Open AccessStructural brain anomalies in patients with FOXG 1 syndrome and in Foxg1+/− mice
Author(s) -
Pringsheim Milka,
Mitter Diana,
Schröder Simone,
Warthemann Rita,
Plümacher Kim,
Kluger Gerhard,
Baethmann Martina,
Bast Thomas,
Braun Sarah,
Büttel HansMartin,
Conover Elizabeth,
Courage Carolina,
Datta Alexandre N.,
Eger Angelika,
Grebe Theresa A.,
HasseWittmer Annette,
Heruth Marion,
Höft Karen,
Kaindl Angela M.,
Karch Stephanie,
Kautzky Torsten,
Korenke Georg C.,
Kruse Bernd,
Lutz Richard E.,
Omran Heymut,
Patzer Steffi,
Philippi Heike,
Ramsey Keri,
Rating Tina,
Rieß Angelika,
Schimmel Mareike,
Westman Rachel,
Zech FrankMartin,
Zirn Birgit,
Ulmke Pauline A.,
Sokpor Godwin,
Tuoc Tran,
Leha Andreas,
Staudt Martin,
Brockmann Knut
Publication year - 2019
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.735
Subject(s) - corpus callosum , fornix , neuroimaging , pathology , medicine , white matter , hypoplasia , magnetic resonance imaging , anatomy , radiology , hippocampus , psychiatry
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.