RESUMO
BACKGROUND: Limited information exists in the prenatal literature regarding the neuroimaging features of fetal hemimegalencephaly. SUMMARY: This report describes ultrasound and magnetic resonance imaging (MRI) findings in a second-trimester fetus with an isolated, severe form of hemimegalencephaly. The most prominent imaging findings included unilateral enlarged cerebral hemisphere and ipsilateral ventriculomegaly causing cerebral asymmetry, midline shift, and macrocephaly. Abnormal cortical development imaging signs were also evident. A literature review encompassing 23 reports describing 36 cases, including ours, is presented. KEY MESSAGES: Characteristic ultrasound findings for the diagnosis of hemimegalencephaly are not always apparent prenatally. Asymmetric ventriculomegaly emerges as the most common but nonspecific presenting feature during routine second- or third-trimester ultrasound scans. Subsequent high-resolution prenatal neurosonography and fetal MRI facilitate definitive prenatal diagnosis, showcasting associated features primarily related to cortical migration, differentiation, and maturation. Postnatally, the prognosis is poor due to intractable seizures, hemiplegia, and progressive neurodevelopmental delay.
Assuntos
Hemimegalencefalia , Hidrocefalia , Malformações do Sistema Nervoso , Gravidez , Feminino , Humanos , Hemimegalencefalia/patologia , Ultrassonografia Pré-Natal/métodos , Diagnóstico Pré-Natal/métodos , Feto/patologia , Hidrocefalia/patologia , Imageamento por Ressonância Magnética/métodos , NeuroimagemRESUMO
Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies.
Assuntos
Epilepsia , Hemimegalencefalia , Malformações do Desenvolvimento Cortical , Humanos , Encéfalo/patologia , Mosaicismo , Mutação , Epilepsia/genética , Epilepsia/patologia , Hemimegalencefalia/genética , Hemimegalencefalia/patologia , Malformações do Desenvolvimento Cortical/genéticaRESUMO
It is known that somatic activation of PI3K-AKT-MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated-S6 ribosomal protein (P-RPS6) (Ser240/244) were observed in the polymicrogyria-like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K-AKT-MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K-AKT-MTOR pathway.
Assuntos
Hemimegalencefalia , Polimicrogiria , Humanos , Hemimegalencefalia/genética , Hemimegalencefalia/metabolismo , Hemimegalencefalia/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Polimicrogiria/metabolismo , Polimicrogiria/patologia , Mosaicismo , Serina-Treonina Quinases TOR/metabolismo , Encéfalo/patologia , MutaçãoRESUMO
Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Hemimegalencefalia , Malformações do Desenvolvimento Cortical , Encéfalo/patologia , Criança , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia/genética , Hemimegalencefalia/genética , Hemimegalencefalia/metabolismo , Hemimegalencefalia/patologia , Humanos , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898-164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3-like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures.
Assuntos
Epilepsia/genética , Proteínas Ativadoras de GTPase/genética , Hemimegalencefalia/genética , Convulsões/genética , Serina-Treonina Quinases TOR/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Epilepsia/patologia , Feminino , Predisposição Genética para Doença , Hemimegalencefalia/tratamento farmacológico , Hemimegalencefalia/patologia , Humanos , Recém-Nascido , Convulsões/patologia , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues. Laser capture microdissection showed enrichment of RHEB variants in dysmorphic neurons and balloon cells. Our findings support the role of RHEB in a spectrum of cortical malformations confirming that FCD and HME represent a disease continuum, with the extent of dysplastic brain directly correlated with the somatic variant load.
