ARTICLE OPEN ACCESS

Delineating FOXG1 syndromeFrom congenital microcephaly to hyperkinetic encephalopathy

Nancy Vegas MD Mara Cavallin MD Camille Maillard MD Nathalie Boddaert MD PhD

Joseph Toulouse MD Elise Schaefer MD Tally Lerman-Sagie MD Dorit Lev MD Barth Magalie MD

Sebastien Moutton MD Eric Haan MD Bertrand Isidor MD Delphine Heron MD Mathieu Milh MD PhD

Stephane Rondeau MD Caroline Michot MD PhD Stephanie Valence MD Sabrina Wagner MD

Marie Hully MD Cyril Mignot MD Alice Masurel MD Alexandre Datta MD Sylvie Odent MD PhD

Mathilde Nizon MD Leila Lazaro MD Marie Vincent MD Benjamin Cogne MD Anne Marie Guerrot MD

Stephanie Arpin MD Jean Michel Pedespan MD Isabelle Caubel MD Benedicte Pontier MD PhD

Baptiste Troude MD Francois Rivier MD PhD Christophe Philippe MD PhD Thierry Bienvenu MD PhD

Marie-Aude Spitz MD Amandine Bery PhD and Nadia Bahi-Buisson MD PhD

Neurol Genet 20184e281 doi101212NXG0000000000000281

Correspondence

Pr Bahi-Buisson

nadiabahi-buissonaphpfr

AbstractObjectiveTo provide new insights into the FOXG1-related clinical and imaging phenotypes and refine thephenotype-genotype correlation in FOXG1 syndrome

MethodsWe analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic orlikely pathogenic FOXG1 variant and performed phenotype-genotype correlations

ResultsA total of 37 FOXG1 different heterozygous mutations were identified of which 18 are novelWe described a broad spectrum of neurodevelopmental phenotypes characterized by severepostnatal microcephaly and developmental delay accompanied by a hyperkinetic movementdisorder stereotypes and sleep disorders and epileptic seizures Our data highlighted 3 patternsof gyration including frontal pachygyria in younger patients (267) moderate simplifiedgyration (244) and mildly simplified or normal gyration (489) corpus callosum hypo-genesis mostly in its frontal part combined with moderate-to-severe myelination delay thatimproved and normalized with age Frameshift and nonsense mutations in the N-terminus ofFOXG1 which are the most common mutation types show the most severe clinical featuresand MRI anomalies However patients with recurrent frameshift mutations c460dupG andc256dupC had variable clinical and imaging presentations

ConclusionsThese findings have implications for genetic counseling providing evidence that N-terminalmutations and large deletions lead to more severe FOXG1 syndrome although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations Togetherthese analyses support the view that FOXG1 syndrome is a specific disorder characterized byfrontal pachygyria and delayed myelination in its most severe form and hypogenetic corpuscallosum in its milder form

Funding information and disclosures are provided at the end of the article Full disclosure form information provided by the authors is available with the full text of this article atNeurologyorgNG

The Article Processing Charge was funded by the authors

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

Mutations in the FOXG1 gene have been shown to causea rare neurodevelopmental disorder Initially described asa ldquocongenital variant of Rett syndromerdquo12 subsequent reportsallowed delineation of the FOXG1 syndrome which is nowconsidered a distinct clinical entity3ndash7

To date more than 90 individuals with FOXG1 mutationshave been described mostly within small case series57 Thedisorder comprises a complex constellation of clinical fea-tures including severe postnatal microcephaly deficient socialreciprocity combined stereotypies and dyskinesias epilepsypoor sleep patterns and unexplained episodes of crying3 Inparallel to these clinical criteria the importance of brain MRIfeatures has been emphasized138 However the spectrum ofMRI features in FOXG1 syndrome is yet to be fully defined

FOXG1 encodes a transcription factor containing a highlyconserved domain spanning from the forkhead binding do-main (FBD) to the C-terminus and a variable N-terminus9

FOXG1 mutations include frameshifts deletions and pointmutations710 A recent study suggests that more severe phe-notypes are associated with truncating FOXG1 variants in theN-terminus and the FBD and milder phenotypes with mis-sense variants in the FBD The most significant differenceswere related to motor and speech development while onlyborderline differences were found concerning corpus cal-losum anomalies delayed myelination and microcephaly7

