Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females

Abstract

Subcortical band heterotopia (SBH) or double cortex syndrome is a neuronal migration disorder, which occurs very rarely in males: to date, at least 110 females but only 11 in males have been reported. The syndrome is usually associated with mutations in the doublecortin (DCX) (Xq22.3-q23) gene, and much less frequently in the LIS1 (17p13.3) gene. To determine whether the phenotypic spectrum, the genetic basis and genotype-phenotype correlations of SBH in males are similar to those in females, we compared the clinical, imaging and molecular features in 30 personally evaluated males and 60 previously reported females with SBH. Based on the MRI findings, we defined the following band subtypes: partial, involving one or two cerebral lobes; intermediate, involving two lobes and a portion of a third; diffuse, with substantial involvement of three or more lobes; and pachygyria-SBH, in which posterior SBH merges with anterior pachygyria. Karyo typing and mutation analysis of DCX and/or LIS1 were performed in 23 and 24 patients, respectively. The range of clinical phenotypes in males with SBH greatly overlapped that in females. MRI studies revealed that some anatomical subtypes of SBH, such as partial and intermediate posterior, pachygyria-SBH and diffuse bands with posterior predominance, were more frequently or exclusively present in males. Conversely, classical diffuse SBH and diffuse bands with anterior predominance were more frequent in females. Males had either mild or the most severe band subtypes, and these correlated with the over-representation of normal/borderline intelligence and severe mental retardation, respectively. Conversely, females who had predominantly diffuse bands exhibited mostly mild or moderate mental retardation. Seven patients (29%) had missense mutations in DCX; in four, these were germline mutations, whereas in three there was evidence for somatic mosaicism. A germline missense mutation of LIS1 and a partial trisomy of chromosome 9p were identified in one patient (4%) each. One male each had a possible pathogenic intronic base change in both DCX and LIS1 genes. Our study shows that SBH in males is a clinically heterogeneous syndrome, mostly occurring sporadically. The clinical spectrum is similar to that of females with SBH. However, the greater cognitive and neuroradiological heterogeneity and the small number of mutations identified to date in the coding sequences of the DCX and LIS1 genes in males differ from the findings in females. This suggests other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes, gonadal or somatic mosaicism, and finally mutations of other genes.

Assessment of gray matter heterotopia by magnetic resonance imaging

“…The inversion recovery sequence was considered useful for the demonstration of heterotopic gray matter and the assessment of cortical thickness as it provides a strong contrast between gray and white matter. A similar frequency and MRI appearance has been reported in the literature [1][2][3][4][5] . SEH is characterized by periventricular nodules adjacent to the lateral ventricular walls just beneath and abutting the ependyma giving the nodular ventricular wall, and is not enhanced after intravenous contrast administration.…”

“…They do not contain blood vessels or CSF. The thicker the band of heterotopic neurons; the worse the disability and increased prevalence of developmental delay [1,4,9] . In the present study, MRI showed band heterotopia in three females.…”

“…It results from an in utero arrest of radial migration of neurons from the germinal matrix in the wall of the lateral ventricle to the developing cerebral cortex between 6 and 16 weeks of gestation [1,2] . It is usually discovered during the evaluation of children or young adults with epilepsy, children with neurodevelopmental abnormalities, or as an incidental finding [3][4][5] . The pathogenic mechanisms of gray matter heterotopia are not fully understood, but they lead to distinct clinicoradiological syndromes.…”

Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia

“…Although SBH is generally associated with defects in the DCX gene, a posterior-toanterior grade of severity has been associated with LIS1 mutations. 11,15 This group of patients was also found not to have deletions or duplications of the DCX gene.…”

What is new in paediatric epilepsy?

“…These women may have mild or no intellectual deficits and partial or focal epilepsy. Affected males typically have a more severe brain malformation, such as lissencephaly (smooth brain without sulcal markings) associated with severe mental handicap and West syndrome (7). Therefore, defining the brain malformation that underlies a child's epilepsy may have implications for other family members.…”