Paula and Bobby
Parents of Lillie
Band Heterotopia of Brain
What is Band Heterotopia of Brain?
Band Heterotopia of Brain is a rare disease. It is also known as Double cortex syndrome Subcortical laminar heterotopia X-linked isolated lissencephaly X-linked subcortical laminar heterotopia and lissencephaly syndrome XLIS XSCLH/LIS.
This entity has a characteristic NMR appearance in that there is a layer of grey matter underlying the cortex and separated from it by a normal looking layer of white matter. There is a 6-layered cortex (Viot et al., 2004). The children reported by Livingston and Aicardi (1990) were not severely retarded and were unrelated. Ricci et al., (1992) reported two severely mentally handicapped girls aged 14 and 18 who had band heterotopia and Lennox-Gastaut syndrome. The sex ratio of affected cases is 20:1 (F:M), and there is a suggestion that males are severely affected, whereas females in families can have more mild abnormalities, possibly indicating X-linked dominant inheritance. Up until 2002 there had been 110 females, but only 11 males with the condition reported (D'Agostino et al., 2002). These authors reported 22 further males where the band phenotype ranged from mild to severe and seemed to correlate with IQ. Pinard et al., (1994) reported two families where males with severe pachygyria or lissencephaly had female relatives with band heterotopia, low IQ, and seizures. The pedigrees were consistent with X-linked dominant inheritance. A female with an X:autosome translocation, with breakpoints at Xq22.3, has been reported (Dobyns, 1996). Des Portes et al., (1997) present further linkage data supporting a localization to Xq22. Ross et al., (1997) mapped the gene to Xq21-q24 and provided more information on the balanced translocation case reported by Dobyns et al., (1996). des Portes et al., (1998) and Gleeson et al., (1998) demonstrated mutations in the gene for a novel putative brain signaling protein (XLIS, doublecortin, DCX). des Portes et al., (1998) reported further mutations. Sossey-Alaoui et al., (1998) showed that the doublecortin gene codes for a calcium-dependent signalling protein. Horesh et al., (1999) showed that the doublecortin protein binds microtubules directly, stabilizes them and causes bundling. Further mutations in 8 out of 8 pedigrees were reported by Gleeson et al., (1999).
Pilz et al., (1998) studied patients with isolated lissencephaly, looking for mutations of the LIS1 or DCX genes and estimated that mutations in these genes accounted for approximately 75% of cases. In patients with LIS1 mutations, brain malformations were more severe over the parietal and occipital regions, whereas in patients with XLIS mutations the abnormalities were more severe over the frontal cortex. Pilz et al., (1999) reported the appearance of subcortical band heterotopia in two boys with missense mutations of the DCX gene. They also found a missense mutation in the LIS1 gene in another boy with band heterotopia. Kato et al., (1999) reported further mutations from Japan. Sapir et al., (2000) reported further mutations in conserved functional domains. Matsumoto et al., (2001) found DCX mutations in 20 out of 26 (85%) of sporadic cases with band heterotopia and 11 out of 11 (100%) of familial cases. Maternal germline mosaicism was found in one family. There was no evidence for skewed X-inactivation in affected females. Among patients with diffuse thick bands of heterotopia, a small spectrum of mutations was found except for missense mutations in exon 7-9. Amongst patients with frontal thin bands, all were familial and all had missense mutations in exon 4-6. Four females with normal MRI scans, but with mild retardation, were found to have doublecortin mutations (Guerrini et al., 2003). These authors state that mutation analysis must be carried out in females in families, despite a normal scan.
Ross et al., (2001) classified the group of conditions characterised by lissencephaly with cerebellar hypoplasia (LCH). Group LCHa is characterised by lissencephaly with mild cerebellar vermis hypoplasia. One patient was reported with a DCX mutation and this brain scan appearance.
Pinard et al., (1995) have reported a further family and suggest that all mothers of males with non-deletional lissencephaly, need an MRI for genetic counselling purposes. Dobyns et al., (1996) provide a good review. In the family reported by Berg et al., (1998), the mother with band heterotopia had mild retardation, whereas her son had lissencephaly. These authors suggest that the absence of inferior olive heterotopia might distinguish this lissencephaly from others. These authors suggest that the absence of inferior olive heterotopia might distinguish this lissencephaly from others. Note that band heterotopia has also been found in trisomy 9p (Federico et al., 1999).
Yoshimura et al., (1998) reported an unusual family where a mother who had a normal MRI scan, gave birth two sons and a daughter with focal pachypolymicrogyria. The father of one male case was unrelated, however the father of the other two sibs was a first cousin, and he himself had mental retardation with focal pachypolymicrogyria on scan. The daughter of this union was severely affected. Two sisters both epileptic and developmentally delayed, were reported by van der Valk et al., (1999). Their mother was of normal intelligence and had one seizure-like episode at 39 years of age. All had the mutation in the doublecortin gene. Gleeson et al., (2000) reported evidence for a high degree of germline mosaicism in this condition, suggesting caution in genetic counselling. Genetic and radiological heterogeneity were emphasised in the report by Gleeson et al., (2000).
Do be careful of incomplete penetrance - some gene carriers have normal MRI scans (Demelas et al., 2001). Somatic mosaicism and non penetrance was again emphasised by Aigner et al., (2003). These authors found mutations in 7 families and in 3 there was mosaicism. In one of the 3 there was an apparently heterozygous mutation in blood lymphocytes and hair roots with a normal pattern of X inactivation, but she was clinically normal. Further examples of mosaicism (3 affected males) were reported by Sicca et al., (2003). These authors suggest that denaturing high-pressure liquid chromatography should be considered in patients with posteriorly predominant subcortical band heterotopia and pachygyria.
Fox and Walsh (1999) and Barkovich et al., (2001) provide good reviews of the genetics of neuronal migration defects. Kuzniecky and Barkovich (2001) and Kato and Dobyns provide good reviews of abnormalities of cortical development.
Leger et al., (2008) showed that almost 80% of the DCX mutations clustered around the N-DC and C-DC domains and that those with C-DC domain mutations tended to have less severe lissencephaly. Mosaic DCX deletions in males can cause band heterotopia (Quelin et al., 2012). This might not be infrequent (Jamuar et al., 2014)
* This information is courtesy of the L M D.
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What gene changes cause Band Heterotopia of Brain?
The syndrome is inherited in the following inheritance pattern/s:
X-Linked Dominant - With syndromes inherited in an X-linked dominant pattern, a mutation in just one of the copies of the gene causes the syndrome. This can be in one of the female X chromosomes, and in the one X chromosome males have. Males tend to have more severe symptoms than females.
Uncertain - The exact mode of inheritance was unknown at the time this entry was recorded.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 600348 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
EML1 - 14q32.2
What are the main symptoms of Band Heterotopia of Brain?
The typical symptoms of the syndrome are:
Abnormality of the skeletal system, Seizure, Gray matter heterotopia
How does someone get tested for Band Heterotopia of Brain?
The initial testing for Band Heterotopia of Brain can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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