In light of these recent findings the aim of this study was toprovide a comprehensive overview of FOXG1-related clinicaland imaging phenotypes by thorough analysis of a cohort of 45clinically well-characterized patients with FOXG1 mutation andrefine the phenotype-genotype correlation in FOXG1 syndrome

MethodsWe recruited patients with pathogenic or likely pathogenicFOXG1 mutations from different cohorts through a large na-tional and international network Genetic testing was performedby array comparative genomic hybridization (CGH) (545)Sanger sequencing (3145) targeted panel high-throughputsequencing (445) and whole-exome sequencing (445)

Standard protocol approvals registrationsand patient consentsThe study was approved by the ethics committee of the Uni-versity Hospital of Necker Enfants Malades Paris France andthe relevant local institutional review boards Parental writteninformed consent was obtained for all affected patients

All patients were personally known to at least 1 of the co-authors and were reexamined for the purpose of the study

Five patients had been reported previously and were reas-sessed for the study81112 Standardized clinical informationwas recorded Movement disorders were characterized inperson by investigators and classified according to establishedcriteria13 Epileptic seizures were classified according to therecommendations of the Commission on Classification andTerminology of the International League Against Epilepsy

In addition for patients filmed we obtained additional autho-rization for disclosure of any recognizable persons in videos

The genetic testings were performed in accordance with therespective national ethics guidelines and approved by the localauthorities in the participating study centers

MRI studiesAs the MRI studies were performed over a period of 10 yearsat many different imaging centers and on many different typesof MR scanners the imaging techniques that were useddiffered substantially although a majority had at least axialand sagittal T1-weighted and axial T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences Imagingassessment was based on agreement between 2 investigators(NB and NB-B) who reviewed the images Each made initialevaluations independently and any disagreements regardingthe final conclusion were resolved by consensus

Statistical analysisAll statistical analyses were performed in GraphPad Prismversion 600 Data are described as mean plusmn SEM Differenceswere evaluated using the 2-way analysis of variance withmultiple comparison tests

The study was approved by the ethics committee of the Uni-versity Hospital of Necker Enfants Malades Paris France andthe relevant local institutional review boards Parental writteninformed consent was obtained for all affected patients

ResultsOur cohort totaled 45 patients with FOXG1 mutations 22males and 23 females ranging in age from 19 months to 42years (median 573 years) at the time of evaluation (table e-1linkslwwcomNXGA97)

A total of 37 FOXG1 different heterozygous mutations wereidentified of which 18 are novel They comprised 32 smallintragenic mutations and 5 large deletions of the whole FOXG1locus All mutations were de novo except 1 reported previouslyas a germinal mosaic12 Point mutations were mostly frameshifts(1432 4375) and missense mutations (1232 375) witha small number of nonsense (432 125) and in-frame

GlossaryFBD = forkhead binding domain

2 Neurology Genetics | Volume 4 Number 6 | December 2018 NeurologyorgNG

mutations (232 625) (figure 1 A and B) Three recurrentmutations c460dupG c256dupC and c256delC wereidentified

Clinical presentation in patients withFOXG1 mutationsPatients first came to medical attention at a median age of 3months (birth to 20 months) because of developmental delayand microcephaly (1545 333) or with lack of eye contactor strabismus (1645 356) Epileptic seizures or move-ment disorder were less common (445 lt10) In 5 cases(111) brain anomalies were diagnosed prenatally

At birth a majority of patients had normal body measure-ments and low normal birth head size (3843 884) Severepostnatal microcephaly (minus4 to minus6 SD) became apparent afterthe age of 1 month

At the age of the last evaluation (median 5 years 19months to42 years) all patients had profound developmental delay withpermanent esotropia (3842 907) (video 1 linkslwwcomNXGA99) Hand usewas severely limited to involuntary grossmanipulation (1344 295) (video 2 linkslwwcomNXGA100) On examination a complexmovement disorder was themost prominent feature characterized by generalized hyperki-netic and dyskinetic movements that was present at rest and

