Miller-Dieker Syndrome (17p13.3 Deletion Syndrome)

Definition

Lissencephaly is a defect in neuronal migration characterized by a smooth cerebral surface, either with agyria (absent gyri) or pachygyria (abnormally broad brain folds), a thickened cerebral cortex, and an increased ratio of gray to white matter. Mutation in the causative LIS1 gene leads to a spectrum of disorders encompassing isolated lissencephaly, subcortical band heterotopia, and MDS. Patients with MDS tend to have larger deletions, resulting in more severe lissencephaly in combination with craniofacial dysmorphisms, as well as other associated anomalies.

Prevalence and Epidemiology

Due to the rarity of disease, the prevalence of MDS is unknown. At least 29 cases of MDS with the 17p13.3 deletion and prenatal findings have been reported in the literature. Classical lissencephaly is reported to occur in 11.7–40 : 1 million births.

Etiology, Pathophysiology, and Embryology

Impaired neuronal migration between 6 and 15 weeks' gestation is the underlying etiologic mechanism for lissencephaly. Postmitotic neurons are unable to migrate to their final destination and therefore do not correctly populate the cortical plate of the cerebral cortex. This leads to the absence of sulci and gyri on the surface of the brain, as well as abnormal cortical thickness.

Heterozygous deletions in the region of chromosome 17p13.3 result in the MDS phenotype. Located within this region is the responsible lissencephaly gene (LIS1 or PAFAH1B1), which has been highly conserved throughout evolution. This gene encodes the β subunit of the platelet-activating factor acetylhydrolase brain isoform, which inactivates platelet-activating factor, a neuroregulatory molecule. While deletions in LIS1 are observed in both isolated lissencephaly and MDS, it is thought that the more severe phenotype observed in MDS is caused by a combined genetic effect from deletions in both LIS1 as well as the YWHAE gene, located about 40 kb telomeric to LIS1 within a region known as the “MDS telomeric critical region.” Loss of the YWHAE gene, not including LIS1 , results in facial dysmorphism, intrauterine growth restriction (IUGR), and neuroradiologic changes. Large deletions that extend farther toward the 17p telomere, including the YWHAE gene, result in the more severe phenotype as observed in MDS. Approximately 80% of patients with MDS have a de novo deletion in the 17p13.3 region, and the remaining 20% are thought to inherit the deletion from a parent who carries a balanced chromosomal translocation.