI, but 47 of these then had confirmed postnatal PVNH. The presence of PVNH was not a significant risk factor for postnatal seizures in early childhood. The average neurodevelopmental scores were not significantly different among heterotopia groups for cognitive, language, and motor domains. CONCLUSION: The presence of PVNH in patients with a prenatal diagnosis of MMC does not indicate an increased risk for neurodevelopmental delay at 1 year of age. We did not demonstrate an association with seizures/epilepsy. These findings can aid clinicians in prenatal consultation regarding fetal repair of open spinal dysraphism. Long-term follow-up is required to discern the true association between PVNH seen on prenatal imaging and postnatal seizures/epilepsy and neurodevelopmental outcomes.

Cerebral organoids to unravel the mechanisms underlying malformations of human cortical development.

Genetic studies identified multiple mutations associated with malformations of cortical development (MCD) in humans. When analyzing the underlying mechanisms in non-human experimental models it became increasingly evident, that these mutations accumulate in genes, which functions evolutionary progressed from rodents to humans resulting in an incomplete reflection of the molecular and cellular alterations in these models. Human brain organoids derived from human pluripotent stem cells resemble early aspects of human brain development to a remarkable extent making them an attractive model to investigate MCD. Here we review how human brain organoids enable the generation of fundamental new insight about the underlying pathomechanisms of MCD. We show how phenotypic features of these diseases are reflected in human brain organoids and discuss challenges and future considerations but also limitations for the use of human brain organoids to model human brain development and associated disorders.

A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome.

KCNB1 encodes the α-subunit of Kv2.1, the main contributor to neuronal delayed rectifier potassium currents. The subunit consists of six transmembrane α helices (S1-S6), comprising the voltage-sensing domain (S1-S4) and the pore domain (S5-P-S6). Heterozygous KCNB1 pathogenic variants are associated with developmental and epileptic encephalopathy. Here we report an individual who shows the milder phenotype compared to the previously reported cases, including delayed language development, mild intellectual disability, attention deficit hyperactivity disorder, late-onset epilepsy responsive to an antiepileptic drug, elevation of serum creatine kinase, and peripheral axonal neuropathy. On the other hand, his brain MRI showed characteristic findings including periventricular heterotopia, polymicrogyria, and abnormal corpus callosum. Exome sequencing identified a novel de novo KCNB1 variant c.574G>A, p.(Ala192Thr) located in the S1 segment of the voltage-sensing domain. Functional analysis using the whole-cell patch-clamp technique in Neuro2a cells showed that the Ala192Thr mutant reduces both activation and inactivation of the channel at membrane voltages in the range of -50 to -30 mV. Our case could expand the phenotypic spectrum of patients with KCNB1 variants, and suggested that variants located in the S1 segment might be associated with a milder outcome of seizures.

Periventricular heterotopia in a male child with USP9X missense variant.

The ubiquitin-specific protease USP9X has been found to play a role in multiple aspects of neural development including processes of neuronal migrations. In males, hemizygous partial loss of function variants in USP9X lead to a clinical phenotype primarily characterized by intellectual disability, hypotonia, speech and language impairment, behavioral disturbances accompanied by additional clinical features with variable expressivity. Structural brain abnormalities are reported in all cases where neuro-imaging was performed. The most common radiological features described include hypoplasia/agenesis of the corpus callosum, widened ventricles, white matter disturbances, and cerebellar hypoplasia. Here we report a child harboring a missense variant in USP9X presenting with the classical neurodevelopmental phenotype and a previously unreported radiological picture of periventricular heterotopia. This case expands the phenotypic landscape of this emergent condition and supports the critical role of USP9X in neuronal migration processes.

Periventricular nodular heterotopia associated with a "transmantle band sign" in patients with epilepsy.

OBJECTIVE: Previous studies using advanced magnetic resonance imaging (MRI) techniques have documented abnormal transmantle bands connecting ectopic nodules to overlying cortex in patients with periventricular nodular heterotopia (PNH). We describe a similar finding using conventional MRI techniques. METHODS: Patients were identified by means of a full-text search of radiological reports. All scanning was performed using conventional sequences at 3 Tesla (3T). Scans were reviewed by three neuroradiologists, and we characterized imaging features based on type of PNH and cortical irregularities associated with the transmantle band. RESULTS: A total 57 PNH patients were reviewed, of whom 41 demonstrated a "transmantle band" connecting the nodule to the overlying cortex. One or more periventricular heterotopic nodules was present in all 41 patients-this was bilateral in 29 of 41 (71%) and unilateral in the remaining 29%. In many cases there was more than one such band, and in some cases this band was nodular. In 19 of the cases, the cortex to which the band connected was abnormal, showing thinning in 4 cases, thickening in 5 cases, and polymicrogyria in another 10. SIGNIFICANCE: The transmantle band can be seen frequently in both unilateral and bilateral cases of PNH and can be visualized with conventional 3T MRI sequences. The band highlights the underlying neuronal migration issues at play in the pathogenesis of this disorder, but its underlying role in the complex, patient-specific epileptogenic networks in this cohort has yet to be determined and warrants further investigation.

