Malformations Of Cerebral Cortical Development Research Articles

Cilia in hereditary cerebral anomalies.

Ciliopathies are complex genetic multi-system disorders causally related to abnormal assembly or function of motile or non-motile cilia. While most human cells possess a non-motile sensory/primary cilium (PC) during development and/or in adult tissues, motile cilia are restricted to specialised cells. As a result, PC-associated ciliopathies are characterised by high phenotypic variability with extensive clinical and genetic overlaps. In the present review, we have focused on cerebral developmental anomalies, which are commonly found in PC-associated ciliopathies and which have mostly been linked to Hedgehog signalling defects. In addition, we have reviewed emerging evidence that PC dysfunctions could be directly or indirectly involved in the mechanisms underlying malformations of cerebral cortical development including primary microcephaly.

Role of Magnetic Resonance Imaging in the Diagnosis of Fetal Brain Anomalies

ABSTRACT Prenatal Ultrasonagraphy (US) is the mainstay modality to diagnose fetal abnormalities especially in early pregnancy. Fetal Magnetic Resonance Imaging (MRI) is a useful tool to confirm and to characterize a pathology that is suspected on US, especially in the detection of central nervous system pathologies. The use of ultrafast imaging tecniques gives additional importantant informations and optimal imaging quality, despite fetal motion, in clinical practice. Diffusion Weighted Imaging (DWI), Diffusion Tensor Imaging (DTI), MR Spetroscopy and Functional studies have potential applications in the fetal brain imaging. Fetal MRI could recognize, in contradistinction to US, the development of fetal brain, the multilayered appearance of the cerebral parenchyma, the timing of sulci development and the myelination. The most common indications for fetal MRI are ventriculomegaly, midline anomalies, malformations of cerebral cortical development, posterior fossa anomalies, suspected haemorraghic-ischemic lesions, tumors. Fetal MRI is a safe and powerful complement to US for clinical management and prognostication. How to cite this article Resta M, Dicuonzo F, Resta M. Role of Magnetic Resonance Imaging in the Diagnosis of Fetal Brain Anomalies. Donald School J Ultrasound Obstet Gynecol 2017;11(4):328-340.

Focal Cortical Dysplasia.

Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been classified into neuropathological subtypes (type Ia, Ib, IIa, IIb, and III) based on the severity of cytoarchitectural disruption--tangential or radial dispersion, or loss of laminar structure--and the presence of unique cells types such as cytomegalic neurons or balloon cells. Most focal cortical dysplasias can be identified on neuroimaging and many require resective epilepsy surgery to cure refractory seizures. The pathogenesis of focal cortical dysplasias remains to be defined, although there is recent evidence to suggest that focal cortical dysplasias arise from de novo somatic mutations occurring during brain development. Some focal cortical dysplasia subtypes show a link to the mammalian target of rapamycin signaling cascade; this has now extended to other cortical malformations, including hemimegalencephaly.

Microdeletion 5q14.3 and anomalies of brain development

5q14.3 deletions spanning and flanking MEF2C as well as intragenic MEF2C mutations have recently been described as a cause of severe intellectual disability, epilepsy, and muscular hypotonia, with variable brain and other anomalies. With an increasing number of patients described, the clinical presentation of the patients appears to be relatively uniform, however the structural brain phenotypes described are variable. We describe two unrelated patients with overlapping de novo interstitial deletions of 4.1 and 1.9 Mb, including MEF2C in 5q14.3, one of whom had a complex brain malformation which could be best described as microcephaly with simplified gyral pattern (MSG). Expression analysis in both patients confirmed haploinsufficiency for MEF2C, decreased MECP2 expression and increased C3ORF58 (DIA1) expression, which is a new finding. A detailed analysis of brain and white matter abnormalities reported in patients with 5q14.3 deletion syndrome to date revealed a greater number of reported abnormalities in patients with deletions not including MEF2C than those with deletions or mutations directly affecting MEF2C. Screening an additional 43 patients with malformations of cerebral cortical development (MCD) for mutations in MEF2C and/or deletions in 5q14.3q15, did not detect any additional mutations, allowing us to conclude that 5q14.3 deletion syndrome is a rare cause of microcephaly with simplified gyral pattern.

A developmental and genetic classification for malformations of cortical development: update 2012

Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.

Periventricular nodular heterotopia and distal limb deficiency: A recurrent association

Malformations of cerebral cortical development, in particular periventricular nodular heterotopia (PNH), and distal transverse limb deficiency have been reported as associated congenital anomalies. Patients with PNH and transverse limb deficiency can be classified as having amniotic band sequence or Adams-Oliver syndrome (AOS). Controversy exists whether these should be considered separate entities. In some AOS patients, autosomal recessive inheritance has been shown, but in most patients causes are unknown, and both environmental and genetic factors have been implicated. We present three patients with PNH and distal transverse limb deficiency to support the hypothesis that these should be considered part of one group of disorders, and highlight the variable severity of the clinical and neuroradiological phenotype. Chromosome abnormalities were excluded by copy number analysis on 250K SNP microarray data.Research done on limb deficiency as on PNH caused by mutations in known genes, suggests the involvement of vascular developmental pathways. The combination of limb deficiency and PNH may have a common causative mechanism. Recognition and grouping of patients with this combination of abnormalities will help elucidating the cause.

