Brain, Vol. 125, No. 11, 2507-2522,
November 2002
© 2002 Oxford University Press
Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females
1 Department of Neurology and Neurosurgery, and the Montreal Neurological Institute and Hospital, Departments of 2 Human Genetics and 3 Pediatrics, McGill University, Montreal, 4 Health Sciences Centre, Winnipeg, Canada, 5 Department of Human Genetics, University of Chicago, Chicago, 6 Pediatric Neurology Service, Shodair Children’s Hospital, Helena, 7 Division of Pediatric Neurology, Department of Neurosciences, University of California, San Diego, 8 Epilepsy Center, Swedish Medical Center, Seattle, 9 Department of Neurology, Walter Reed Army Medical Center, Washington, USA, 10 Clinical Hospital, Sao Paulo University, Sao Paulo, 11 Porto Alegre Epilepsy Surgery Program, Hospital Sao Lucas, Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, 12 Department of Medical Genetics, University of Campinas, Campinas, Brazil, 13 Department of Neurology, Austin and Repatriation Medical Centre, University of Melbourne and Royal Children’s Hospital, Melbourne, Australia, 14 Neuroscience Unit, Institute of Child Health and Great Ormond Street Hospital for Children, University College London, London, UK, 15 Centre Saint-Paul, Marseille, France, 16 Division of Pediatrics, Toyonaka Municipal Hospital, Toyonaka, Japan, 17 Department of Neurosciences, ‘Santa Maria della Misericordia’ Hospital, Udine, and Associazione Anni Verdi, 18 Neurometabolic Unit, Institute of Neurological Sciences, University of Siena, Siena and Associazione Anni Verdi, Rome, 19 Ospedale Bellaria C.A. Pizzardi, Bologna and 20 Centre for Pediatric Neurology, Bologna University, Bologna, Italy
Correspondence to: Eva Andermann, MD, PhD, FCCMG, Neurogenetics Unit, Montreal Neurological Hospital and Institute, 3801 University Street, Montreal, Quebec H3A 2B4, Canada E-mail: mida{at}musica.mcgill.ca
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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