Assuntos
Encéfalo/patologia , Epilepsia/etiologia , Hemimegalencefalia , Malformações do Desenvolvimento Cortical , Neurônios/patologia , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Criança , Pré-Escolar , Feminino , Hemimegalencefalia/diagnóstico por imagem , Hemimegalencefalia/etiologia , Hemimegalencefalia/genética , Hemimegalencefalia/patologia , Humanos , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/etiologia , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Mutação , Serina-Treonina Quinases TOR/genética , Adulto JovemRESUMO
Hemimegalencephaly is a rare malformation of cortical development characterised by enlargement of one cerebral hemisphere. The association between hemimegalencephaly and tuberous sclerosis complex, an autosomal dominant genetic disorder, is uncommon and has so far been reported only in a few cases. Intractable epilepsy and severe developmental delay are typical clinical manifestations. Aberrant activation of the mTOR signalling pathway is considered to be the hallmark of the pathogenesis of these two disorders. Thus, mTOR inhibitors such as everolimus represent a promising therapeutic approach to mTOR-associated manifestations. We present a thorough literature review of the association between hemimegaloencephaly and tuberous sclerosis complex.
Assuntos
Hemimegalencefalia/complicações , Esclerose Tuberosa/complicações , Everolimo/uso terapêutico , Hemimegalencefalia/patologia , Humanos , Masculino , Serina-Treonina Quinases TOR/antagonistas & inibidores , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologiaRESUMO
PURPOSE: To investigate the gross white matter abnormalities in the structural brain MR imaging as well as white matter microstructural alterations using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) in both affected and contralateral cerebral hemispheres of children with hemimegalencephaly (HMEG). METHODS: From 2003 to 2019, we retrospectively reviewed brain MR images in 20 children (11 boys, 2 days-16.5 years) with HMEG, focusing on gross white matter abnormalities. DTI was evaluated in 12 patients (8 boys, 3 months-16.5 years) with HMEG and 12 age-, sex-, and magnetic field strength-matched control subjects. TBSS analysis was performed to analyze main white matter tracts. Regions of significant differences in fractional anisotropy (FA) were determined between HMEG and control subjects and between affected and contralateral hemispheres of HMEG. RESULTS: Gross white matter abnormalities were noted in both affected (n = 20, 100%) and contralateral hemisphere (n = 4, 20%) of HMEG. FA values were significantly decreased in both hemispheres of HMEG, compared with control subjects (P < 0.05). Contralateral hemispheres of HMEG showed regions with significantly decreased FA values compared with affected hemispheres (P < 0.05). CONCLUSIONS: In addition to gross white matter abnormalities particularly evident in affected hemispheres, DTI analysis detected widespread microstructural alterations in both affected and contralateral hemispheres in HMEG suggesting HMEG may involve broader abnormalities in neuronal networks.
Assuntos
Imagem de Tensor de Difusão/métodos , Hemimegalencefalia/diagnóstico por imagem , Hemimegalencefalia/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adolescente , Anisotropia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos RetrospectivosRESUMO
Focal cortical dysplasia (FCD) type II and hemimegalencephaly (HME) are currently considered as a continuum of pathology, the most important distinction being the extent or the size/volume of the lesion. While partial HME involving the posterior cortex has been well described, we present an unusual case with a dysplastic lesion of the whole frontal lobe. A 17-year-old boy had focal seizures from the age of nine years. Apart from diminished right-hand dexterity, his neurological and cognitive status were unremarkable. The course of his epilepsy exhibited a relapsing-remitting pattern, with prolonged periods of remission. Imaging showed dysplastic left frontal lobe (including paracentral lobule) thickened cortex with an abnormal gyration pattern resembling polymicrogyria, as well as dystrophic calcifications and hypodensity scattered throughout the white matter. This patient represents an intermediate case within the FCD type II/HME spectrum. Localization of the lesion in the frontal lobe as well as clinical characteristics (childhood onset, relapsing-remitting epilepsy, without hemiparesis and overt cognitive impairment) are more consistent with FCD type II, while a range of MRI features is shared between HME and FCD type II.
Assuntos
Epilepsia/patologia , Lobo Frontal/patologia , Hemimegalencefalia/patologia , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Malformações do Desenvolvimento Cortical/patologia , Adolescente , Córtex Cerebral/patologia , Eletroencefalografia/métodos , Epilepsia/diagnóstico , Hemimegalencefalia/diagnóstico , Hemimegalencefalia/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/fisiopatologia , Malformações do Desenvolvimento Cortical do Grupo I/diagnósticoRESUMO
Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood-brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population.
