Chromosome X and 17-linked lissencephaly (smooth brain) syndromes
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Abstract:
Lissencephaly (smooth brain) is a severe malformation of neuronal migration with a relatively smooth cerebral surface, thick and poorly organized cortex, and clinical signs of severe neurologic dysfunction. Subcortical band heterotopia is part of the lissencephaly malformation spectrum now referred to as the agyriapachygyria-band spectrum. Chromosome 17-linked lissencephaly (patients with Miller-Dieker syndrome) have classical lissencephaly, characteristic facial features, and perhaps other associated birth defects. The critical region for the lissencephaly phenotype has been mapped to 17 p 13.3, but the identity of the chromosome 17 lissencephaly gene remains unknown. The gene responsible for X-linked lissencephaly has been mapped to Xq22.3. Autosomal recessive classical lissencephaly is thought to exist, although it is considered rare. © 1996 Wiley-Liss, Inc.Keywords:
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Lissencephaly is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The lissencephaly spectrum consists of agyria, pachygyria, and subcortical band heterotopia. At least 19 genes have been identified in the causation of lissencephaly and related syndrome. Lissencephaly is associated with many other congenital disorders but the association of lissencephaly with congenital hypothyroidism is rarely reported. We report a case of a 10-year-old girl having lissencephaly with congenital hypothyroidism. Early diagnosis of lissencephaly and genetic counselling can be made in suspected cases and further possible interventions can be taken. Also, regular follow-up, monitoring, and better conservative management lead to a better prognosis.
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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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Abstract Classification based on Dobyns and Truwit (1995). Lissencephaly (agyria/pachygyria diffuse with abnormally thick cortex and only four layers). Also called lissencephaly type 1: classical: Miller-Dieker syndrome; Lissencephaly sequence; lissencephaly with very small head including a small cerebellum; Cobblestone lissencephaly or lissencephaly type II (a mixture of agyria, pachygyria and polymicrogyria, enlarged ventricles, small brainstem, cerebellun, especially vermis and cerebellar polymicrogyria): Hydrocephalus, agyria, retinal dysplasia (HARD) (seep. 56); the congenital muscular dystrophies (seep. 218);
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Background: Classical lissencephaly or "smooth brain" is a human brain malformation that consists of diffuse agyria and pachygyria. Two genes associated with classical lissencephaly have recently been cloned—LIS1 from chromosome 17p13.3 and XLIS (also called DCX) from Xq22.3-q23. Objective: We performed genotype-phenotype analysis in children with lissencephaly associated with mutations of different genes. Methods: We compared the phenotype, especially brain imaging studies, in a series of 48 children with lissencephaly, including 12 with Miller-Dieker syndrome (MDS), which is associated with large deletions of LIS1 and other genes in the region, 24 with isolated lissencephaly sequence caused by smaller LIS1 deletions or mutations, and 12 with isolated lissencephaly sequence caused by XLIS mutations. Results: We found consistent differences in the gyral patterns, with the malformation more severe posteriorly in individuals with LIS1 mutations and more severe anteriorly in individuals with XLIS mutations. Thus, mutations of LIS1 are associated with a posterior-to-anterior gradient of lissencephaly, whereas mutations of XLIS are associated with an anterior-to-posterior gradient. We also confirmed differences in severity between MDS and ILS17. Hypoplasia of the cerebellar vermis proved to be more common with XLIS mutations. Conclusion: It is often possible to predict the gene mutation from careful review of brain imaging studies.
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Lissencephaly is characterized by absent (agyria) or decreased (pachygyria) cortical convolutions, resulting in a smooth cerebral surface. The affected cortex is abnormally thick, usually measuring 10-15 mm in agyria with almost no visible sulcation, and 6-9 mm in pachygyria (also called “incomplete lissencephaly”) with the presence of only a few shallow sulci and broad gyri. Complete agyria or pachygyria are unusual, and most cases are a combination of agyria and pachygyria. The thick, smooth cortex characteristically shows a peripheral stripe of high T2 signal and low CT attenuation, corresponding to sparse cell zone. The white matter is very thin and may be reduced to periventricular areas only. Several different patterns of lissencephaly have been described depending on the severity of the gyral simplification and the gradient along the anterior to posterior axis, with good correlation between the phenotypic spectrum and the underlying genetic abnormality. The most severe pattern is characterized by complete agyria with smooth cerebral surface and absent opercularization (“figure eight” configuration of the brain). Children with LISI and TUBA1A mutations have predominant posterior lissencephaly with a posterior to anterior (P>A) gradient. TUBAIA mutations may also show perisylvian pachygyria with typical dysgenesis of the anterior limb of the internal capsules. Children with DCX mutations have predominant anterior lissencephaly, with anterior to posterior (A>P) gradient. Other lissencephaly-associated abnormalities may include microcephaly, commissural abnormalities (in particular callosal anomalies), brainstem abnormalities (such as severe hypoplasia of the pons and medulla) and abnormalities of the cerebellum (in particular hypo/dysplasia of the vermis).
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Lissencephaly type I is a diffuse type of migration disorder that contains agyria and/or pachygyria on the brain surface. We experienced 5 cases of this disease and evaluated their electroencephalographic findings and seizure types based on the neuroradiological classification of lissencephaly. Ages at seizure onset ranged from 2 months to 4 months (mean 3.2 months). The patients with complete agyria had generalized tonic seizures, and those with pachygyria partial seizures or tonic spasms. The characteristic findings of complete agyria in electroencephalogram were high-voltage alfa activity. The amount of high-voltage slow waves increased with the ratio of pachygyria on the brain surface. The appearance of multifocal spikes and sharp waves suggested irregular arrangement of pachygyria on the brain surface.
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