PAFAH1B1

Many variants (also called mutations) in the PAFAH1B1 gene have been found to cause isolated lissencephaly sequence (ILS), a condition characterized by abnormal brain development that results in the brain having a smooth surface (lissencephaly) instead of its normal folds and grooves. Individuals with ILS have severe intellectual disabilities and recurrent seizures (epilepsy) that begin in the first two years of life.

The PAFAH1B1 gene variants that cause ILS reduce the amount of functional protein available to help neurons in the developing brain migrate to their proper location. This impairs brain development and leads to the severe neurological problems seen in people with ILS.

Several variants in the PAFAH1B1 gene have been found to cause subcortical band heterotopia. This condition causes abnormal brain development that results in signs and symptoms that are typically less severe than those seen in ILS. Some researchers consider these two conditions to be part of the same disease spectrum and use the term PAFAH1B1-related isolated lissencephaly sequence/subcortical band heterotopia to refer to both conditions. Individuals with subcortical band heterotopia typically have developmental delays, which can range from mild to severe. Additional signs and symptoms can include intellectual disabilities and seizures that may be drug-resistant.

Some variants in the PAFAH1B1 gene change single protein building blocks (amino acids) in the PAFAH1B1 protein, while other variants change the protein's length or structure. These variants alter the protein's ability to interact with microtubules and to form the PAFAH1B complex, both of which are needed for neuronal migration. Without proper neuronal migration, neurons in the developing brain can be misplaced, leading to the neurological problems seen in people with subcortical band heterotopia. 

A deletion of genetic material near the end of the short (p) arm of chromosome 17 causes Miller-Dieker syndrome. This region contains numerous genes, including the PAFAH1B1 gene. Signs and symptoms of Miller-Dieker syndrome include lissencephaly, intellectual disabilities, seizures, and distinctive facial features.

As a result of the deletion, people with this condition have only one copy of the PAFAH1B1 gene in each cell instead of the usual two copies. A deletion of one copy of the PAFAH1B1 gene in each cell reduces the amount of available PAFAH1B1 protein. Researchers believe that a shortage of this protein is responsible for the lissencephaly, intellectual disabilities, and seizures seen in people with Miller-Dieker syndrome.

Other deleted genes in the same region of chromosome 17 likely contribute to the other features of Miller-Dieker syndrome.