Lissencephaly, X-Linked, 1

A number sign (#) is used with this entry because X-linked lissencephaly-1 (LISX1) and subcortical band heterotopia are caused by mutation in the gene encoding doublecortin (DCX; 300121).

For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).

Description

Lissencephaly ('smooth brain') results from migrational arrest of cortical neurons short of their normal destination, and can result in profound mental retardation and seizures. In X-linked lissencephaly-1, affected males generally have more a severe phenotype compared to females. DCX mutations cause classic lissencephaly with mental retardation in hemizygous males and a milder phenotype known as subcortical band heterotopia in females, sometimes in the same family. The subcortical lamina heterotopia found in heterozygous females is also referred to as 'double cortex' (DC) syndrome (des Portes et al., 1997).

There are several X-linked loci that affect neuronal migration, including the Aicardi locus (304050).

Clinical Features

Berry-Kravis and Israel (1994) reported a family in which 5 male infants in 2 generations had lissencephaly inherited in an X-linked pattern. All the affected infants had intractable seizures, severe retardation, growth failure, and microphallus, and died during infancy. Radiologic studies in 3 of the affected infants demonstrated pachygyria-agyria and agenesis of the corpus callosum. Previous evidence for a possible lissencephaly locus on the X chromosome came from Dobyns et al. (1992), who reported a single female patient with complete agyria, agenesis of the corpus callosum, and a de novo translocation with breakpoints at Xq22 and 2p25.

DiMario et al. (1993) reported the case of a 16-year-old patient and her mother, both with band heterotopias associated with seizures. Palmini et al. (1991) and Palmini et al. (1993) emphasized the variable clinical spectrum of this disorder and mentioned potential heritability and female preponderance. They suggested that the appearance of band heterotopias on MRI is distinct from that of classic subependymal nodules of tuberous sclerosis.

Huttenlocher et al. (1994) reported a family in which 6 females spanning 4 generations had nodular subependymal masses of heterotopic gray matter and seizures. Cognitive function was normal. There was a high rate of spontaneous abortion, consistent with X-linked dominant inheritance and lack of viability in affected males. The authors postulated a CNS migration disorder.

Toyama et al. (1998) described the clinical features and magnetic resonance imaging (MRI) findings in a 20-year-old man and his mother who were diagnosed as having a neuronal migration disorder. The son had severe psychomotor retardation and the mother had intractable seizures and mild psychomotor retardation. MRI demonstrated moderate pachygyria in the son and subcortical heterotopia in the mother. In both patients, the frontal parts of the brain were characteristically more affected than any other areas. The disorder in this family was thought to be consistent with X-linked lissencephaly.

Poolos et al. (2002) reported 2 male patients with complete subcortical band heterotopia, mild mental retardation, and seizures, resembling the female phenotype; both cases resulted from somatic mosaicism for DCX mutations (1 a missense mutation and 1 a deletion). The authors noted that somatic mosaicism in males is the functional equivalent of X inactivation in females and thus most likely accounts for the milder phenotype.

Chou et al. (2009) reported a 7-year-old girl with LISX caused by deletion of exon 5 of the DCX gene. She had a severe phenotype, with psychomotor retardation, seizures, lissencephaly, dysplastic ventricles, and microcephaly. She also had dysmorphic facial features, including sloping forehead with bitemporal narrowing, ptosis, and bulbous nasal tip. X-inactivation studies showed fully skewed X inactivation, suggesting preferential expression of the mutant allele.

Mapping

Srivastava et al. (1996) mapped the LISX gene to chromosome Xq22.3-q23 by using a combination of (1) linkage studies in 5 multiplex families, and (2) physical mapping of an X/autosome translocation, t(X;2)(q22.3;p25.1), reported by Dobyns et al. (1992) in a girl with classic lissencephaly. Linkage analysis identified the LISX critical region between Xq21.3 and Xq24. Using available markers from the region, Srivastava et al. (1996) mapped the X-chromosome breakpoint to a 1- to 2-Mb region in Xq22.3-q23 by analysis of a somatic cell hybrid that retained the derivative chromosome 2. (See also Ross et al., 1997.) The location of markers centromeric and telomeric to the breakpoint was confirmed by fluorescence in situ hybridization using genomic probes on the metaphase chromosomes from the patient. The breakpoint was further mapped within a YAC.