worsened with attempts to movement (videos 3 and 4 linkslwwcomNXGA101 and linkslwwcomNXGA102) withorolingual dyskinesias (1233 364) (video 5 linkslwwcomNXGA103) 34 of 43 patients (791) also showed handstereotypies consisting of hand pressingwringing or handmouthing (videos 6 and 7 linkslwwcomNXGA104 linkslwwcomNXGA105) which are unusual in the context ofdyskinetic movement disorders Thirty-two of 44 patients (727) had feeding difficulties associated with gastroesophagealreflux (videos 8 and 9 linkslwwcomNXGA106 and linkslwwcomNXGA107) Sleep problems were frequent (2742643) and included multiple nocturnal awakenings or diffi-culties in falling asleep with irritability and inconsolable cryingor inappropriate laughing (2540 625) Seizures weredocumented in 778 (3545) of patients and occurred ata mean age of 25 years (range 2 days to 12 years) Generalizedtonic or tonic-clonic seizures were the most frequent seizuretype (2135 60) Of the 35 patients 17 (486) developedrefractory epilepsy with multiple seizure types and 5 (143)experienced at least 1 episode of status epilepticus (table 1)

Because FOXG1mutations had been previously associated withcongenital Rett variant we examined the prevalence of con-genital Rett-supportive manifestations Overall 2 of 21 females(95) and 1 of 21males (476) fulfilled the diagnostic criteriafor Rett syndrome14 (table e-2 linkslwwcomNXGA98)

Figure 1 Schematic representation of FOXG1 gene protein domain structure and positions of FOXG1 mutations

(A) Schematic representation of FOXG1 gene and (B) FOXG1 protein domain structure and positions of the variations identified N-terminal domain FBDdomain (forkhead DNA binding domain amino acids 181ndash275) GBD domain (Groucho binding domain amino acids 307ndash317) JBD domain (JARID1B bindingdomain amino acids 383ndash406) and C-terminal domain are indicated Mutations are located all along the FOXG1 gene within different protein domainsMissensemutations are predominantly located in the FBD (917) whereas frameshiftmutations aremore prominent in theN-terminal domain (571) Thenovel variants described in this article are highlighted in bold and the recurrent variants are underlined with the corresponding number of recurrencesindicated in brackets FBD = forkhead binding domain GBD = Groucho binding domain JBD = JARID1B binding domain

NeurologyorgNG Neurology Genetics | Volume 4 Number 6 | December 2018 3

Table 1 Individual data on epilepsy and MRI pattern on 45 patients with de novo FOXG1 mutationsdeletions

PatientsexAge at lastfollow-up Mutation Epilepsy

Age atseizure onset Seizure history

Age atMRI MRI Pattern

Tel02M 4 y 6 mo pGln73dup Yes 1 y Brief GTS (every 2 wk) under AED 2 y 8 mo Moderate SIMP with cortical atrophy severemyelination delay hypoplastic CC andnormal cerebellum

Trs1F 3 y 6 m pGln86Prosfs35 Yes 6 mo IS then evolved to GTS (1 SE at 2 y 6 m)followed by GTCS drug resistant

11 m Mild SIMP gyral pattern moderatemyelination delay hypogenesis of the CCaffecting the rostrum and normalcerebellum

Im11F 1 y 7 mo pGln86Profs35 No mdash mdash 2 y 6 mo Moderate SIMP mild myelination delayhypogenesis of the CC affecting the rostrumand normal cerebellum

Im05M 10 y 2 mo pGln86Profs35 Yes 5 mo GTCS (1 each 6 mo) with LTG and CZP 2 y 8 mo Moderate SIMP gyral with cortical atrophysevere myelination delay hypogenesis of theCC affecting the rostrum and normalcerebellum

Nan02F 3 y pGln86Aspfs34 Yes 1 y 6 mo 2 SE then GTS (1m) with AED with LTG VPACZP

3 y Moderate SIMP with mild cortical atrophysevere myelination delay complete agenesisof the CC and normal cerebellum

Bay01F 7 y 5 mo pGln86Argfs106 No mdash mdash 3 y 2 mo Normal gyral pattern mild myelination delayhypogenesis of the CC affecting the rostrumand normal cerebellum

Mon01M 10 y pGln86Argfs106 Yes 1 y IS then myoclonic seizures withphotosensitivity seizure free from the age of4

3 y 6 mo Mild SIMP gyral pattern severe corticalatrophy mildmyelination delay complete CCagenesis and normal cerebellum

Rou01M 3 y pGlu136Glyfs39 Yes 1 y 3 mo GTS and IS 1 SE drug-resistant multifocalepilepsy with VGB and TPM

34 mo Pachygyria severe myelination delayhypoplastic CC and normal cerebellum

Ren01M 12 y pGlu154Glyfs301 Yes 6 y 1 episode of FS then seizure free 12 y 8 mo Mild SIMP gyral pattern with mild corticalatrophy normal myelination hypogenesis ofthe CC affecting the rostrum and cerebellaratrophy