Malformations of Cerebral Cortical Development

Malformations of cortical development (MCDs) comprise a variable spectrum of clinical, neuroradiologic, and histopathologic findings. MCDs are increasingly recognized as significant causes of epilepsy, developmental delays, and congenital neurologic deficits. The aim of this study was to determine the types, relative frequencies, and clinical and imaging features of MCDs. Data were collected in 2 hospitals and a medical imaging center during a 9-year period. Twenty-six patients (17 men and 9 women; age range, 5 mo to 29 y; mean age, 10.8 y) with an MCD were evaluated. The results of magnetic resonance imaging studies were retrospectively reviewed for type, extension, and classification of the malformations and for associated findings. Clinical findings were obtained by a review of the patients' medical records. Of the patients studied, epilepsy was present in 65%, mental and/or motor retardation was identified in 34.6%, and skin lesions were noted in 15%. The following types of MCD were identified: malformations of the heterotopic gray matter in 35% of the subjects, focal cortical dysplasia (23%), subependymal and cortical tubers (19%), pachygyria (15%), polymicrogyria (15%), schizencephaly (15%), and type 1 lissencephaly (8%). Approximately, 27% of the subjects had the following other types of cerebral malformation: callosal agenesis (8%), ventriculomegaly (8%), or agenesis of the septum pellucidum (4%). Our study indicated that the most common forms of MCD are heterotopia and focal cortical dysplasia. Patients with an MCD tended to have a higher prevalence of epilepsy, developmental delays, and neurologic deficits. Most patients with heterotopia had other malformations of cortical dysplasia. Some patients with an MCD also exhibited other malformations of the brain.

Neuroimaging studies in the evaluation of developmental delay/mental retardation.

The employment of neuroimaging studies in the evaluation of individuals with developmental delay/mental retardation (DD/MR) is still highly debated. The Consensus Conference of the American College of Medical Genetics has suggested that "neuroimaging appears to have an especially important role in patients with microcephaly or macrocephaly, seizures, loss of psychomotor skills and neurologic signs," whereas the value of neuroimaging investigations "in the normocephalic patient without focal neurological signs is unclear" [Curry et al., 1997]. However, recent literature reports show how the latest neuroimaging techniques (in vivo proton magnetic resonance spectroscopy [H-MRS]) may prove to be useful in the diagnostic process of those individuals with DD/MR and no neurological signs/symptoms. The use of these techniques can, in addition, help in monitoring treatment in distinct metabolic disorders. This review will focus on the usefulness of neuroimaging studies in some of the newer metabolic disorders. This paper will also cover those recognizable patterns of human malformation where neuroimaging findings seem to be relevant both toward diagnosis and management, and add to our understanding of the related behavior phenotype. The essential role of magnetic resonance imaging (MRI) on the progress in the diagnostic recognition of malformations of cerebral cortical development is stressed.

Radiologic classification of malformations of cortical development.

Malformations of cerebral cortical development are common birth defects that can cause delayed development, epilepsy, focal neurologic deficits, and mental retardation. Rational classification of these disorders is essential for proper prognosis, genetic testing and counseling, and investigation of the underlying molecular causes. A rational approach to this classification is a framework based on whether these disorders are the result of abnormal cell proliferation or apoptosis, abnormal migration of immature neurons, or abnormal horizontal and radial orientation in the cortex. Superimposed on this framework are subclassifications that are based on topology of the malformation, associated central nervous system (CNS) or extra-CNS malformations, and results of molecular genetic testing. Characteristics that correlate with and enforce this system of classification can be identified by modern neuroimaging studies.

Neuroimaging of focal malformations of cortical development.

Neuroimaging is playing an increasingly important role in the evaluation of patients with malformations of cerebral cortical development. In this review, the authors address optimal neuroimaging of cortical malformations using x-ray computed tomography, single-photon-emission computed tomography, positron emission tomography, magnetic resonance imaging, and magnetic resonance spectroscopy. Initially, the authors discuss the strengths and weaknesses of the various imaging techniques. This is followed by a discussion of the clinical and neuroimaging characteristics of several different imaging manifestations of focal malformations of cortical development, including polymicrogyria, focal subcortical heterotopia, schizencephaly, focally thickened gyri, focally irregular gyri, hemimegalencephaly, and transmural dysplasia. The authors intend that, after reading this review, the reader will have a better understanding of the optimal neuroimaging techniques for evaluating these malformations and their many neuroimaging appearances.