FOXG1 syndrome

FOXG1 syndrome

Overview

FOXG1 syndrome is a rare neurodevelopmental condition caused by pathogenic variants in the FOXG1 gene. The disorder can cause a wide range of symptoms with varying severity. The most common symptoms include epilepsy, movement disorders and neurodevelopmental impairment that affects cognitive, motor, speech and visual function.

FOXG1 syndrome is a neurological and developmental disorder that affects boys and girls. Symptoms of FOXG1 syndrome usually begin in infancy, often in the second month of life. Irritability occurs first, with repeated seizures (epilepsy) occurring later. These seizures are typically difficult to treat with medications. Children with FOXG1 syndrome may have a special type of epilepsy called spasms. They also have delayed development, intellectual disability, and trouble walking and sitting. Many patients have difficulty seeing, a condition called cortical visual impairment. Patients with FOXG1 syndrome usually have an abnormal MRI scan of the brain.

Symptoms

The symptoms of FOXG1 syndrome vary widely, but generally include severe global developmental delays, a significant movement disorder characterized by excessive involuntary movements, and seizures. The majority of children also have microcephaly, or a smaller head size, and many will also have characteristic differences in the way their brain was formed, visible on MRI.

Most children with FOXG1 syndrome have severe intellectual disability. Many of the children affected by the disorder cannot sit or walk independently, cannot talk or feed themselves, and require use of a wheelchair. Some may have scoliosis, visual impairment, gastrointestinal difficulties such as reflux and constipation, and sleep problems. Nearly all affected individuals have low muscle tone (hypotonia), though increased muscle tone can become a problem later in life.

Cause

The FOXG1 (forkhead-box G1) gene is responsible for creating a protein necessary for normal brain development and function. Pathogenic variants in the FOXG1 gene reduce the amount of functional FOXG1 protein or alter its activity in neurons. A shortage (deficiency) of FOXG1 or impairment of its function disrupts brain development.

Most pathogenic variants within the FOXG1 gene occur spontaneously and are not passed down through families. However, in rare cases, families in which multiple siblings were affected with the same pathogenic variant have been reported. This is usually due to a finding called mosaicism in one parent.  Mosaicism occurs when some, but not all, of a person’s cells contain a genetic change. Because most of their cells do not contain the genetic change, the person may be unaffected but at risk of passing the genetic change on to their children. Both males and females are equally affected by FOXG1 syndrome.

Diagnosis

Diagnosis of FOXG1 syndrome may be suspected based on a child’s symptoms, medical history and a physical exam, but because these features can overlap those seen in many other conditions, the diagnosis must be confirmed by molecular genetic testing. This can usually be performed by either a blood or saliva sample that is sent to a laboratory for genetic sequencing. It may take a couple of weeks or a few months for the results of genetic testing, depending on the specific testing that is performed. 

Brain MRI (magnetic resonance imaging) may also be helpful in identifying some of the characteristic brain differences that can be seen in children with FOXG1 syndrome, and an electroencephalogram (EEG) may be required for children suspected of having seizures.

Treatment

At CHOP, treatment is focused on managing symptoms, providing support to children and their families, and maximizing each child’s abilities and skills. In our clinic, children meet with an interdisciplinary team of specialists that provides a personalized treatment plan to guide the child’s local medical, therapeutic and educational teams. Children with suspected FOXG1 syndrome are typically followed by multiple providers, including dedicated specialists in neurogenetics, genetic counseling, gastroenterology, rehabilitation medicine, orthopedics, ophthalmology and physiotherapy.

For children with suspected seizures, anti-seizure medications are used. In some children the seizures become well controlled with medications, though in others the seizures can be more difficult to treat. No single anti-seizure medication has been found to be uniformly effective to treat FOXG1 syndrome. In children with movement disorders, medications can be tried, but this often remains a difficult health issue to manage. For children who develop increased muscle tone, medications may be helpful, or in some cases, surgical intervention may be needed.

Physiotherapy (also called physical therapy) helps improve overall muscle tone, trunk stability, strength, and balance and foot alignment, prevent foot deformities, and keep heel cords lengthened. Early intervention in the form of physical therapy, occupational therapy, vision therapy, and speech and augmentative communication therapy is key. We also provide psychosocial support for families caring for a loved one with FOXG1 syndrome to help them navigate the complexities of raising a child with a lifelong neurodevelopmental disorder.

Type of Doctor Department :Neurogenetics, Genetic counseling, Gastroenterology, Rehabilitation medicine, Orthopedics, Ophthalmology and Physiotherapy.