Lissencephaly and subcortical band heterotopia: molecular basis and diagnosis
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Pachygyria
Heterotopia
Doublecortin
Doublecortin (DCX) mutations cause abnormal development of the DCX protein that normally aids in neuronal migration during fetal development. These mutations lead to lissencephaly, or the appearance of a “smooth brain,” which is varying levels of pachygyria or agyria in severe cases. Many genetic variants of the mutation have been identified, and an even greater range of phenotypic presentations have been described in the literature. The X-linked lissencephaly (DCX) mutation leads to an X-linked gender-dependent condition that causes subcortical heterotopia in females and lissencephaly in males. The authors report the case of a 13-year-old male who presented to our clinic for new-onset seizure disorder. He had a past medical history of developmental delay and features of autism spectrum disorder which was diagnosed at age 5 years at an outside clinic. Magnetic resonance imaging (MRI) brain at age 5 years showed pachygyria of the frontal and temporal lobes. After extensive genetic testing over the course of over a decade, the patient was found to have a de novo mutation in the DCX gene diagnosed via whole-exome sequencing. Specifically, he was found to have a mosaic mutation of the DCX gene as a c.30-31 deletion. His previous MRI findings were consistent with a diagnosis of X-linked sporadic lissencephaly sequence and included mainly a diffuse bilateral pachygyria (isolated lissencephaly sequence X chromosome). Thickening of the cortex and pachygyria or agyria are classic findings of lissencephaly, but do not help specify any mutation in the gene, of which there are over 70 possibilities. Our patient is unique in that most individuals with DCX mutation have infantile seizures, severe intellectual disability, orthopedic complications, and postnatal microcephaly, which our patient does not have.
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Classical lissencephaly and double cortex are genetic neuronal migration disorders associated with mental retardation and epilepsy. In classical lissencephaly, the six-layered cortex is replaced by a four layered structure lacking normal gyri or sulci. In double cortex, a second layer of cortical neurons underlies a normal cortex. A mutation in LIS1 or doublecortin can lead to either classical lissencephaly or double cortex, but because LIS1 is autosomal and doublecortin is X-linked (on the X chromosome), the disease inheritance pattern and risk of recurrence for the two genes are distinct. Mutation analysis for LIS1 and doublecortin is essential in determining the etiology of the disease in patients and may be helpful in determining the recurrence risk in families.
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Neuronal migration is a critical process in the development of the nervous system. Defects in the migration of the neurons are associated with diseases like lissencephaly, subcortical band heterotopia (SBH), and pachygyria. Doublecortin (DCX) is an essential factor in neurogenesis and mutations in this protein impairs neuronal migration leading to several pathological conditions. Although DCX is capable of modulating and stabilizing microtubules (MTs) to ensure effective migration, the mechanisms involved in executing these functions remain poorly understood. Meanwhile, there are existing gaps regarding the processes that underlie tumor initiation and progression into cancer as well as the ability to migrate and invade normal cells. Several studies suggest that DCX is involved in cancer metastasis. Unstable interactions between DCX and MTs destabilizes cytoskeletal organization leading to disorganized movements of cells, a process which may be implicated in the uncontrolled migration of cancer cells. However, the underlying mechanism is complex and require further clarification. Therefore, exploring the importance and features known up to date about this molecule will broaden our understanding and shed light on potential therapeutic approaches for the associated neurological diseases. This review summarizes current knowledge about DCX, its features, functions, and relationships with other proteins. We also present an overview of its role in cancer cells and highlight the importance of studying its gene mutations.
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Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development. One of the most frequent disorders is lissencephaly characterized by a paucity of normal gyri and sulci resulting in a “smooth brain”. There are two pathologic subtypes: classical and cobblestone. Classical lissencephaly results from an arrest of neuronal migration, whereas cobblestone lissencephaly results from overmigration. Another important neuronal migration disorder is heterotopia characterized by a cluster of normal neurons in abnormal locations and it is divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Polymicrogyria develops at the last stages of neuronal migration to the earliest phases of cortical organization; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested by mild mental retardation, epilepsy and pseudobulbar palsy. Schizencephaly is another important disorder of neuronal migration whose clinical characteristics are extremely variable. Focal cortical dysplasia represents one of most severe causes of epilepsy in children. This review reports the main clinical, genetical, neuroradiological aspects of these disorders.
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Neuronal migration disorders can now be recognised by MRI. This paper reports two families in which the mothers had subcortical laminar heterotopia and four of their children had either similar heterotopia (two girls) or severe pachygyria or lissencephaly (two boys). Laminar heterotopia was more evident on MRI T2 weighted images. The patients had mild to severe epilepsy and mental retardation depending on the extent of cortical abnormalities. In these families, subcortical laminar heterotopia, pachygyria, and lissencephaly seem to share the same X linked or autosomal dominant gene. No chromosomal abnormalities, especially of chromosome 17, could be identified. For appropriate genetic counselling of the family of a child with lissencephaly or subcortical laminar heterotopia, MRI should be performed in parents or siblings with mental retardation or epilepsy.
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Type I lissencephaly is a cortical malformation disorder characterized by disorganized cortical layers and gyral abnormalities and associated with severe cognitive impairment and epilepsy. The exact pathophysiological mechanisms underlying the epilepsy and mental retardation in this and related disorders remain unknown. Two genes, LIS1 and doublecortin, have both been shown to be mutated in a large proportion of cases of type I lissencephaly and a milder allelic disorder, subcortical laminar heterotopia (SCLH). Studying the protein products of these genes and the biochemical pathways in which they belong is likely to yield important information concerning both normal and abnormal cortical development. The relationships between the LIS1 and Doublecortin proteins are not yet well defined, but both are believed to play a critical role in cortical neuronal migration. Lis1 is expressed from very early development in the mouse and in both proliferating cells and post-mitotic neurons of the cortex. This protein is likely to have multiple functions since it is a subunit of the enzyme platelet-activating factor acetylhydrolase, which degrades platelet activating factor, and has also been shown to be involved in microtubule dynamics, potentially influencing nuclear migration through its interaction with the dynein motor protein complex. Doublecortin on the other hand is exclusively expressed in post-mitotic neurons and is developmentally regulated. In young developing neurons Doublecortin has a specific subcellular localization at the ends of neuritic and leading processes. This localization, combined with our previous data showing that it is a microtubule-associated protein and that it interacts with adapter complexes involved in vesicle trafficking, suggests a role in the growth of neuronal processes, downstream of directional or guidance signals. The observations summarized here favor the suggestion that whereas LIS1 may play a role in nuclear migration, Doublecortin is instead restricted to functions at the leading edge of the cell.
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