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

Milka Pringsheim, Diana Mitter, Simone Schröder, Rita Warthemann, Kim Plümacher, Gerhard Kluger, Martina Baethmann, Thomas Bast, Sarah Braun, Hans Martin Büttel, Elizabeth Conover, Carolina Courage, Alexandre N. Datta, Angelika Eger, Theresa A. Grebe, Annette Hasse-Wittmer, Marion Heruth, Karen Höft, Angela M. Kaindl, Stephanie KarchTorsten Kautzky, Georg C. Korenke, Bernd Kruse, Richard E. Lutz, Heymut Omran, Steffi Patzer, Heike Philippi, Keri Ramsey, Tina Rating, Angelika Rieß, Mareike Schimmel, Rachel Westman, Frank Martin Zech, Birgit Zirn, Pauline A. Ulmke, Godwin Sokpor, Tran Tuoc, Andreas Leha, Martin Staudt, Knut Brockmann

Research output: Contribution to journalArticle

Abstract

Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 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 FOXG1 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 FOXG1 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 FOXG1 syndrome.

Original languageEnglish (US)
Pages (from-to)655-668
Number of pages14
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number4
DOIs
StatePublished - Apr 2019

Fingerprint

Neuroimaging
Corpus Callosum
Brain
Phenotype
Telencephalon
Genetic Association Studies
Frontal Lobe
Basal Ganglia
Hyperplasia
Staining and Labeling

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

Cite this

Pringsheim, M., Mitter, D., Schröder, S., Warthemann, R., Plümacher, K., Kluger, G., ... Brockmann, K. (2019). Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice. Annals of Clinical and Translational Neurology, 6(4), 655-668. https://doi.org/10.1002/acn3.735

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice. / Pringsheim, Milka; Mitter, Diana; Schröder, Simone; Warthemann, Rita; Plümacher, Kim; Kluger, Gerhard; Baethmann, Martina; Bast, Thomas; Braun, Sarah; Büttel, Hans Martin; Conover, Elizabeth; Courage, Carolina; Datta, Alexandre N.; Eger, Angelika; Grebe, Theresa A.; Hasse-Wittmer, 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, Frank Martin; Zirn, Birgit; Ulmke, Pauline A.; Sokpor, Godwin; Tuoc, Tran; Leha, Andreas; Staudt, Martin; Brockmann, Knut.

In: Annals of Clinical and Translational Neurology, Vol. 6, No. 4, 04.2019, p. 655-668.

