Forkhead. In our Epilepsiome series we are reviewing all major epilepsy genes. This week, we discuss FOXG1, a gene previously described as the cause for a congenital variant of Rett Syndrome. However, since its initial discovery in 2008, a much broader spectrum has been recognized. FOXG1 syndrome typically includes developmental delay and microcephaly. Many patients have severe, early-onset epilepsy and a prominent hyperkinetic movement disorder. In addition, some patients have brain malformations. Here is a brief introduction to our Epilepsiome review of FOXG1, an epilepsy gene that stands out from other causes of genetic epilepsies given its prominent role in forebrain development.
Epilepsiome page. This cover page is an introduction to the Epilepsiome page for FOXG1 that was written by our genetic counseling student Kathy Kenley and supervised by Liz Dechene and myself. Again, our Epilepsiome effort is currently our gene curation effort that aims to review and provide information on all major epilepsy genes in the next two years. As with our previous post on MECP2, FOXG1 presented a challenge to us, as it is usually a gene that is discussed in the context of Rett Syndrome. However, while this historical context is important to understand current ways of classifying genes, FOXG1 is emerging as one of the more common genes for early-onset epileptic encephalopathies. Understanding how this historical subdivision is sometimes blinding us is probably the key of appreciating the diagnostic spectrum of FOXG1 syndrome.
The Rett illusion. As we discussed in our introduction to the MECP2 gene page, Rett Syndrome was known long before any gene was found. In 1954, Dr. Andreas Rett noticed two young females in his waiting room making the same repetitive hand-washing motions. Over the next 12 years, Dr. Rett identified other females who had the same repetitive movements. Dr. Rett published his findings in several German medical journals, but it was not until 1988 that clinical criteria for the diagnosis of Rett syndrome were established. In 2016, the novel technologies allow us to diagnose children earlier, sometimes even in the first few months of life. The classical hand-washing movements are a relatively late finding in patients with MECP2 pathogenic variants and variants in genes for atypical Rett Syndrome. The clinical features seen in children at the time of diagnosis may be different – for both CDKL5 and FOXG1 seizures and developmental delay are often the critical findings at the time of diagnosis.
Epileptic-dyskinetic encephalopathy. A recent publication used the term epileptic-dyskinetic encephalopathy for FOXG1 syndrome, which I found an interesting way to set FOXG1 apart from other epileptic encephalopathies. Patients with FOXG1 often have very prominent movement disorders that phenotypically set these patients apart from other patients with early-onset epileptic encephalopathies. In some cases, the movement disorder can represent the most active and medically most challenging feature of this disease. This is in contrast to other genetic epilepsies such as CDKL5 encephalopathy, SCN2A encephalopathy, or STXBP1 encephalopathy. All conditions can have movement disorders, but the dyskinesias are often not as prominent as in FOXG1.
In summary, FOXG1 syndrome is an increasingly recognized early-onset genetic epilepsy with prominent movement disorder, microcephaly and severe intellectual disability.