Miller-Dieker syndrome

Miller-Dieker syndrome (MDS), also known as Miller-Dieker lissencephaly syndrome (MDLS), is a rare genetic disorder characterized by classical lissencephaly (smooth brain) and distinctive facial features. It results from a deletion of genetic material on the short arm of chromosome 17 (17p13.3), which includes the PAFAH1B1 (LIS1) gene and the YWHAE gene. The deletion of LIS1 is primarily responsible for the lissencephaly, while loss of additional genes in the deleted region contributes to the characteristic craniofacial abnormalities and other features. The brain malformation arises from defective neuronal migration during embryonic development, resulting in a smooth or nearly smooth cerebral surface with a thickened cortex and absent or reduced gyri and sulci. The syndrome primarily affects the central nervous system, leading to severe intellectual disability, profound developmental delay, and seizures that typically begin in infancy and are often refractory to treatment. Affected individuals usually have significant hypotonia (low muscle tone) that may progress to spasticity. Characteristic facial features include a prominent forehead, bitemporal hollowing, short nose with upturned nares, a thickened upper lip, and a small jaw (micrognathia). Microcephaly (abnormally small head) is also commonly present. Additional features may include feeding difficulties, failure to thrive, and congenital heart defects in some cases. The prognosis for Miller-Dieker syndrome is poor, with most affected children surviving only into early childhood, though some may live longer with supportive care. There is currently no cure or disease-modifying treatment. Management is supportive and symptomatic, focusing on seizure control with antiepileptic medications, nutritional support (often requiring gastrostomy tube feeding), physical therapy, and management of respiratory complications. Genetic counseling is important for families, as the deletion may arise de novo or may result from a balanced chromosomal rearrangement in a parent, which carries a significant recurrence risk.

Common questions about Miller-Dieker syndrome