Leu01F 5 y pGlu154Glyfs301 No mdash mdash 5 y Normal gyral pattern mild myelination delayand normal CC and cerebellum

Thi01F 9 y pGlu154Glyfs301 Yes 2 y GTS then seizure free 9 y 3 mo Moderate SIMP with mild cortical atrophymild myelination delay complete agenesis ofthe CC and cerebellar atrophy

Im06F 4 y 10 mo pGlu154Glyfs301 No mdash mdash 1 y 11 mo Pachygyria severe myelination delayhypogenesis of the CC with absence ofrostrum and mild cerebellar atrophy

Continued

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Table 1 Individual data on epilepsy and MRI pattern on 45 patients with de novo FOXG1 mutationsdeletions (continued)

PatientsexAge at lastfollow-up Mutation Epilepsy

Age atseizure onset Seizure history

Age atMRI MRI Pattern

Im09M 6 y pGlu154Glyfs301 Yes 4 y Occasional GTCS (1y) with VPA (normal EEG) 3 y 3 mo Mild SIMP mild myelination delayhypogenesis of the CC affecting the rostrumand normal cerebellum

Ang02M 2 y pGlu154Glyfs301 Yes 3 mo Focal motor seizures (4mo) 1 y 3 mo Mild SIMP gyral pattern with moderatecortical atrophy severe myelination delayhypogenesis of the CC affecting the rostrumand normal cerebellum

Im04F 11 y pGlu155Glyfs300 Yes 4 mo Myoclonic seizures treated with VPA thenseizure free from the age of 4 y

1 y 10 mo Mild SIMP gyral pattern severe myelinationdelay hypogenesis of the CC affecting therostrum and normal cerebellum

Tou01M ND pGlu155 Yes 10 mo Drug-resistant multifocal epilepsy (LennoxGastaut like)

2 y 6 mo Pachygyria severe myelination delayhypoplastic CC and normal cerebellum

Im10M 4 y 12 mo pLys162Serfs51 Yes 2 y Occasional GTCS with VPA 4 y Moderate SIMP gyral pattern with corticalatrophy severe myelination delay partialagenesis of the CC and normal cerebellum

Rdb02M 6 y pTyr179 Yes 11 mo Focal seizures with secondary generalizationrefractory

2 y 3 mo Pachygyria with moderate cortical atrophysevere myelination delay partial agenesis ofthe CC and normal cerebellum

Im03F 2 y 4 mo pSer185Glnfs270 Yes 1 y 5 mo Focal seizures with secondary generalizationthen seizure free with AED

2 y Mild SIMP gyral pattern with mild corticalatrophy moderate myelination delayextremely hypoplastic CC and normalcerebellum

Pit02M 22 y pIle194Serfs19 Yes 1 y GTS then seizure free ND Mild SIMP gyral pattern myelination delayhypoplastic CC with hypoplastic rostrum

Ren03M 32 y pGln196 Yes 4 y 1 SE then occasional GTCS between 4 and 10 ythen seizure free

7 mo Partial agenesis of the CC and normalcerebellum

Ade01M 7 y pTyr208_Ile211del Yes 1 y 8 mo Recurrent seizures (3d) then seizure freewith AED

2 y 7 mo Mild SIMP withmild cortical atrophy absenceof myelination delay hypogenesis of the CCaffecting the rostrum and normalcerebellum

Str03M 20 y pVal242Cysfs84 Yes 6 mo Myoclonic seizures and then GTCS 8 mo Pachygyria moderate myelination delayhypoplastic CC and normal cerebellum

Im01F 10 y pTyr254Thrfs72 Yes 3 y GTCS FS under 3 AED 7 y 4 mo Moderate SIMP with cortical atrophy mildmyelination delay hypoplastic CC affectingthe rostrum and normal cerebellum

Continued

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Table 1 Individual data on epilepsy and MRI pattern on 45 patients with de novo FOXG1 mutationsdeletions (continued)

PatientsexAge at lastfollow-up Mutation Epilepsy

Age atseizure onset Seizure history

Age atMRI MRI Pattern

Tel01M 3 y 6 mo pIle266Tyrfs189 No mdash FS once 11 mo Moderate SIMP mild myelination delayhypoplastic CC and normal cerebellum

