Miller-Dieker syndrome

Miller-Dieker syndrome is a condition characterized by a pattern of abnormal brain development called lissencephaly. Normally, the surface of the brain (cerebral cortex) has folds and grooves. Lissencephaly causes the surface of the brain to be abnormally smooth, with fewer folds and grooves. In people with Miller-Dieker syndrome, lissencephaly is typically associated with severe intellectual disabilities, developmental delays, weak muscle tone (hypotonia), and seizures. Seizures usually begin in the first few months of life.  

People with Miller-Dieker syndrome often have distinctive facial features that include a prominent forehead; a sunken appearance in the middle of the face (midface hypoplasia); a small, upturned nose; low-set and abnormally shaped ears; a small jaw; and a thick upper lip.  Some individuals with this condition also grow more slowly than their peers. Less often, affected individuals have heart problems, kidney abnormalities, or an opening in the wall of the abdomen (an omphalocele) that allows the abdominal organs to protrude through the navel. Because of these severe health issues, most individuals with Miller-Dieker syndrome do not survive beyond early childhood.

Miller-Dieker syndrome appears to be a rare disorder, although its exact prevalence is unknown.

In the majority of cases, Miller-Dieker syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 17. This area of chromosome 17 is called the MDS critical region. Though the size of the deleted segment varies among affected individuals, it typically includes the PAFAH1B1 and YWHAE genes.

Researchers are working to identify all of the genes that contribute to the features of Miller-Dieker syndrome. They have determined that the loss of the PAFAH1B1 gene is responsible for the lissencephaly seen in people with this condition. The loss of the YWHAE gene is thought to increase the severity of lissencephaly in people with Miller-Dieker syndrome. The loss of additional genes in the MDS critical region likely contributes to the other features of Miller-Dieker syndrome.

In approximately 10 percent of people with the signs and symptoms of Miller-Dieker syndrome, the cause of the condition is unknown.

In most cases, Miller-Dieker syndrome is not inherited. The chromosome 17 deletion is usually a random event that occurs during the formation of reproductive cells (eggs or sperm) or during early fetal development. Affected people typically have no history of the disorder in their family.

Some people with Miller-Dieker syndrome inherit a chromosome abnormality from an unaffected parent. In these cases, the parent carries a chromosomal rearrangement called a balanced translocation, in which no genetic material is gained or lost. Balanced translocations usually do not cause any health problems; however, they can become unbalanced when they are passed to the next generation. Children who inherit an unbalanced translocation can have a chromosomal rearrangement with extra or missing genetic material. Individuals with Miller-Dieker syndrome who inherit an unbalanced translocation are missing genetic material from the short arm of chromosome 17, which results in the health problems that are seen in people with this disorder.