Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and...

Primary microcephaly is a disorder of brain development characterized by a congenitally small but normally formed brain, and non-progressive mild-to-moderate mental retardation. Most cases are inherited in an autosomal recessive pattern, with genetic heterogeneity, the ASPM locus being most common. Postnatal imaging data are scarce and prenatal imaging unreported. Microcephaly with simplified gyral pattern shares features with primary microcephaly, but it is not clear whether these disorders are part of a phenotypic continuum. We examined a consanguineous family with a daughter affected with primary microcephaly and an ongoing pregnancy. We performed prenatal and postnatal brain magnetic resonance imaging and genetic analyses in the course of genetic evaluation. The affected daughter and the fetus were homozygous for polymorphic markers linked to the ASPM locus, and we identified a novel, truncating ASPM mutation by direct sequencing of the gene. Imaging at 30 and 35 gestational weeks showed microcephaly with simplified gyration, more severe anteriorly. The antero-posterior gradient of gyration persisted 1 week after birth. Brain imaging in the affected sister also showed some degree of a predominantly anterior simplification of gyration. Our data suggest that one form of autosomal recessive microcephaly is allelic to at least a subset of microcephaly with simplified gyral pattern, and that the neuronal depletion associated with the ASPM defect predominantly affects the anterior cortex.