Ren02F 10 y pPro182Leu Yes 9 mo Atypical absence GTCS drug resistant 1 y Pachygyria moderate myelination delayhypoplastic CC affecting the rostrum andnormal cerebellum

Rdb01M 8 y pAsn187Asp Yes 1 y 6 mo IS then multifocal drug-resistant epilepsy 18 mo Pachygyria severe myelination delayhypoplastic CC affecting the rostrum andnormal cerebellum

Lau01M 2 y pAsn187Lys Yes 12 mo IS then multifocal drug-resistant epilepsy 2 y 5 mo Moderate SIMP with cortical atrophy severemyelination delay hypoplastic CC andnormal cerebellum

Im08M 22 mo pArg195Pro Yes 8 mo GTS (10d every 6 mo) with VPA and CZP 2 y 2 mo Moderate SIMP gyral pattern with moderatecortical atrophymoderatemyelination delayhypoplastic CC and normal cerebellum

Pit01F 42 y pLeu204Phe Yes 8 y GTCS then seizure free 39 y Mild SIMP with mild cortical atrophy mildwhite matter loss hypoplastic CC affectingthe rostrum and cerebellar atrophy

Mar01F 4 y pPhe215Leu Yes 10 y GTCS seizure free with VPA 3 y Normal gyral pattern with mild corticalatrophy moderate myelination delayhypoplastic CC affecting the rostrum andnormal cerebellum

Im12F 2 y 7 mo pGly224Ser Yes 6 mo IS then seizure free under LTG CZP from 2 y 2 y 6 mo Normal gyral pattern mild myelination delayhypoplastic CC and normal cerebellum

Ang01M 2 y 4 mo pArg230His No mdash mdash 1 y 11 mo Pachygyria moderate myelination delayhypoplastic CC affecting the rostrum andnormal cerebellum

Str02F 9 y pGly252Val No mdash mdash 19 mo Pachygyria severe myelination delayhypoplastic CC and normal cerebellum

Lyo01M 4 y pTrp255Arg Yes 1 y ND 2 y 2 mo Mild SIMP gyral pattern mild myelinationdelay CC hypogenesis and normalcerebellum

Nan03F 17 y pLeu257Pro No mdash mdash 4 y Normal cortex anterior part CCnonmyelinated

Nan01F 7 y 1 mo pAsn408Ile Yes 9 y Atypical absences with VPA 13 y Normal

Continued

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Table 1 Individual data on epilepsy and MRI pattern on 45 patients with de novo FOXG1 mutationsdeletions (continued)

PatientsexAge at lastfollow-up Mutation Epilepsy

Age atseizure onset Seizure history

Age atMRI MRI Pattern

Im02M 4 y 9 mo pSer326Glufs129 Yes 1 y IS treated with VGB and steroids then seizurefree

1 y 1 mo Moderate SIMP with mild cortical atrophymoderate myelination delay hypogenesis ofthe CC affecting the rostrum and normalcerebellum

Cle01F 18 y pTyr400 No mdash mdash 7 y 11 mo Normal

Dij01F 18 y 2 mo c-715delinsTACCAAAA Yes 1 y 6 mo GTCS then seizure free under VPA (3 ys)currently no treatment (11 y)

15 y 11 mo Mild SIMP gyral pattern with mild corticalatrophy absence of myelination delayhypogenesis of the CC affecting the rostrumand cerebellar atrophy

Lyo02F 1 y 6 mo del14q12 (29222002ndash29258618) Yes 1 y 4 mo IS seizure free under VGB 8 mo Mild SIMP gyral pattern mild myelinationdelay hypogenesis of the CC affecting therostrum and normal cerebellum

Lyo03F 3 y 9 mo del14q12 (26415516ndash29677148) Yes 1 y 3 mo GTS then seizure free during 2 mo drugresistant (seizure frequency 1w)

9 mo Mild SIMP gyral pattern moderatemyelination delay hypogenesis of the CCaffecting the rostrum and the genu andnormal cerebellum

Im07F 2 y del14q12q131 No mdash mdash 5 mo Moderate SIMP gyral pattern moderatemyelination delay complete agenesis of theCC and normal cerebellum

Aix01M 7 y del14q12 (18798641ndash19484013) Yes 2 d of life FS (lt1mo) 2 y Mild SIMP gyral pattern with moderatecortical atrophymoderatemyelination delayhypoplastic CC and normal cerebellum

