TY - JOUR
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, Gian Luigi
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
N1 - Funding Information:
The authors wish to thank Ms Maria Teresa Bogdalek, Dr Neda Ladbon-Bernasconi, Ms Aman Badhwar, Mr Sridar Narayanan and Mr Nigel A. Goddard for their assistance and support with this project. M.D.D. was the recipient of fellowships from the Savoy Foundation for Epilepsy Research and from Parke-Davis Canada for epilepsy research training at the Montreal Neurological Institute. E.A. was funded by grants from the Medical Research Council of Canada (CIHR).
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.
KW - DCX
KW - Double cortex
KW - LIS1
KW - Male
KW - Subcortical band heterotopia
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U2 - 10.1093/brain/awf248
DO - 10.1093/brain/awf248
M3 - Article
C2 - 12390976
AN - SCOPUS:0036845824
SN - 0006-8950
VL - 125
SP - 2507
EP - 2522
JO - Brain
JF - Brain
IS - 11
ER -