FOXG1 Syndrome

What Causes FOXG1 Syndrome?

FOXG1 syndrome is caused by problems in the FOXG1 gene, which is vital in the early development of the brain. In some cases, the gene has undergone an abnormal change (mutation), and in other cases, the gene is entirely missing from the chromosome that usually carries it. In all cases, the abnormality causes improper production of a protein called forkhead box G1, a compound essential for embryonic brain development.

Is FOXG1 Syndrome Hereditary?

FOXG1 syndrome is known as an autosomal dominant condition. This means that the disorder may develop if a person has only one copy of the altered FOXG1 gene. However, in all known cases of the disorder, the gene alteration seemed to have occurred spontaneously during embryonic development and was not inherited from either parent.

In theory, a person with an altered FOXG1 gene could pass the gene to their children. However, no one with FOXG1 syndrome has been known to have children; a person can carry a FOXG1 mutation without having the disorder themselves.

How Is FOXG1 Syndrome Detected?

Because the symptoms of FOXG1 syndrome may be similar to those of other neurological disorders, the condition is sometimes misdiagnosed. For example, cerebral palsy is a common misdiagnosis.

FOXG1 syndrome was also once thought to be a type of Rett syndrome, but because of differences in the two conditions, FOXG1 is now considered to be a distinct disorder. In particular, FOXG1 affects both males and females, while Rett syndrome almost exclusively affects females.

The social and communication symptoms of FOXG1 syndrome are similar to those of autism spectrum disorder.

How Is FOXG1 Syndrome Diagnosed?

If a child shows symptoms that could indicate FOXG1 syndrome, a doctor will typically begin the diagnostic process with tests to rule out other potential causes. Diagnostic tests can include blood tests, hearing and vision tests, urine tests, brain activity exams, and imaging exams.

To make a diagnosis of FOXG1 syndrome, doctors will look for distinctive symptoms of the disorder, including:

• Irritability
• Repetitive, unusual hand movements
• Language impairments
• Problems with motor or coordination skills such as walking
• Intellectual or developmental delays
• Impaired vision
• Swallowing or breathing problems
• Abnormal arm or leg movement
• Seizures that are resistant to medication
• Evidence of brain malformation in imaging scans

If these diagnostic criteria suggest FOXG1 syndrome, doctors may conduct genetic testing to detect the FOXG1 alterations associated with the disorder.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is FOXG1 Syndrome Treated?

There is no cure for FOXG1 syndrome. Treatment of the disorder focuses on alleviating symptoms and preventing complications. Standard treatment courses include:

• Medications to control breathing difficulties, sleep issues, muscle tone problems, and other complications
• Feeding assistance
• Anti-seizure medications
• Physical therapy
• Occupational therapy
• Speech therapy
• Regular monitoring for potential complications such as scoliosis

How Does FOXG1 Syndrome Progress?

FOXG1 syndrome is rare, and research into the disorder is relatively new. Because it has been typically diagnosed in childhood and few adults with the disorder have been studied, the life expectancy of people with the condition is unknown. FOXG1 syndrome is not progressive, and the disorder itself is not fatal. However, some complications of the disorder, such as seizures or respiratory infections, may be life-threatening.

How Is FOXG1 Syndrome Prevented?

There is no known way to prevent FOXG1 syndrome.

FOXG1 Syndrome Caregiver Tips

• Learn as much as you can about the disorder. The effects of FOXG1 syndrome are complex and vary significantly from child to child. The more you know about how the condition works, the better you’ll be able to deal with your child’s unique circumstances.
• Get support. The support of people who know what you’re going through is a crucial part of maintaining your health. The International FOXG1 Foundation can guide you to support resources.

FOXG1 Syndrome Brain Science

The FOXG1 gene is a transcription factor gene. This type of gene contains instructions for making proteins that turn other genes on and off to control the growth and development of cells.

In this case, the FOXG1 gene is responsible for producing the forkhead box G1 protein, which plays a vital role in developing an embryonic brain structure called the telencephalon. The telencephalon eventually develops into several different mature brain structures. One of these structures is the cerebellum; this is the largest part of the brain and controls critical functions such as movement, language, memory, sensory perception, and learning.