In 3 unrelated families with X-linked lissencephaly, des Portes et al. (1997) carried out exclusion mapping using 38 microsatellite markers evenly distributed on the X chromosome. Potential intervals of assignment in Xq22.3-q23 or in Xq27 were found. Although the number of informative meioses did not allow a decision between these 2 loci, it was noted that the former interval was compatible with the mapping of the breakpoint involved in the balanced translocation reported by Dobyns et al. (1992). In 1 family, a woman with SCLH had 2 daughters with SCLH and a son with lissencephaly, each by a different father. No male-to-male transmission has ever been described with this disorder. The absence of overlap between the region defined by des Portes et al. (1997) for the SCLH/LISX syndrome and Xq28 where the bilateral periventricular nodular heterotopia syndrome (NHBP; 300049) had been mapped excluded the possibility that these 2 X-linked cortical malformations are allelic. In 2 families reported by des Portes et al. (1997), haplotype analysis indicated that all affected children had alleles at Xq22.3-q23, inherited from their healthy grandfather.

Molecular Genetics

In affected individuals from 3 unrelated families with LISX or subcortical laminar heterotopia and a girl with subcortical laminar heterotopia and pachygyria, des Portes et al. (1998) identified mutations in the DCX gene (300121.0001-300121.0004). Gleeson et al. (1998) also identified several mutations in the DCX gene (300121.0002; 300121.0005-300121.0010) in affected individuals from unrelated families with LISX or subcortical laminar heterotopia and in females with sporadic subcortical laminar heterotopia.

Gleeson et al. (2000) found evidence for somatic or germline mosaic DCX mutations in 6 of 20 patients with LISX/SCLH. Germline mosaicism was identified in 2 unaffected women, each with 2 affected children. Additionally, 1 affected male with SCLH was found to be a somatic mosaic, which presumably spared him from the more severe phenotype of lissencephaly. The high rate of mosaicism indicated that there may be a significant recurrence risk for these disorders in families at risk, even when the mother is unaffected.

In 7 families with SBH/LISX, Aigner et al. (2003) identified 4 missense and 3 nonsense mutations in the DCX gene (see 300121.0014). There was a high rate of somatic mosaicism in male and female patients with incomplete penetrance of bilateral SBH, including nonpenetrance in a heterozygous woman. In 1 family, prenatal diagnosis was performed. The authors emphasized the variability of mutation expression and suggested that genetic analysis should include examination of several tissues.

Using multiplex ligation-dependent probe amplification (MLPA) analysis, Haverfield et al. (2009) identified intragenic deletions of the DCX gene in 3 (33%) of 9 females with subcortical band heterotopia or SBH/pachygyria in whom no molecular defect had previously been identified. All had more severe involvement of the anterior region of the brain. No deletions or duplications of DCX were found in 13 females or 7 males with the more severe pachygyria or in 2 males with SBH/pachygyria in whom no molecular defect had previously been identified. Haverfield et al. (2009) suggested that genetic testing for SBH and pachygyria should include both mutation and deletion/duplication analysis of the DCX gene.

Jamuar et al. (2014) used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations, including 30 with double cortex syndrome, 20 with polymicrogyria with megalencephaly (see MPPH1, 603387), 61 with periventricular nodular heterotopia (300049), and 47 with pachygyria. Validated, causal mutations were found in 27 individuals (17%; range, 10-30% for each phenotype). Mutations were somatic in 8 (30%) of the 27. Six of these individuals had double cortex syndrome, of which 3 had mutations in DCX and 3 in LIS1 (601545).

