Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations.
DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria-SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative beta-sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X-inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X-inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non-syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal.
Guerrini
Renzo
R
Division of Child Neurology and Psychiatry, University of Pisa, Pisa, Italy. renzo.guerrini@inpe.unipi.it
Moro
Francesca
F
Andermann
Eva
E
Hughes
Elaine
E
D'Agostino
Daniela
D
Carrozzo
Romeo
R
Bernasconi
Andrea
A
Flinter
Frances
F
Parmeggiani
Lucio
L
Volzone
Anna
A
Parrini
Elena
E
Mei
Davide
D
Jarosz
Jozef M
JM
Morris
Robin G
RG
Pratt
Polly
P
Tortorella
Gaetano
G
Dubeau
François
F
Andermann
Frederick
F
Dobyns
William B
WB
Das
Soma
S
D000293:Adolescent; D000328:Adult; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology; D002828:Choristoma / Q000235:genetics*; D004252:DNA Mutational Analysis; D004303:Dosage Compensation, Genetic; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004827:Epilepsy / Q000150:complications* / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics*; D009483:Neuropsychological Tests; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012720:Severity of Illness Index
C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides