SCN2A and Its Related Epileptic Phenotypes

Focal cortical dysplasias (FCDs) include a spectrum of anomalies of cortical development that consist in one or more areas with altered lamination and in some cases, neurons of abnormal morphology. Clinically, these structural anomalies led to arise of epilepsy, which is more often a focal, drug-resistant type with onset in pediatric or adolescent age. Occasionally, other symptoms have been reported in patients with FCDs, such as headache, movement disorders, and cognitive impairment. According to International League against Epilepsy scheme of 2011, three main subtypes of FCD can be distinguished, based of anatomopathological feature, radiological signs, and clinical expression. Magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography, and neurophysiology are the cornerstones of diagnosis, although their negativity cannot exclude FCD in symptomatic patients, especially in FCD type I which often is elusive. In MRI, the main finding is the irregularity of the cortical–subcortical signal, specifically reduction of cortical thickness and absence of clear demarcation between gray and white matters, which is strongly diagnostic for FCD. Epilepsy related to FCD is difficult to manage and until now there is not a clear direction for treatment's rules. FCD shows poor response to antiepileptic drugs (AEDs), and there is no evidence of some AED that has proved more efficacy than others in patients with FCDs. Considering genetical and pathophysiological recent acquisitions, mammalian target of rapamycin inhibitors may play a fundamental role in future treatment of FCDs, but nowadays, surgery still remains the main weapon, with 50% of patients who undergo neurosurgery.

“…A positive surgical outcome is associated with multidisciplinary management, use of SEEG and PET in the preoperative assessment, [57][58][59] early surgical timing. 18…”

Section: Surgical Treatment Of Fcd-related Epilepsymentioning

confidence: 99%

Focal Cortical Dysplasia: Diagnosis, Classification, and Treatment Options

Pizzo,

Fichera,

Zanghì

et al. 2024

“…It is widely acknowledged that MDS is a contiguous gene deletion syndrome, implying that it arises from the removal of multiple genes located closely together on the chromosome. 41,42 Individuals affected by MDS typically exhibit pronounced LIS, often classified as grade 1 or 2. In contrast, patients with ILS tend to display milder forms of LIS, typically falling within the range of grades 2 to 4.…”

Section: Isolated Lissencephaly Sequence and Miller-dieker Syndromementioning

confidence: 99%

Lissencephaly, Pachygyrias, Band Heterotopias, RELN Pathway, and ARX Mutations (Incomplete Neuron Migration)

Sciuto,

Fichera,

Zanghì

et al. 2024

Self Cite

Lissencephaly (LIS) is a group of malformations of cortical development consisting of a defective neuronal migration that results in lack of formation of the normal cerebral convolutions. It includes a spectrum of defect with varying degrees of severity, from agyria and pachygyria to subcortical band heterotopia. The etiopathogenesis of LIS includes both genetic and environmental factors. Although nongenetic forms of LIS have been reported, genetic causes are certainly more frequent and to date 19 LIS-SBH-associated genes have been identified. Most common mutations involve LIS1, DCX, ARX, and RELN genes. Clinically affected individuals present with early hypotonia, which can progress to limb spasticity, seizures, and psychomotor retardation. Convulsive episodes usually appear early (first months of life) and include infantile spasms, akinetic or myoclonic seizures, up to the development of complex epileptic syndromes, including atypical absences, myoclonia, and partial or tonic–clonic seizures. Several clinical entities are associated with classical LIS, including the following: isolated lissencephaly sequence (ILS); Miller–Dieker syndrome (MDS; OMIM 247200); subcortical band heterotopia (OMIM 300067); X-linked LIS with abnormal genitalia; and LIS with cerebellar hypoplasia. Diagnosis primarily depends on genetic and neuroimaging. Magnetic resonance imaging (MRI) is the gold standard, and it detects the presence of thick cortical cortex, its location, and the layers' architecture. Based on neuroimaging, it is possible to distinguish six subtypes of gyral malformations. Clinical and therapeutic management of these patients is challenging, considering the necessity to face drug-resistant epilepsy, intellectual disability, spasticity, and dysphagia and feeding problems. At the present moment, no gene-specific treatment for LIS is available.

“…41,42 Cephalocele Cephaloceles are congenital abnormalities identified by the protrusion of meninges and/or brain tissue through a congenital defect in the skull bone. 43,44 This protrusion is typically covered by either skin or mucous membrane. They are classified according to their location and contents: the herniation of brain tissue with the overlying meninges through a cranial defect is defined as meningoencephalocele or encephalocele, while the herniation of meninges without brain tissue is defined as cranial meningocele.…”

Section: Cranioectomesodermal Hypoplasiamentioning

confidence: 99%

Anomalies of the Mesenchyme (Meninges and Skull)—Defects of Neural Tube Closure: Cephalocele and Other Calvarial and Skull Base Defects; Intracranial Lipomas; Arachnoid Cysts; Nonsyndromic and Syndromic Craniosynostoses

Carnazzo,

La Cognata,

Zanghì

et al. 2024

Self Cite

Within the embryonic head, a layer of mesenchyme envelops the brain beneath the surface ectoderm. This cranial mesenchyme is responsible for the formation of the meninges, the calvaria (upper portion of the skull), and the scalp's dermis. Irregular development of these structures, particularly the meninges and the calvaria, is associated with notable congenital defects in humans, such as defects in neural tube closure. Anencephaly is the most common neural tube defect (NTD) and one of the most severe malformations of the central nervous system; it consists in the complete or partial absence of the brain, associated with the absence of the bones of the cranial vault. Iniencephaly is an uncommon congenital NTD characterized by abnormalities in the occipital region, including rachischisis of the cervicothoracic spine and a fixed retroflexion deformity of the head. Unlike anencephaly, in iniencephaly, there is a skull cavity and a normal-looking skin that entirely covers the head and the medullary retroflex area. Cephaloceles are congenital abnormalities distinguished by the protrusion of meninges and/or brain tissue through a naturally occurring defect in the skull bone. This anomaly is typically covered by skin or mucous membrane. Intracranial lipoma is a relatively uncommon and generally benign tumor that occurs in an abnormal location within the brain; it probably represents a disturbance of the differentiation of the primordial meninges: for unknown causes, the meningeal mesenchyme can differentiate into adipose tissue. Arachnoid cysts are sacs filled with cerebrospinal fluid (CSF) situated between the brain or spinal cord and the arachnoid membrane. Typically, these cysts originate within CSF cisterns and gradually expand their boundaries. Craniosynostosis is the early fusion of one or more cranial sutures. It can occur spontaneously, be associated with a syndrome, or have a familial connection. It can involve one or multiple cranial sutures. Pfeiffer's, Crouzon's, and Apert's syndromes are among the more prevalent syndromic craniosynostoses.