ARF1 haploinsufficiency causes periventricular nodular heterotopia with variable clinical expressivity.

The primary anatomical defect leading to periventricular nodular heterotopia occurs within the neural progenitors along the neuroepithelial lining of the lateral ventricles and results from a defect in the initiation of neuronal migration, following disruption of the neuroependyma and impaired neuronal motility. Growing evidence indicates that the FLNA-dependent actin dynamics and regulation of vesicle formation and trafficking by activation of ADP-ribosylation factors (ARFs) can play an important role in this cortical malformation. We report the first inherited variant of ARF1 in a girl with intellectual disability and periventricular nodular heterotopia who inherited the variant from the father with previously undiagnosed single nodular heterotopia and mild clinical expression. Additionally, both patients presented some features suggestive of hypohidrotic ectodermal dysplasia. These clinical features showed similarities to those of three previously reported cases with ARF1 missense variants, confirming that haploinsufficiency of this gene causes a recognisable neurological disorder with abnormal neuronal migration and variable clinical expressivity.

Periventricular nodular heterotopias is associated with mutation at the FLNA locus-a case history and a literature review.

BACKGROUND: Periventricular nodular heterotopia (PNH), associated with FLNA mutations, is a rare clinical condition potentially associated with multiple systemic conditions, including cardiac, pulmonary, skeletal, and cutaneous diseases. However, due to a paucity of information in the literature, accurate prognostic advice cannot be provided to patients with the disease. CASE PRESENTATION: We report a 2-year-old female whose PNH was associated with a nonsense mutation in the q28 region of the X chromosome, in exon 31 of FLNA (c.5159dupA). The patient is currently seizure-free and has no congenital heart disease, lung disease or skeletal or joint issues, and her development is normal. CONCLUSIONS: FLNA-associated PNH is a genetically-heterogeneous disease, and the FLNA mutation, c.5159dupA (p.Tyr1720*) is a newly identified pathogenic variant. FLNA characterization will help the clinical diagnosis and treatment of PNH and provide individualized genetic counseling for patients.

Is periventricular heterotopia a useful endpoint for developmental thyroid hormone system disruption in mouse toxicity studies?

In rats, hypothyroidism during fetal and neonatal development can disrupt neuronal migration and induce the formation of periventricular heterotopia in the brain. However, it remains uncertain if heterotopia also manifest in mice after developmental hypothyroidism and whether they could be used as a toxicological endpoint to detect TH-mediated effects caused by TH system disrupting chemicals. Here, we performed a mouse study where we induced severe hypothyroidism by exposing pregnant mice (n = 3) to a very high dose of propylthiouracil (PTU) (1500 ppm) in the diet. This, to obtain best chances of detecting heterotopia. We found what appears to be very small heterotopia in 4 out of the 8 PTU-exposed pups. Although the incidence rate could suggest some utility for this endpoint, the small size of the ectopic neuronal clusters at maximum hypothyroidism excludes the utility of heterotopia in mouse toxicity studies aimed to detect TH system disrupting chemicals. On the other hand, parvalbumin expression was manifestly lower in the cortex of hypothyroid mouse offspring demonstrating that offspring TH-deficiency caused an effect on the developing brain. Based on overall results, we conclude that heterotopia formation in mice is not a useful toxicological endpoint for examining TH-mediated developmental neurotoxicity.

Intracranial Electroencephalography Reveals Selective Responses to Cognitive Stimuli in the Periventricular Heterotopias.

Our recent work suggests that non-lesional epileptic brain tissue is capable of generating normal neurophysiological responses during cognitive tasks, which are then seized by ongoing pathologic epileptic activity. Here, we aim to extend the scope of our work to epileptic periventricular heterotopias (PVH) and examine whether the PVH tissue also exhibits normal neurophysiological responses and network-level integration with other non-lesional cortical regions. As part of routine clinical assessment, three adult patients with PVH underwent implantation of intracranial electrodes and participated in experimental cognitive tasks. We obtained simultaneous recordings from PVH and remote cortical sites during rest as well as controlled experimental conditions. In all three subjects (two females), cognitive experimental conditions evoked significant electrophysiological responses in discrete locations within the PVH tissue that were correlated with responses seen in non-epileptic cortical sites. Moreover, the responsive PVH sites exhibited correlated electrophysiological activity with responsive, non-lesional cortical sites during rest conditions. Taken together, our work clearly demonstrates that the PVH tissue may be functionally organized and it may be functionally integrated within cognitively engaged cortical networks despite its anatomic displacement during neurodevelopment.SIGNIFICANCE STATEMENT Periventricular heterotopias (PVH) are developmentally abnormal brain tissues that frequently cause epileptic seizures. In a rare opportunity to obtain direct electrophysiological recordings from PVH, we were able to show that, contrary to common assumptions, PVH functional activity is similar to healthy cortical sites during a well-established cognitive task and exhibits clear resting state connectivity with the responsive cortical regions.

