FOXG1-Related Disorder

FOXG1 syndrome
Other names	FOXG1-related epileptic-dyskinetic encephalopathy, Rett syndrome, congenital variant.
FOXG1 syndrome is inherited in an Autosomal dominant fashion
Specialty	Medical genetics, Neurology
Usual onset	From birth
Causes	Mutation in a gene FOXG1
Differential diagnosis	Rett syndrome, CDKL5 deficiency disorder, Angelman syndrome
Treatment	Physical therapy,Anti-dyskinetic medications, Antiseizure medication
Frequency	1:30 000 live births

FOXG1-Related Disorder (FOXG1 syndrome) is a rare genetic disorder which is caused by mutation in a gene FOXG1. The main signs of this disease are: severe intellectual disability, microcephaly, epilepsy, and hyperkinetic-dyskinetic movement disorder and hypotonia. with brain structure anomalies

FOXG1 syndrome is inherited in autosomal dominant fashion.

FOXG1 syndrome affects about 1/30 000 births, also about 1200 cases had been reported (As of January 1, 2025).

Symptoms

Symptoms of FOXG1 syndrome are:

Very frequent

• Abnormal hand movements
• Problems with walking
• Dyskinesia
• Diffiuclties with feeding
• Hypotonia
• Strabismus
• Progressive microcephaly

Frequent

• Anomalies of corpus callosum
• Abnormal movement
• Absence of speech
• Autistic behavior
• Bilateral tonic-clonic seizure
• Teeth grinding or clenching
• Choreoathetosis
• Intellectual disability
• Constipation
• Weight loss
• Delay in myelination
• Dystonic disorder
• Sialorrhea
• Focal seizures
• Gastro-esophageal reflux
• Hyperkinesis
• Frequently cries without apparent cause
• Infantile spasms
• Myoclonic jerks
• Oral-Facial Dyskinesia
• Paroxysmal bursts of laughter
• Poor eye contact
• Low height
• Severe postnatal growth deficiency
• Muscle Spasticity
• Vision problems

Occasional

• Abnormal breathing
• Corpus callosum agenesis/hypoplasia
• Developmental regression
• Scoliosis with or without kyphosis
• Pachygyria
• Hypoplasia of optic disk
• Poor speech
• Incapability to ambulate

Very rare

• Repeated seizure without recovery

Cause

As mentioned above, FOXG1 syndrome is caused by a heterozygous mutations in the gene FOXG1, This gene provides instructions for making a protein (Forkhead box protein G1).

Most people with FOXG1 syndrome have a de-novo mutation (which means that mutation is new and none of the parents have it), although there have been cases of person inheriting the pathogenic variant of FOXG1 from healthy, mosaic parent.

Pathophysiology

The FOXG1 protein is widely expressed in brain and is important for cortical development.

Cortical Stem Cell Growth

One of the FOXG1 function is to regulate cell cycle of the neural progenitor cell, through activation of the proliferation and hindering the precoucious neural differentiation, in case of loss of the FOXG1, neural stem cell's cell cycle gets legnthened and exits the cell cycle.

FOXG1 antagonizes the FOXO/SMAD pathway, which stimulates cortical neuron differentiation, because of antagonization, there is the reduced expression of p21, consequently low level of the p21 promotes stem cell pool expansion and prevents precocious exit from the cell cycle.

Induction of Cortical Laminar Subtypes by FOXG1

Alongside the expansion of the progenitor cell pool through control of cell cycle regulators, the onset of FOXG1 expression in the forming forebrain activates a series of genetic and molecular processes in corticogenesis. These events include dorsoventral patterning of the telencephalon to designate future compartments and specifying cell types through global switches in gene expression of targeted genes. The activation of FOXG1 and the early patterning of the forebrain seems to be primarily maintained across vertebrates, where compartmentalization of the forebrain is established by reciprocal interactions between morphogens and transcription factors. In the telencephalic territory, SIX3 expressed in the anterior neural plate, which competes with FOXG1 expression, whereby FGF8 which is expressd in the anterior neural ridge induces FOXG1 and helps to organize the telencephalic region.

When the telencephalon's compartments have been established, FOXG1 regulates neuron specification. Progenitor cells divide asymmetrically and begin producing TBR1-expressing neurons, which become layer 1 and layer 6 neurons at the surface and the deepest regions of the cortical plate. Progenitor cells further produce layer 5 FEZF2- and BCL11B/CTIP2-expressing corticospinal projection cells, followed by RORβ-expressing sensory input cells, and then layer 2/3 SATB2 and POU3F2/BRN2-expressing callosal projection neurons. These neurons incorporate into the cortical plate through an inside-out layering pattern, where more recently generated neurons migrate past those that were born earlier, settling in the superficial region. Notably, while FOXG1 is expressed in many of the cortical progenitor cells and neurons, its function differs between subtypes and varies in a spatiotemporal manner (by progenitor cell proliferation and neuronal differentiation mechanism).

