Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice

Abstract

Objective FOXG 1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG 1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. Methods We compiled 34 patients with a heterozygous (likely) pathogenic FOXG 1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re‐analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1 +/− mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. Results Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG 1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. Interpretation Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG 1 syndrome.

Network for Therapy in Rare Epilepsies (NETRE): Lessons From the Past 15 Years

“…This has led to new insights, not only regarding therapeutic options, but also for describing further the clinical phenotype in these rare epilepsies, such as the chewing-induced seizures in SYNGAP1 patients, or the bathing epilepsy in SYN1 patients, or the characteristic MRI findings in FOXG1 patients. With this additional clinical information, it may in the future be possible to diagnose patients earlier ( 42 , 46 ).…”

“…Duplications, deletions, frameshifts and point mutations are described as being responsible for characteristic phenotypes. The first report of a patient with a FOXG1 mutation was published in 2005 ( 46 ).…”

“…In a second study, 34 MRI findings of the previously described patients with FOXG1 mutation were reanalyzed by Pringsheim et al, leading to the identification of characteristic brain anomalies, corpus callosum anomaly in 82%, thickening of the fornix in 74%, and a simplified gyration in 56%. The authors concluded that this triad in the MRI is highly characteristic for the FOXG1 syndrome and may help in the diagnosis ( 46 ).…”

scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse

“…Current evidence suggests that CC dysgenesis significantly contributes to cognitive impairment and associative dysfunction in intellectual disability, autism and schizophrenia ( Bedeschi et al, 2006 ; Paul et al, 2007 ; Rao et al, 2011 ; Siffredi et al, 2013 ; Badaruddin et al, 2007 ). Intriguingly, several of the predicted TCF4 interactors have been linked to neurodevelopmental disorders featuring corpus callosum abnormalities ( Pringsheim et al, 2019 ; Filatova et al, 2019 ; Tzeng et al, 2014 ; Snijders Blok et al, 2019 ; Hempel et al, 2016 ), suggesting a pathophysiological relevance of the proposed TCF4 TF network.…”

Behavioral Phenotypes of Foxg1 Heterozygous Mice

“…Foxg1 haploinsufficiency also leads to disrupted forebrain development, including a significant reduction in the volume of the neocortex, hippocampus and striatum ( Eagleson et al, 2007 ; Cargnin et al, 2018 ). Foxg1 haploinsufficiency decreases the population of cortical intermediate progenitors via increased p21 expression, leading to thinner neocortices than wild-type controls, specifically in the supragranular layers ( Siegenthaler et al, 2008 ; Cargnin et al, 2018 ; Pringsheim et al, 2019 ). Notably, Foxg1 HET mice show thinner neocortices than wild-type controls, mainly due to reduction of the supragranular layers.…”