Platelet function and filamin A expression in two families with novel FLNA gene mutations associated with periventricular nodular heterotopia and panlobular emphysema.

Pathogenic variants of the X-linked FLNA gene encoding filamin A protein have been associated with a wide spectrum of symptoms, including the recently described pulmonary phenotype with childhood-onset panlobular emphysema. We describe three female patients from two families with novel heterozygous FLNA variants c.5837_2del and c.508C > T. Analysis of immunofluorescence of peripheral blood smears and platelet function was performed for all patients. FLNA-negative platelets were observed, suggesting that these variants result in the loss of a functional protein product. All three patients also had periventricular nodular heterotopia and panlobular emphysema. However, they had considerably milder symptoms and later age of onset than in the previously reported cases. Therefore, patients with pathogenic FLNA variants should be studied actively for lung involvement even in the absence of pronounced respiratory symptoms. Conversely, any patient with unexplained panlobular emphysema should be analyzed for pathogenic FLNA variants. We also suggest that immunofluorescence analysis is a useful tool for investigating the pathogenicity of novel FLNA variants.

Using magnetic resonance fingerprinting to characterize periventricular nodular heterotopias in pharmacoresistant epilepsy.

OBJECTIVE: We aimed to use a novel magnetic resonance fingerprinting (MRF) technique to examine in vivo tissue property characteristics of periventricular nodular heterotopia (PVNH). These characteristics were further correlated with stereotactic-electroencephalographic (SEEG) ictal onset findings. METHODS: We included five patients with PVNH who had SEEG-guided surgery and at least 1 year of seizure freedom or substantial seizure reduction. High-resolution MRF scans were acquired at 3 T, generating three-dimensional quantitative T1 and T2  maps. We assessed the differences between T1 and T2  values from the voxels in the nodules located in the SEEG-defined seizure onset zone (SOZ) and non-SOZ, on -individual and group levels. Receiver operating characteristic analyses were performed to obtain the optimal classification performance. Quantification of SEEG ictal onset signals from the nodules was performed by calculating power spectrum density (PSD). The association between PSD and T1 /T2  values was further assessed at different frequency bands. RESULTS: Individual-level analysis showed T1 was significantly higher in SOZ voxels than non-SOZ voxels (p < .05), with an average 73% classification accuracy. Group-level analysis also showed higher T1 was significantly associated with SOZ voxels (p < .001). At the optimal cutoff (normalized T1 of 1.1), a 76% accuracy for classifying SOZ nodules from non-SOZ nodules was achieved. T1  values were significantly associated with ictal onset PSD at the ultraslow, θ, ß, γ, and ripple bands (p < .05). T2  values were significantly associated with PSD only at the ultraslow band (p < .05). SIGNIFICANCE: Quantitative MRF measures, especially T1 , can provide additional noninvasive information to separate nodules in SOZ and non-SOZ. The T1 and T2 tissue property changes carry electrophysiological underpinnings relevant to the epilepsy, as shown by their significant positive associations with power changes during the SEEG seizure onset. The use of MRF as a supplementary noninvasive tool may improve presurgical evaluation for patients with PVNH and pharmacoresistant epilepsy.

ECE2 regulates neurogenesis and neuronal migration during human cortical development.

During embryonic development, excitatory projection neurons migrate in the cerebral cortex giving rise to organised layers. Periventricular heterotopia (PH) is a group of aetiologically heterogeneous disorders in which a subpopulation of newborn projection neurons fails to initiate their radial migration to the cortex, ultimately resulting in bands or nodules of grey matter lining the lateral ventricles. Although a number of genes have been implicated in its cause, currently they only satisfactorily explain the pathogenesis of the condition for 50% of patients. Novel gene discovery is complicated by the extreme genetic heterogeneity recently described to underlie its cause. Here, we study the neurodevelopmental role of endothelin-converting enzyme-2 (ECE2) for which two biallelic variants have been identified in two separate patients with PH. Our results show that manipulation of ECE2 levels in human cerebral organoids and in the developing mouse cortex leads to ectopic localisation of neural progenitors and neurons. We uncover the role of ECE2 in neurogenesis, and mechanistically, we identify its involvement in the generation and secretion of extracellular matrix proteins in addition to cytoskeleton and adhesion.