Assuntos
Encéfalo/patologia , Epilepsia/patologia , Hemimegalencefalia/patologia , Malformações do Desenvolvimento Cortical/patologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/genética , Feminino , Hemimegalencefalia/genética , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical/genética , Mutação/genética , Neurônios/patologiaRESUMO
BACKGROUND: Hemispherotomy can be an effective treatment for refractory childhood epilepsy. However, the extent of postoperative brain development after hemispherotomy remains incompletely understood. This study aims to provide an anatomic foundation in assessing development of the contralateral hemisphere, by measuring volumetric growth after hemispherotomy. METHODS: Eleven patients with hemimegalencephaly, Rasmussen's encephalitis, and cerebral infarction who underwent hemispherotomy before age 12 years, an immediate preoperative magnetic resonance imaging, and at least three years of follow-up magnetic resonance imagings were retrospectively analyzed. The volume of the contralateral hemisphere was measured before and after surgery. Growth curves were compared with those of healthy individuals from an open database. The growth rate relative to the healthy individuals ("catch-up rate") was calculated. RESULTS: A positive volumetric growth of the contralateral hemisphere was observed across all pathologies. The hemimegalencephaly subgroup underwent hemispherotomy at the earliest time and had the largest postoperative growth rate, which exceeded that of healthy individuals. The Rasmussen subgroup underwent surgery at the second earliest time and had an intermediate growth rate, which was similar to that of healthy individuals. The infarction subgroup underwent surgery at the latest time and had the slowest growth rate, which was less than that of healthy individuals. CONCLUSIONS: The contralateral hemisphere continues to increase in volume after hemispherotomy in childhood. Further studies with a larger sample size and correlation with cognitive outcomes may aid in characterizing the prognosis after hemispherotomy.
Assuntos
Infarto Cerebral/cirurgia , Cérebro/crescimento & desenvolvimento , Cérebro/cirurgia , Epilepsia Resistente a Medicamentos/cirurgia , Encefalite/cirurgia , Hemimegalencefalia/cirurgia , Hemisferectomia , Adolescente , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/patologia , Cérebro/diagnóstico por imagem , Cérebro/patologia , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/patologia , Encefalite/diagnóstico por imagem , Encefalite/patologia , Feminino , Seguimentos , Hemimegalencefalia/diagnóstico por imagem , Hemimegalencefalia/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Fatores de TempoRESUMO
OBJECTIVE: Cerebellar dysmaturation and injury is associated with a wide range of neuromotor, neurocognitive and behavioral disorders as well as with preterm birth. We used diffusion tensor MR imaging to investigate a disruption in structural cortico-ponto-cerebellar (CPC) connectivity in children with infantile-onset severe epilepsy. METHODS: We performed CPC tract reconstructions in 24 hemimegalencephaly (HME) patients, 28 West syndrome (WS) of unknown etiology patients, and 25 pediatric disease control subjects without a history of epilepsy nor brain abnormality on MRI. To identify the CPC tract, we placed a seeding ROI separately in each right and left cerebral peduncle. We evaluated the distribution patterns of the CPC tracts to the cerebellum and their correlation with clinical findings. RESULTS: In control and WS of unknown etiology groups, both sides' CPC tracts descended to bilateral hemispheres in 20 (80.0%) and 21 (75.0%); mixed (bilateral on one side and unilateral on the other side) in five (20.0%) and five (17.9%); and unilateral in zero (0.0%) and two (7.1%), respectively. However, in the HME, both sides' CPC tracts descended to bilateral hemispheres in four (16.7%); mixed in 13 (54.1%); and unilateral in seven (29.2%). These CPC patterns differed significantly between the HME and other groups (pâ¯<â¯0.001). Among HME patients, those with a unilateral cerebellar distribution on both sides had significantly earlier seizure onset (pâ¯=â¯0.049) and more frequent seizures (pâ¯=â¯0.052) at a trend level compared to those with bilateral and mixed distributions. CONCLUSION: Disrupted CPC tracts were observed more frequently in HME patients than in WS of unknown etiology patients and controls, and they may be correlated with earlier seizure onset and more frequent seizures in HME patients. DTI is a useful and non-invasive method for speculating the pathology in the developing brain.
