Subcortical Laminar Heterotopia Research Articles

High Expression of Doublecortin and KIAA0369 Protein in Fetal Brain Suggests Their Specific Role in Neuronal Migration

The X-linked subcortical laminar heterotopia and lissencephaly syndrome is a disorder of neuronal migration caused by a mutation in XLIS, a recently cloned gene on chromosome Xq22.3-q23. The predicted protein product for XLIS, doublecortin (DC), shows high homology to a putative calcium calmodulin-dependent kinase, KIAA0369 protein (KI). Here we identified DC and KI in the brains of human and rat fetuses by immunochemical and immunohistochemical means. In this study, Western blotting demonstrated that both DC and KI are specific to the nervous system and are abundant during the fetal period, around 20 gestational weeks in humans and embryonic days 17 to 20 in rats. Immunostaining of the developing neocortex disclosed localization of DC and KI immunoreactivities in neuronal cell bodies and processes in the zones of ongoing neuronal migration. Although KI showed a somewhat wider distribution than DC, the temporal and spatial patterns of their expression were similar. These results suggest that DC and KI participate in a common signaling pathway regulating neuronal migration.

Periventricular Heterotopia and the Genetics of Neuronal Migration in the Cerebral Cortex

In recent years, remarkable contributions to our understanding of how the brain develops have come from the field of genetics. The study of brain development is important, not only to further our understanding of this complex phenomenon, but because gross brain malformations are now recognized to cause significant proportions of cognitive and neurologic disorders. When the cerebral cortex fails to form properly, the result is often severe mental retardation. Even mild dysgenesis of the cortex is frequently associated with epilepsy.

Subcortical laminar heterotopia in two sisters and their mother: MRI, clinical findings and pathogenesis.

MR imaging, clinical data and underlying pathogenesis of subcortical laminar heterotopia (SCLH), also known as band heterotopia, in two sisters and their mother are presented. On MR imaging a different degree of SCLH was found in all three affected family-members. The inversion recovery sequence was considered most useful in the demonstration of the heterotopic band of gray matter and the assessment of cortical thickness. The younger sister presented with epileptic seizures at the age of five months and a delayed achievement of developmental milestones. The older sister of seven years had epileptic seizures since the age of one year, and developmental delay. Their mother has only had one seizure-like episode at the age of 39. Her psychomotor development had been normal. Investigation of DNA samples of the three female family-members revealed a mutation in the X-linked doublecortin gene. Within families with band heterotopia, this gene has also been related to male family members with lissencephaly.

Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons.

Recently, we and others reported that the doublecortin gene is responsible for X-linked lissencephaly and subcortical laminar heterotopia. Here, we show that Doublecortin is expressed in the brain throughout the period of corticogenesis in migrating and differentiating neurons. Immunohistochemical studies show its localization in the soma and leading processes of tangentially migrating neurons, and a strong axonal labeling is observed in differentiating neurons. In cultured neurons, Doublecortin expression is highest in the distal parts of developing processes. We demonstrate by sedimentation and microscopy studies that Doublecortin is associated with microtubules (MTs) and postulate that it is a novel MAP. Our data suggest that the cortical dysgeneses associated with the loss of Doublecortin function might result from abnormal cytoskeletal dynamics in neuronal cell development.

Double Cortex Syndrome

The incidence of mutations in the X-linked gene doublecortin in patients with “double cortex” syndrome (DC; also called subcortical band heterotopia or laminar heterotopia) and familial DC with lissencephaly was investigated in a cohort of 8 pedigrees and 47 sporadic patients with DC examined at the Division of Neurogenics, Beth Israel Deaconess Medical Center, Boston, and multiple centers in the US and abroad.

Expression of doublecortin correlates with neuronal migration and pattern formation in diverse regions of the developing chick brain.

The development of functional layers in the brain involves spatially and temporally regulated gene expression. Through cDNA library screening, we have identified genes that are expressed in a neural-specific manner during brain development. Sequencing and expression data indicate that one of the clones, 18C15, is the chick homologue of doublecortin, a human X-linked gene found to be mutated in subcortical laminar heterotopia (double cortex syndrome) and lissencephaly. The 18C15 mRNA contains multiple motifs that are known to regulate mRNA stability in response to inductive signals, and these motifs are conserved between the chick and human sequences. Doublecortin is found to be expressed at peak levels during early development of the cerebellum and forebrain, and is expressed in other regions including the tectum, spinal cord, and dorsal root ganglia. This study demonstrates both spatial and temporal regulation of doublecortin expression in the chick, which is associated with early events in brain development, including neuronal migration.

Cloning and Developmental Expression of the Murine Homolog ofdoublecortin

While analyzing active genes in neonatal mouse hippocampus by quantitative 3′-cDNA collection, we identified a highly conserved murine homolog ofdoublecortin,the causative gene of X-linked lissencephaly (XLIS) and subcortical laminar heterotopia (SCLH) syndrome. Them-doublecortincDNA contains nearly 8 kb 3′ UTR homologous tohs-doublecortinand it was mapped to the X chromosome. The expression ofm-doublecortinis limited to the developing CNS, especially the cortical plate, supporting that XLIS/SCLH syndrome is associated with an arrest of neuronal migration in the cerebral cortex. Them-doublecortinmRNA was absent in the ventricular zone where neuronal precursors proliferate, and interestingly it was found in various brain structures that are not typically affected in patients with this syndrome.