Research output: Contribution to journalArticle

Pringsheim, M, Mitter, D, Schröder, S, Warthemann, R, Plümacher, K, Kluger, G, Baethmann, M, Bast, T, Braun, S, Büttel, HM, Conover, E, Courage, C, Datta, AN, Eger, A, Grebe, TA, Hasse-Wittmer, A, Heruth, M, Höft, K, Kaindl, AM, Karch, S, Kautzky, T, Korenke, GC, Kruse, B, Lutz, RE, Omran, H, Patzer, S, Philippi, H, Ramsey, K, Rating, T, Rieß, A, Schimmel, M, Westman, R, Zech, FM, Zirn, B, Ulmke, PA, Sokpor, G, Tuoc, T, Leha, A, Staudt, M & Brockmann, K 2019, 'Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice', Annals of Clinical and Translational Neurology, vol. 6, no. 4, pp. 655-668. https://doi.org/10.1002/acn3.735
Pringsheim M, Mitter D, Schröder S, Warthemann R, Plümacher K, Kluger G et al. Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice. Annals of Clinical and Translational Neurology. 2019 Apr;6(4):655-668. https://doi.org/10.1002/acn3.735
Pringsheim, Milka ; Mitter, Diana ; Schröder, Simone ; Warthemann, Rita ; Plümacher, Kim ; Kluger, Gerhard ; Baethmann, Martina ; Bast, Thomas ; Braun, Sarah ; Büttel, Hans Martin ; Conover, Elizabeth ; Courage, Carolina ; Datta, Alexandre N. ; Eger, Angelika ; Grebe, Theresa A. ; Hasse-Wittmer, 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, Frank Martin ; Zirn, Birgit ; Ulmke, Pauline A. ; Sokpor, Godwin ; Tuoc, Tran ; Leha, Andreas ; Staudt, Martin ; Brockmann, Knut. / Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice. In: Annals of Clinical and Translational Neurology. 2019 ; Vol. 6, No. 4. pp. 655-668.
@article{c560b40595aa4c24aa1115b2e6a404df,
title = "Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice",
abstract = "Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 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 FOXG1 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 FOXG1 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 FOXG1 syndrome.",
author = "Milka Pringsheim and Diana Mitter and Simone Schr{\"o}der and Rita Warthemann and Kim Pl{\"u}macher and Gerhard Kluger and Martina Baethmann and Thomas Bast and Sarah Braun and B{\"u}ttel, {Hans Martin} and Elizabeth Conover and Carolina Courage and Datta, {Alexandre N.} and Angelika Eger and Grebe, {Theresa A.} and Annette Hasse-Wittmer and Marion Heruth and Karen H{\"o}ft and Kaindl, {Angela M.} and Stephanie Karch and Torsten Kautzky and Korenke, {Georg C.} and Bernd Kruse and Lutz, {Richard E.} and Heymut Omran and Steffi Patzer and Heike Philippi and Keri Ramsey and Tina Rating and Angelika Rie{\ss} and Mareike Schimmel and Rachel Westman and Zech, {Frank Martin} and Birgit Zirn and Ulmke, {Pauline A.} and Godwin Sokpor and Tran Tuoc and Andreas Leha and Martin Staudt and Knut Brockmann",
year = "2019",
month = "4",
doi = "10.1002/acn3.735",
language = "English (US)",
volume = "6",
pages = "655--668",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
publisher = "John Wiley and Sons Ltd",
number = "4",

}

TY - JOUR

T1 - Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice

AU - Pringsheim, Milka

AU - Mitter, Diana

AU - Schröder, Simone

AU - Warthemann, Rita

AU - Plümacher, Kim

AU - Kluger, Gerhard

AU - Baethmann, Martina

AU - Bast, Thomas

AU - Braun, Sarah

AU - Büttel, Hans Martin

AU - Conover, Elizabeth

AU - Courage, Carolina

AU - Datta, Alexandre N.

AU - Eger, Angelika

AU - Grebe, Theresa A.

AU - Hasse-Wittmer, Annette

AU - Heruth, Marion

AU - Höft, Karen

AU - Kaindl, Angela M.

AU - Karch, Stephanie

AU - Kautzky, Torsten

AU - Korenke, Georg C.

AU - Kruse, Bernd

AU - Lutz, Richard E.

AU - Omran, Heymut

AU - Patzer, Steffi

AU - Philippi, Heike

AU - Ramsey, Keri

AU - Rating, Tina

AU - Rieß, Angelika

AU - Schimmel, Mareike

AU - Westman, Rachel

AU - Zech, Frank Martin

AU - Zirn, Birgit

AU - Ulmke, Pauline A.

AU - Sokpor, Godwin

AU - Tuoc, Tran

AU - Leha, Andreas

AU - Staudt, Martin

AU - Brockmann, Knut

PY - 2019/4

Y1 - 2019/4

N2 - Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 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 FOXG1 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 FOXG1 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 FOXG1 syndrome.

AB - Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 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 FOXG1 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 FOXG1 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 FOXG1 syndrome.

UR - http://www.scopus.com/inward/record.url?scp=85064497498&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064497498&partnerID=8YFLogxK

U2 - 10.1002/acn3.735

DO - 10.1002/acn3.735

M3 - Article

C2 - 31019990

AN - SCOPUS:85064497498

VL - 6

SP - 655

EP - 668

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

SN - 2328-9503

IS - 4

ER -