Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females.
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.
D'Agostino
Maria Daniela
MD
Department of Neurology and Neurosurgery, and the Montreal Neurological Institute and Hospital, Quebec, Canada.
Bernasconi
Andrea
A
Das
Soma
S
Bastos
Alexandre
A
Valerio
Rosa M
RM
Palmini
André
A
Costa da Costa
Jaderson
J
Scheffer
Ingrid E
IE
Berkovic
Samuel
S
Guerrini
Renzo
R
Dravet
Charlotte
C
Ono
Jiro
J
Gigli
GianLuigi
G
Federico
Antonio
A
Booth
Fran
F
Bernardi
Bruno
B
Volpi
Lilia
L
Tassinari
Carlo Alberto
CA
Guggenheim
Mary Anne
MA
Ledbetter
David H
DH
Gleeson
Joseph G
JG
Lopes-Cendes
Iscia
I
Vossler
David G
DG
Malaspina
Elisabetta
E
Franzoni
Emilio
E
Sartori
Roberto J
RJ
Mitchell
Michael H
MH
Mercho
Suha
S
Dubeau
François
F
Andermann
Frederick
F
Dobyns
William B
WB
Andermann
Eva
E
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000293:Adolescent; D000328:Adult; D002465:Cell Movement / Q000235:genetics; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D002828:Choristoma / Q000235:genetics* / Q000473:pathology*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics* / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics; D010641:Phenotype; D011247:Pregnancy; D012727:Sex Characteristics
C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human