A Novel CNS Gene Required for Neuronal Migration and Involved in X-Linked Subcortical Laminar Heterotopia and Lissencephaly Syndrome

X-SCLH/LIS syndrome is a neuronal migration disorder with disruption of the six-layered neocortex. It consists of subcortical laminar heterotopia (SCLH, band heterotopia, or double cortex) in females and lissencephaly (LIS) in males, leading to epilepsy and cognitive impairment. We report the characterization of a novel CNS gene encoding a 40 kDa predicted protein that we named Doublecortin and the identification of mutations in four unrelated X-SCLH/LIS cases. The predicted protein shares significant homology with the N-terminal segment of a protein containing a protein kinase domain at its C-terminal part. This novel gene is highly expressed during brain development, mainly in fetal neurons including precursors. The complete disorganization observed in lissencephaly and heterotopia thus seems to reflect a failure of early events associated with neuron dispersion.

Dominant X linked subcortical laminar heterotopia and lissencephaly syndrome (XSCLH/LIS): evidence for the occurrence of mutation in males and mapping of a potential locus in Xq22.

X linked subcortical laminar heterotopia and lissencephaly syndrome (XSCLH/ LIS) is an intriguing disorder of cortical development, which causes classical lissencephaly with severe mental retardation and epilepsy in hemizygous males,...

Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients.

Cerebral cortical dysgenesis (CD) is a heterogeneous disorder of cortical development and organization commonly associated with epilepsy, with a variety of subtypes. We reviewed the clinical, EEG and neuroimaging features in 100 adult patients with CD. There were 39 men and 61 women with a median age of 27 years (range 15-63 years). All patients were referred because of medically refractory epilepsy. Median age at seizure onset was 10 years (range 3 weeks to 39 years); in 30 patients, onset was in adulthood. The epilepsy was classified as generalized in 16 patients and localization-related in 84. Of the latter, the epileptic syndromes in decreasing frequency were frontal (32%), temporal (31%), parietal (14%) and occipital (7%). Only 15% of patients had a history of status epilepticus. Prenatal/perinatal problems were reported in 32 patients but these were severe in only four: exposure to drugs (three) and infection (one) during the first trimester. Delayed developmental milestones were seen in 10%, mental retardation in 9%, additional congenital abnormalities in 4% and neurological deficits in 14% of patients. Diagnosis of CD was based on neuroimaging in 70, pathology in four and both methods in the remaining 26. The following subcategories were identified: agyria/diffuse macrogyria (four patients), focal macrogyria (16), focal polymicrogyria (one), focal macrogyria/polymicrogyria associated with a cleft (11), minor gyral abnormalities (seven), subependymal grey matter heterotopia (20), bilateral subcortical laminar grey matter heterotopia (eight), tuberous sclerosis (five), focal cortical dysplasia/microdysgenesis (seven) and dysembryoplastic neuroepithelial tumours (DNT) (21). Sixty-eight percent of patients had normal CT and 19 out of 36 patients had normal previous conventional MRI. MRI-based hippocampal volume measurements in 47 patients revealed ratios (smaller: larger hippocampus) of < 0.90 in 16, 0.90-0.94 in 14 and > or = 0.95 in 17 patients. EEGs were normal in only five patients. Alpha rhythm was preserved in 78 patients, including one patient with bilateral posterior macrogyria. Localized polymorphic slow activity was present in 43 patients. Five of 68 patients with focal/unilateral CD had only bilateral independent/synchronous spiking and 14 out of 32 with diffuse/bilateral CD only focal/unilateral spiking. In 60 patients with nondiffuse CD or with abnormal gyration or DNT, the epileptiform abnormalities were less extensive than coextensive with the lesion in 28, more extensive than and overlapped the lesion in 18 and remote from the lesion in five; nine patients did not have epileptiform abnormalities. There was poor correlation between the epileptic syndromes and EEG abnormalities and the location/extent of CD as defined by MRI and pathology.(ABSTRACT TRUNCATED AT 400 WORDS)

STAGES AND PATTERNS OF CENTRIFUGAL ARREST OF DIFFUSE NEURONAL MIGRATION DISORDERS

Centrifugal migration of newly generated neuroblasts toward the cortical surface can be arrested at different levels, resulting in anatomically different disorders. This is illustrated by three patients with diffuse or generalized neuronal migration disorders (NMDs): pachygyria, subcortical laminar heterotopia ('double-cortex' syndrome), and periventricular laminar heterotopia. All had medically intractable partial and generalized epileptic seizures, but there was no close correlation between the type of dysplasia and intelligence or clinical pattern. The low intelligence found in these patients may relate to the epileptic syndrome, rather than to the NMDs alone. MRI suggested that in this spectrum of disorders the migration process was arrested at different stages, depending on the extent, timing and site of damage to radial glial fibres.