Assuntos
Doenças Cerebelares/patologia , Cerebelo/patologia , Hemimegalencefalia/patologia , Adolescente , Adulto , Encéfalo/patologia , Criança , Pré-Escolar , Imagem de Tensor de Difusão/métodos , Epilepsia/patologia , Feminino , Hemimegalencefalia/metabolismo , Humanos , Lactente , Japão , Masculino , Malformações do Desenvolvimento Cortical/patologia , Vias Neurais/patologia , Ponte/patologia , Espasmos Infantis/patologia , Substância Branca/patologiaRESUMO
Malformations of cortical development are a frequent cause of drug-resistant Epilepsy and developmental delay. Hemimegalencephaly is a Malformation of cortical development characterized by enlargement of all or a part of one cerebral hemisphere. Germline and somatic mutation in genes belonging to the Mammalian Target of Rapamycin (mTOR) pathway has been identified in patients suffering from epilepsy secondary to Hemimegalencephaly and focal cortical dysplasia. We present here a patient suffering from severe neonatal Epilepsy since 3â¯h of life secondary to Hemimegalencephaly, requiring an anatomic hemispherectomy surgical procedure for seizure control, where by means of next-generation sequencing at an ultra-high depth coverage, we were able to identify a novel somatic mutation in the RHEB gene (NM_005614: c.119Aâ¯>â¯T: p. Glu40Val). The histopathological diagnosis was Cortical Dysplasia type IIB determined by the presence of dysmorphic neurons of variable size with nuclear alteration and balloon cells in the context of Hemimegalencephaly, which are similar to that have been demonstrated in hyperactivating RHEB models. This is the first report of a somatic mutation in RHEB gene in a patient suffering from Epilepsy secondary to Hemimegalencephaly. It highlights different current topics in the fields of genetics of Malformations of cortical development: a-somatic mosaicism is not uncommon in these neurodevelopmental disorders; b-the molecular diagnostic approach should involve the use of state-of-the-art methods and the sampling of different tissues; c-new findings might facilitate therapeutics discoveries while providing an improved understanding of normal brain development.
Assuntos
Epilepsia Resistente a Medicamentos/genética , Hemimegalencefalia/genética , Malformações do Desenvolvimento Cortical/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Epilepsia Resistente a Medicamentos/patologia , Feminino , Hemimegalencefalia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Malformações do Desenvolvimento Cortical/patologia , Mutação , Serina-Treonina Quinases TOR/genéticaRESUMO
Focal malformations of cortical development (FMCDs), including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in MTOR have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in MTOR, we discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. We found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, we found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in MTOR contribute to the pathogenesis of cortical dyslamination in FMCDs.
Assuntos
Autofagia/genética , Córtex Cerebral/metabolismo , Cílios , Malformações do Desenvolvimento Cortical/genética , Neurônios/metabolismo , Serina-Treonina Quinases TOR/genética , Adolescente , Animais , Polaridade Celular/genética , Centríolos/metabolismo , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Criança , Pré-Escolar , Feminino , Edição de Genes , Células HEK293 , Hemimegalencefalia/embriologia , Hemimegalencefalia/genética , Hemimegalencefalia/patologia , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical/embriologia , Malformações do Desenvolvimento Cortical/patologia , Camundongos , Mutação , Proteínas/metabolismo , Esclerose Tuberosa/embriologia , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Via de Sinalização WntRESUMO
Hemimegalencephaly is known to occur in Proteus syndrome, but has not been reported, to our knowledge, in the other PTEN mutation-related syndrome of Bannayan-Riley-Ruvalcaba. Here, we report a patient with Bannayan-Riley-Ruvalcaba syndrome who also had hemimegalencephaly and in whom the hemimegalencephaly was evident well before presentation of the characteristic manifestations of Bannayan-Riley-Ruvalcaba syndrome. An 11-year-old boy developed drug-resistant focal seizures on the fifth day of life. MRI revealed left hemimegalencephaly. He later showed macrocephaly, developmental delay, athetotic quadriplegic cerebral palsy, and neuromuscular scoliosis. Freckling of the penis, which is characteristic of Bannayan-Riley-Ruvalcaba syndrome, was not present at birth but was observed at 9 years of age. Gene analysis revealed a c.510 T>G PTEN mutation. This patient and his other affected family members, his father and two siblings, were started on the tumour screening procedures recommended for patients with PTEN mutations. This case highlights the importance of early screening for PTEN mutations in cases of hemimegalencephaly not otherwise explained by another disorder, even in the absence of signs of Proteus syndrome or the full manifestations of Bannayan-Riley Ruvalcaba syndrome.