The analysis of 18 F-FDG PET/MRI, electroencephalography, and semiology in patients with gray matter heterotopia: A pilot study.

OBJECTIVES: To describe 18 F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18 F-FDG PET/MRI) along with semiology and electroencephalography (EEG) in patients with gray matter heterotopia (GMH); to evaluate the concordance between 18 F-FDG PET/MRI and clinical epileptogenic zone (EZ). MATERIALS & METHODS: GMH (subcortical heterotopia [SCH] and periventricular nodular heterotopia [PNH]) patients with epilepsy who underwent 18 F-FDG PET/MRI were retrospectively enrolled. Two radiologists evaluated brain MRI, while two nuclear medicine specialists assessed the 18 F-FDG PET. The SUVmax values of visually hypometabolic cortical areas were compared to the contralateral cortex using a SUVmax threshold value of 10%; the SUVmax values of GMH lesions were compared with that of the right precentral gyrus. The cortex or GMH with hypometabolism on 18 F-FDG PET/MRI was considered representative of the EZ. The clinical EZ was identified using EEG and semiology. RESULTS: Thirty patients (19 PNH; 11 SCH) with a mean age of 28.46 ± 9.52 years were enrolled. The heterotopic nodules were ametabolic in 3 patients (10%), hypometabolic in 16 (33.33%), isometabolic in 13 (26.66%), and hypermetabolic in 4 (10%). 18 F-FDG PET/MRI demonstrated hypometabolism in the cortex and GMH in 22/30 (73.33%) and 16/30 (53.33%). We could identify a clinical EZ in 18 patients, and 15 out of 18 (83.33%) had concordant 18 F-FDG PET/MRI findings. CONCLUSION: Heterotopic nodules in GMH patients show different metabolic patterns on 18 F-FDG PET/MRI, with nearly three-quarters of the patients having cortical hypometabolism. 18 F-FDG PET/ MRI findings are mostly concordant with the clinical EZ.

Hypothalamic hamartoma associated with polymicrogyria and periventricular nodular heterotopia in children: report of three cases and discussion of the origin of the seizures.

PURPOSE: Hypothalamic hamartomas (HH) are malformations responsible for drug-resistant epilepsy. HH are usually isolated or part of a genetic syndrome, such as Pallister-Hall. Exceptionally they can be associated with other brain malformations such as polymicrogyria (PMG) and periventricular nodular heterotopia (PNH). We discuss the origin of the seizures associated with this combination of malformations, through electrophysiological studies, and review the literature on this rarely reported syndrome. METHODS: We retrospectively reviewed the patients with HH who had surgery between 1998 and 2020 and selected those with associated focal PMG and PNH, detected on MRIs. All patients had comprehensive clinical evaluation and surface video-EEG and one underwent stereoelectroencephalography (SEEG). RESULTS: Three male patients out of 182 were identified with a mean age at surgery of 7.5 years. MRI showed unilateral focal PMG (fronto-insulo-parietal, fronto-insulo-parieto-opercular, and fronto-insular, respectively) and multiple PNH homolateral to the main HH implantation side. In two patients, there were strong clinical and scalp EEG arguments for seizure onset within the HH. In the third, due to abnormalities on scalp video-EEG in the same area as PMG and the lack of gelastic seizures, SEEG was indicated and demonstrated seizure onset within the hamartoma. With a mean follow-up of 6 years, two patients were seizure-free. CONCLUSION: Our results show that HH is the trigger of epilepsy, which confirms the high epileptogenic potential of this malformation. In patients such as ours, as in those with isolated HH, we recommend to begin by operating the HH independently of seizure semiology or electrophysiological abnormalities.

Asymmetrical aortic root aneurism in patient with Filamin A mutation.

We report the case of a 28 years old woman with periventricular nodular heterotopia, due to Filamin A mutation. She had an asymmetrical aneurysm of the aortic root, involving, above all, noncoronary Valsalva sinus. She was asymptomatic and she had moderate aortic regurgitation. Reimplantation of the aortic valve with replacement of the aortic root was successfully accomplished. Filamin A is a protein that is encoded by the FLNA gene, which shows X-linked dominant inheritance. This protein is involved in neuronal migration, angiogenesis, cytoskeleton regulation, and cell signaling. Therefore, mutations of FLNA gene might result in brain, blood vessels, heart, and connective tissue disorders. A miscellany of cardiovascular abnormalities could be present in this subset of patients; cardiac symptoms may precede neurological manifestations. Aorta seems to be frequently affected. Consequently, in presence of FLNA gene mutations, cardiovascular evaluation should include vascular magnetic resonance imaging or computed tomography scan.