Genotype/Phenotype Correlations

By direct DNA sequencing of the LIS1 and DCX genes in 25 children with sporadic lissencephaly and no deletion of the LIS1 gene by FISH, Pilz et al. (1998) identified LIS1 mutations in 8 (32%) patients and DCX mutations in 5 (20%). All the LIS1 mutations were de novo, 6 were truncating, and 2 were splice site mutations. Phenotypic studies showed that those with LIS1 mutation had more severe lissencephaly over the parietal and occipital regions, whereas those with DCX mutations had the reverse gradient, with more severe lissencephaly over the frontal regions. All DCX mutation carriers also had mild hypoplasia and upward rotation of the cerebellar vermis was seen in all patients with mutations of XLIS, but these changes were only seen in about 20% of patients with LIS1 mutations. Overall, mutations of LIS1 or DCX were found in 60% of patients Combined with the previously observed frequency of LIS1 mutations detected by FISH, Pilz et al. (1998) concluded that these 2 genes account for about 76% of sporadic ILS.

Dobyns et al. (1999) compared the phenotype of 48 children with lissencephaly, including 12 with MDLS with large deletions including LIS1, 24 with isolated lissencephaly sequence caused by smaller LIS1 deletions or mutations, and 12 with DCX mutations. There were consistent differences in the gyral patterns, with LIS1 mutations associated with more severe malformations posteriorly, and DCX mutations associated with more severe malformations anteriorly. In addition, hypoplasia of the cerebellar vermis was more common in those with DCX mutations.

Matsumoto et al. (2001) performed detailed mutation analysis of the doublecortin gene in a cohort of patients with typical SBH (26 sporadic SBH female patients and 11 LISX/SBH families). A correlation was demonstrated between genotype band phenotype based on cranial MRI scan, as well as familial versus sporadic status.

Animal Model

Using RNA interference (RNAi) of the DCX protein in utero, Bai et al. (2003) generated a rat model with very low levels of DCX protein expression. Inhibition of DCX expression in a cohort of migrating neocortical neurons disrupted radial migration of other migrating neurons. Many neurons prematurely stopped migrating to form subcortical band heterotopias within the intermediate zone and then the white matter, and many neurons migrated into inappropriate neocortical lamina within normotopic cortex. The authors suggested that DCX may be required for migrating cells to organize appropriate cytoskeletal responses to external signals that direct radial migration.

In a rat model of subcortical band heterotopia generated by in utero RNA interference of the Dcx gene, Manent et al. (2009) found that aberrantly positioned neurons could be stimulated to migrate by conditional reexpression of Dcx after birth. Restarting migration in this way both reduced neocortical malformations and restored neuronal patterning. The capacity to reduce SBH continued into early postnatal development. Reexpression at postnatal day 0 (P0) led to marked SBH regression and restored neocortical lamination, whereas reexpression at P5 led to partial restoration of position and SBH regression, and reexpression at P10 led to partial recovery of position without SBH reduction. Intervention after birth also reduced the seizure threshold to a level similar to that of wildtype mice. The findings suggested that disorders of neuronal migration could potentially be treated by reengaging developmental programs both to reduce the size of cortical malformations and to reduce seizure risk.

Kerjan et al. (2009) found that heterozygous and homozygous Dclk2 (613166)-null mice were viable and fertile, had normal brain morphology, and no compensatory changes in expression of either Dcx or Dclk1 (604742). However, double-mutant Dcx/Dclk2-null mice showed poor survival, with only about 10% alive past 5 months of age. In addition, Dcx/Dclk2-null mice showed spontaneous seizures, often associated with behavioral arrest and forelimb myoclonus. These seizures were noted to start at about 3 weeks of age. EEG studies were consistent with a hippocampal focus. Histologic studies showed compounded dyslamination of the hippocampus, with a discontinuous CA1 field, neuronal displacement, and reduced packing density of the dentate granule neuron layer, resulting in increased thickness. The neocortex appeared to have normal organization. Dcx/Dclk2-null mice had reduced GABA inhibition secondary to overall network disorganization, as well as a decrease in dendritic arbors, which suggested an insufficient receptive field for inhibitory input. In situ hybridization studies in normal mice showed coexpression of Dcx and Dclk2 in the hippocampus during embryonic and postnatal stages. Comparative studies in other mutant mice suggested that the Dcx deficiency was the major contributor to lamination defects, and that Dcx and Dclk2 are functionally redundant. Kerjan et al. (2009) concluded that this mutant mouse model shows similarities to human X-linked lissencephaly.