Assuntos
Síndrome do Hamartoma Múltiplo/diagnóstico , Hemimegalencefalia/diagnóstico , PTEN Fosfo-Hidrolase/genética , Criança , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Síndrome do Hamartoma Múltiplo/fisiopatologia , Hemimegalencefalia/genética , Hemimegalencefalia/patologia , Hemimegalencefalia/fisiopatologia , Humanos , Masculino , Mutação , LinhagemRESUMO
Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.
Assuntos
Malformações do Desenvolvimento Cortical/genética , Mutação/genética , Transdução de Sinais , Células-Tronco/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Telencéfalo/patologia , Animais , Linhagem da Célula , Classe I de Fosfatidilinositol 3-Quinases/genética , Hemimegalencefalia/genética , Hemimegalencefalia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Neurônios/metabolismo , Neurônios/patologiaRESUMO
BACKGROUND: Hemimegalencephaly with tuberous sclerosis complex is an uncommon association, usually associated with intractable seizures that begin in the neonatal period or early infancy. Typically, the seizures are managed with medications until the patient is older when surgical treatment is considered safe. PATIENT DESCRIPTION: We describe a 7-week-old infant with tuberous sclerosis (TSC1 mutation) and hemimegalencephaly who underwent a functional hemispherectomy for status epilepticus. No clinical seizures have occurred since surgery nearly 5 years ago and subsequent weaning of antiepileptic drugs 3 years ago. This is one of the youngest patients with tuberous sclerosis complex treated with a hemispherectomy and one of seven patients described in the literature. CONCLUSIONS: Our patient, along with previously reported cases, suggests that a hemispherectomy is a viable option in the very young. With evolution of this surgical process since its inception nearly 6 decades ago, it may now be performed safely in early infancy, engendering the possibility of seizure freedom in most and thus optimizing neurodevelopmental outcome.
Assuntos
Hemimegalencefalia/etiologia , Hemimegalencefalia/cirurgia , Hemisferectomia/métodos , Esclerose Tuberosa/complicações , Esclerose Tuberosa/cirurgia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/cirurgia , Hemimegalencefalia/genética , Hemimegalencefalia/patologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Estado Epiléptico/etiologia , Estado Epiléptico/genética , Estado Epiléptico/patologia , Estado Epiléptico/cirurgia , Resultado do Tratamento , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genéticaAssuntos
Hemimegalencefalia/complicações , Hemimegalencefalia/patologia , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Artéria Carótida Interna/patologia , Angiografia Cerebral , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-IdadeRESUMO
Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer-associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum.
Assuntos
Encéfalo/anormalidades , Hemimegalencefalia/genética , Malformações do Desenvolvimento Cortical/genética , Megalencefalia/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Adolescente , Encéfalo/metabolismo , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Predisposição Genética para Doença/genética , Hemimegalencefalia/metabolismo , Hemimegalencefalia/patologia , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/metabolismo , Malformações do Desenvolvimento Cortical/patologia , Megalencefalia/metabolismo , Megalencefalia/patologia , Mutação , Neuroimagem , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismoRESUMO
A magnetic resonance diffusion fiber tracking study in neonate diagnosed with left hemisphere hemimegalencephaly is presented. Despite diffuse morphologic deformities identified in conventional imaging, all major pathways were identifiable bilaterally with minor aberrations in vicinity of morphologic lesions.