FOXG1 syndrome occurs when alterations in the FOXG1 gene result in insufficient or abnormal protein production. The deficiency of functional forkhead box G1 protein leads to abnormal brain development in the embryonic stage and, ultimately, the brain malformations characteristic of the disorder.

FOXG1 Syndrome Research

Title:  Natural History of Rett Syndrome & Related Disorders

Stage: Recruiting

Principal Investigator: Richard Haas, MD

University of California San Diego

San Diego, CA

The purpose of this study is to advance understanding of the natural history of Rett syndrome (RTT), MECP2-duplication disorder (MECP2 Dup), CDKL5, FOXG1, and individuals with MECP2 mutations who do not have RTT, including the range of clinical involvement and to correlate genotype-phenotype over a broad spectrum of phenotypes. While much has been learned about RTT, improvements are required in understanding the role of factors such as X chromosome inactivation, genetic background, and others, including the environment, on the significant variability observed even between individuals with the same MECP2 mutation. These data will be essential to the development and conduct of clinical trials anticipated from ongoing studies in animal models for RTT. This study will not include clinical trials but should set the stage for such trials and other translational research projects (e.g., development of biomarkers).

At present, effective treatments for RTT, MECP2 Dup, or Rett-related disorders are lacking. Substantial progress has been made in RTT over the past eleven years; this study represents a narrowing of focus to mutations or duplications of the MECP2 gene and related disorders, including those with phenotypic overlap. Understanding of RTT has advanced remarkably well through the Rett Syndrome Natural History Clinical Protocol (NHS), and correspondingly advancement in the basic science realm has moved forward with equivalent success. Thus, progress in clinical and basic science has established clinical trials and other translational studies that hold promise for additional clinical trials in the future. In the process, however, additional MECP2- and RTT-related disorders unknown at the time of the original proposal have been identified. In addition, substantial clinical variability in individuals with RTT that cannot be explained by differences in mutations alone must be explored further. Variability among individuals with identical mutations has led to the search for additional explanations. At the time of the initial application (2002), just three years after identifying the gene, MECP2, as the molecular link to RTT, the variation in clinical disorders related to MECP2 mutations or the related but quite different MECP2 Dup was unknown. Each disorder is characterized by significant neurodevelopmental features related either to alterations in the MECP2 gene or related to phenotypes closely resembling those seen in individuals with RTT. Further, the phenotypic overlap with RTT due to mutations in CDKL5 and FOXG1 was also unexplored. This new study will build on the substantial progress made in understanding both classic and variant RTT and add these related disorders, MECP2 Dup and the Rett-related disorders including CDKL5, FOXG1, and individuals with MECP2 mutations who do not have RTT. A comprehensive clinical research program will be performed, including clinical, neurophysiologic, and molecular and biochemical markers across these different but related disorders. This protocol will address the natural history components only and serve as the basis for other study protocols, including the neurophysiologic and biomarker studies. Thereby, these studies will represent a continuing pathway to focus and inform the ongoing and emerging clinical trials.

Title: Biobanking of Rett Syndrome and Related Disorders

Stage: Recruiting

Principal investigator:  Alan Percy, MD

The University of Alabama at Birmingham

Birmingham, AL

The overarching purpose of this study is to advance understanding of the natural history of Rett syndrome (RTT), MECP2-duplication disorder (MECP2 Dup), RTT-related disorders, including CDKL5, FOXG1, and individuals with MECP2 mutations who do not have RTT. Although all these disorders result from specific genetic changes, there remains broad clinical variation that is not entirely accounted for by known biological factors. Additionally, clinical investigators currently do not have any biomarkers of disease status, clinical severity, or responsiveness to therapeutic intervention. To address these issues, biological materials (DNA, RNA, plasma, cell lines) will be collected from affected individuals and, in some cases, from unaffected family members, initial evaluation performed to identify additional biological factors contributing to disease severity, and these materials will be stored for future characterization.