Delineating FOXG1 syndrome From congenital microcephaly to hyperkinetic encephalopathy

First Author: Nancy Vegas, MD (More authors)
Journal: Neurology Genetics
Year: 2018

A new case series led by Dr. Bahi-Buisson adds 45 additional ‘foxes’ to the medical literature (bringing the total number >130). Importantly, this study increases the range of ages reported in FOXG1 syndrome - 6 of the new cases are 18 years or older, providing valuable information about what life is like for affected adults. As seen in other case series, the majority of causative mutations are ‘frameshift’ variants that remove part of the FOXG1 protein.

The first symptoms most commonly reported in the 45 new cases included: developmental delay, microcephaly (small head size), and differences in visual tracking. By childhood, FOXG1 syndrome is characterized by: developmental and intellectual disabilities, limited functional hand use, and a complex movement disorder. Seizures are reported in ~78%, with age of onset ranging from shortly after birth to childhood; in about half, seizures are not controlled by medication. An important part of this case series focused on brain imaging findings in people with FOXG1 syndrome. The authors describe three main abnormalities: (1) delayed myelination, (2) abnormal gyri, and (3) abnormal corpus callosum. Myelination, which continues even after birth, is an important process that helps neurons transmit information. Brain imaging in FOXG1 syndrome shows that this process may occur more slowly. The gyri are the folds of the brain; in some people with FOXG1 syndrome, there can be fewer folds in the front part of the brain. The corpus callosum is a large tract that connects the two hemispheres of the brain. In FOXG1 syndrome, this tract can look smaller or may be absent. Importantly, in a small number of cases who had brain imaging earlier and later in life, there is interval development. Finally, information from this study supports other work that suggests mutations towards the beginning of the FOXG1 gene, or complete absence of the FOXG1 gene, may be associated with more severe symptoms.

Significance As more cases are published in the medical literature, our understanding of FOXG1 syndrome grows. Knowing the number of people with FOXG1 syndrome and identifying clinical endpoints are important tools for developing treatments.