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

Maria Daniela D'Agostino, Andrea Bernasconi, Soma Das, Alexandre Bastos, Rosa M. Valerio, André Palmini, Jaderson Costa Da Costa, Ingrid E. Scheffer, Samuel Berkovic, Renzo Guerrini, Charlotte Dravet, Jiro Ono, GianLuigi Gigli, Antonio Federico, Fran Booth, Bruno Bernardi, Lilia Volpi, Carlo Alberto Tassinari, Mary Anne Guggenheim, David H. LedbetterJoseph G. Gleeson, Iscia Lopes-Cendes, David G. Vossler, Elisabetta Malaspina, Emilio Franzoni, Roberto J. Sartori, Michael H. Mitchel, Suha Mercho, François Dubeau, Frederick Andermann, William B. Dobyns, Eva Andermann

Research output: Contribution to journalArticle

77 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2507-2522
Number of pages16
JournalBrain
Volume125
Issue number11
Publication statusPublished - Nov 1 2002

Fingerprint

Classical Lissencephalies and Subcortical Band Heterotopias
Lissencephaly
Mutation
Genes
Mosaicism
Germ-Line Mutation
Missense Mutation
Intellectual Disability
Group II Malformations of Cortical Development
Molecular Imaging
Genetic Association Studies
Intelligence

Keywords

  • DCX
  • Double cortex
  • LIS1
  • Male
  • Subcortical band heterotopia

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

D'Agostino, M. D., Bernasconi, A., Das, S., Bastos, A., Valerio, R. M., Palmini, A., ... Andermann, E. (2002). Subcortical band heterotopia (SBH) in males: Clinical, imaging and genetic findings in comparison with females. Brain, 125(11), 2507-2522.

Subcortical band heterotopia (SBH) in males : Clinical, imaging and genetic findings in comparison with females. / D'Agostino, Maria Daniela; Bernasconi, Andrea; Das, Soma; Bastos, Alexandre; Valerio, Rosa M.; Palmini, André; Da Costa, Jaderson Costa; Scheffer, Ingrid E.; Berkovic, Samuel; Guerrini, Renzo; Dravet, Charlotte; Ono, Jiro; Gigli, GianLuigi; Federico, Antonio; Booth, Fran; Bernardi, Bruno; Volpi, Lilia; Tassinari, Carlo Alberto; Guggenheim, Mary Anne; Ledbetter, David H.; Gleeson, Joseph G.; Lopes-Cendes, Iscia; Vossler, David G.; Malaspina, Elisabetta; Franzoni, Emilio; Sartori, Roberto J.; Mitchel, Michael H.; Mercho, Suha; Dubeau, François; Andermann, Frederick; Dobyns, William B.; Andermann, Eva.

In: Brain, Vol. 125, No. 11, 01.11.2002, p. 2507-2522.

Research output: Contribution to journalArticle

D'Agostino, MD, Bernasconi, A, Das, S, Bastos, A, Valerio, RM, Palmini, A, Da Costa, JC, Scheffer, IE, Berkovic, S, Guerrini, R, Dravet, C, Ono, J, Gigli, G, Federico, A, Booth, F, Bernardi, B, Volpi, L, Tassinari, CA, Guggenheim, MA, Ledbetter, DH, Gleeson, JG, Lopes-Cendes, I, Vossler, DG, Malaspina, E, Franzoni, E, Sartori, RJ, Mitchel, MH, Mercho, S, Dubeau, F, Andermann, F, Dobyns, WB & Andermann, E 2002, 'Subcortical band heterotopia (SBH) in males: Clinical, imaging and genetic findings in comparison with females', Brain, vol. 125, no. 11, pp. 2507-2522.
D'Agostino MD, Bernasconi A, Das S, Bastos A, Valerio RM, Palmini A et al. Subcortical band heterotopia (SBH) in males: Clinical, imaging and genetic findings in comparison with females. Brain. 2002 Nov 1;125(11):2507-2522.
D'Agostino, Maria Daniela ; Bernasconi, Andrea ; Das, Soma ; Bastos, Alexandre ; Valerio, Rosa M. ; Palmini, André ; Da Costa, Jaderson Costa ; Scheffer, Ingrid E. ; Berkovic, Samuel ; Guerrini, Renzo ; Dravet, Charlotte ; Ono, Jiro ; Gigli, GianLuigi ; Federico, Antonio ; Booth, Fran ; Bernardi, Bruno ; Volpi, Lilia ; Tassinari, Carlo Alberto ; Guggenheim, Mary Anne ; Ledbetter, David H. ; Gleeson, Joseph G. ; Lopes-Cendes, Iscia ; Vossler, David G. ; Malaspina, Elisabetta ; Franzoni, Emilio ; Sartori, Roberto J. ; Mitchel, Michael H. ; Mercho, Suha ; Dubeau, François ; Andermann, Frederick ; Dobyns, William B. ; Andermann, Eva. / Subcortical band heterotopia (SBH) in males : Clinical, imaging and genetic findings in comparison with females. In: Brain. 2002 ; Vol. 125, No. 11. pp. 2507-2522.
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T1 - Subcortical band heterotopia (SBH) in males

T2 - Clinical, imaging and genetic findings in comparison with females

AU - D'Agostino, Maria Daniela

AU - Bernasconi, Andrea

AU - Das, Soma

AU - Bastos, Alexandre

AU - Valerio, Rosa M.

AU - Palmini, André

AU - Da Costa, Jaderson Costa

AU - Scheffer, Ingrid E.

AU - Berkovic, Samuel

AU - Guerrini, Renzo

AU - Dravet, Charlotte

AU - Ono, Jiro

AU - Gigli, GianLuigi

AU - Federico, Antonio

AU - Booth, Fran

AU - Bernardi, Bruno

AU - Volpi, Lilia

AU - Tassinari, Carlo Alberto

AU - Guggenheim, Mary Anne

AU - Ledbetter, David H.

AU - Gleeson, Joseph G.

AU - Lopes-Cendes, Iscia

AU - Vossler, David G.

AU - Malaspina, Elisabetta

AU - Franzoni, Emilio

AU - Sartori, Roberto J.

AU - Mitchel, Michael H.

AU - Mercho, Suha

AU - Dubeau, François

AU - Andermann, Frederick

AU - Dobyns, William B.

AU - Andermann, Eva

PY - 2002/11/1

Y1 - 2002/11/1

N2 - 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.

AB - 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.

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