The onset of FOXG1 expression in progenitor cells terminates the production of the earliest born neurons, in other words, Cajal-Retzius cells, through direct inhibition of a major transcriptional network. This network comprises, as shown by transcriptome analysis and FOXG1-ChIP sequencing, TBR1, DMRTA1, EBF2, and EBF3.

The timely downregulation of FOXG1 by EGR2, a target of TGFβ, occurs in the lower intermediate zone where cells are transitioning out of the cell cycle, leading to the activation of Nr2f1/COUP-TFI, which enables layer 4 cell competence. In contrast, the absence of EGR2 target sites raises Foxg1 expression and facilitates the development of SATB2/BRN2-positive callosal projection neurons. Since FOXG1 haploinsufficiency leads to agenesis of the corpus callosum in both humans and mice due to impaired upper-layer projection neuron development, these findings suggest that having two functional copies of the Foxg1 gene is essential for regulating the production of cortical neurons and the development of axons necessary for the formation of cortical circuits typical of FOXG1 disorders.

Role of FOXG1 in neural plasticity

According to one study, FOXG1 is expressed in both the region where neurogenesis takes place and differentiated neurons of the adult cerebral cortex, indicating its roles in cognitive skill and neural plasticity. By altering the expression levels of FOXG1 in primary cultured neurons influences the development of dendrites, with increased levels of FOXG1 leading to enhanced dendritic length and branching of neurites, partly by positive regulatory mechanisms of HES1 and CREB1 gene expression.

In the adult hippocampus, a reduction in FOXG1 gene dosage results in a gradual decline in the quantity of dentate granule cells. In one study, the total elimination of Foxg1 in mature neurons was achieved through the use of an inducible Camk2α-CreER along with floxed Foxg1 mice. This deletion of Foxg1 led to impairments in spatial learning and memory, evaluated through the Morris water maze, in addition to a notable decrease in performance on both the contextual and cued fear conditioning tests.

Consquently, in FOXG1 syndrome, these mechanism (as mentioned above) are disrupted.

Diagnosis

There are diagnostic criterias to diagnose FOXG1 syndrome:

Major diagnostic criteria inlcudes:

• De novo mutation of th FOXG1 gene
• Intellectual disability
• Uneventful pre-natal period, beginning withing the first moths of life
• Secondary microcephaly
• Poor muscle tone
• Severe delayed development, Absent speech
• Alterations of EEG

Minor diagnostic includes:

• Irritable mood
• facial dysmorphism, such as: Widely spaced eyes, anteverted ears, bulging forehead.
• Squint
• Grinding of teeth
• GERD
• Constipation disorder
• Seizures
• Sleep pattern anomalies
• Dystonic disorder
• Stereotypies
• Autistic behaviours

Imaging criteria of this disorder are:

• Pachygyria
• Hypoplasia of corpus callosum
• Decreased frontal white matter volume

Treatment

This disease dosn't have a cure. But some of the symptoms can be managed. A multidisciplinary team is generally employed to treat the person's symptoms during their lifetime. The team might include specialist in: neurogenetics, genetic counseling, rehabilitation medicine, orthopedics, gastroenterology, physical therapy and ophthalmology.

Seizures can be managed standartly by antiseizure medication (ASMs), common ASMs include clobazam, valproic acid, vigabatrin, felbamate, lamotrigine and steroids. Although, there isn't universal treatment of the seizures in FOXG1 syndrome.

Dyskinetic movement disorder can be managed through anti-dyskinetic medications (for example: pimozide, tetrabenazine, clonidine, etc), Although no single drug has been found to be effective for this disorder.

Physical therapy is useful to make muscle tone better, it is also useful for strength improvement.

Research

In 2024, there was a study, where postnatal mouse was injected with AAV9-FOXG1 via ICV injection, and results showed improvement in corpus callosum agenesis, also it showed recovery of the dentate gyrus morphology, increased oligodendrocyte numbers with myelin restoration.

Prognosis

Information regarding the long-term course of FOXG1 syndrome is limited, and it is unclear whether lifespan is affected or not. Although one of the oldest individual with that disorder is 32 years old (at the time of article publication).

History

Thee first case of FOXG1 was identified by Shoichet et al in 7-year old female, who had de-novo translocation between chromosome 2 and chromosome 14, which affected FOXG1 gene. Later, in 2008, Ariani et al. identified 2 female patients (First was 22 years and second one was 7 years old, at the time of article publication) with FOXG1 syndrome, although at the time of publication, it was named "Rett syndrome, congenital variant", because of similiraties between Rett syndrome and FOXG1 syndrome. But in 2011, Kortüm F et al. designated the name "FOXG1 syndrome", because of the symptomatic differences between Rett syndrome and FOXG1 syndrome.

See also

• Rett syndrome
• CDKL5 deficiency disorder