Abbreviations AED = antiepileptic drugs CBZ = carbamazepine CC = corpus callosum CZP = clonazepam FS = focal seizures GTCS = generalized tonic-clonic seizures GTS generalized tonic seizures IS = infantileepilepticspasms LEV = levetiracetam LTG = lamotrigine SE = status epilepticus SIMP = simplified gyration TPM = topiramate VGB = vigabatrin VPA = valproic acid

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Brain imagesPatients with FOXG1 syndrome showed a variable degree ofgyration moderate-to-severe myelination delay or whitematter loss (644) and abnormal corpus callosum (956)From our detailed review of these imaging studies we wereable to delineate 3 groups of severity of gyration defect thatare most easily appreciated with multiple views in severalplanes as shown in figures 2 A-L and 3 A-H

The first gyral pattern the most severe consisted of pachy-gyria with thickened cortex with frontal lobe predominance(1245 267) This pattern was seen in the youngestpatients (mean age 18 years) and was accentuated by theunderdevelopment of the frontal lobes and the reduced vol-ume of the subcortical white matter In this group myelina-tion delay was prominent ranging from severe (711 636)to moderately delayed (411 364) The most commoncorpus callosum anomaly was anterior hypogenesis mostlyaffecting the genu and the rostrum (611 545) (figure 2A-L) Sequential MRI performed during the first years of lifeshowed that this pachygyric appearance can be overestimated

between the ages of 12 and 24 months because of the im-mature myelination (figure 3 A-H) Delayed myelinationimproved with age and no case of hypomyelination or dys-myelination was observed after the age of 5 years

The second gyral pattern of intermediate severity met thesubjective criteria of moderately simplified gyral pattern15

This pattern was observed in 244 (1145) of patients withmean age of 31 years In this group myelination was mod-erately to severely delayed The corpus callosum showeda wide range of anomalies including complete agenesis (511455) global hypoplasia (311 273) and anteriorhypogenesis (311 273)

The third gyral pattern the least severe consisted of mildlysimplified to normal gyral pattern These patients (2245489) were older than the 2 previous groups (mean age 61years) White matter anomalies were mostly mild or absent(1422 636) and the corpus callosum was hypogenetic inits anterior part in the majority of cases (1422 636)(figure e-1 linkslwwcomNXGA91)

Figure 2 Representative MRI of pachygyric frontal cortex in FOXG1 patients

Representative images at the level of centrum semiovale in axial T1-weighted (A E I) and T2-weighted (B F J) MRI at the level of lateral ventricles (thirdcolumn) and midline sagittal (right column) Each row shows images from the same patient respectively (AndashD) Str02 aged 19 months (EndashH) Ang01 aged 23months (IndashL) Rou01 aged 34 months The cortex appears mildly thick with a clear predominance in the frontal lobes The appearance of pachygyria isaccentuated by the underdevelopment of frontal lobes T2-weighted (C G K) MRI at the level of the internal capsule showing associated myelination delaywithmaturemyelin only visible in both internal capsules (G and K) T1-weightedmidline sagittal sections showing the wide range of appearance of the corpuscallosum from hypoplastic and thin (D L) to thick with underdevelopment of the genu (H)

8 Neurology Genetics | Volume 4 Number 6 | December 2018 NeurologyorgNG

Genotype-phenotype relationshipsTo assess genotype-phenotype associations in FOXG1 syn-drome we investigated the correlation between the score ofselected FOXG1 criteria in the whole cohort and 5 geneticsubgroups (e-results) (table 2)

Patients with N-terminal mutations and FOXG1 deletionsshowed the highest global severity scores while those withFBD frameshift and nonsense mutations showed the lowestglobal severity scores (p lt 005) Patients with FBD missenseand C-terminal domain mutations tended to have lower globalseverity scores although the differences were not significantbecause of the small size of these groups (figure e-2A linkslwwcomNXGA92)

When covariance analysis was performed in the whole cohortwe found significant positive covariance of gyral and myelina-tion pattern scores suggesting that whatever the type of FOXG1mutation the most severe cortical anomaly (ie pachygyria) iscorrelated with the most severe myelination delay furtherreinforcing the fact that this cortical anomaly may be over-estimated because of the abnormal myelination of the sub-cortical fibers Further analyses showed significant and distinct

covariance relationships in which theMRI pattern appeared themost relevant criteria in distinguishing the genetic groups(figures e-3 linkslwwcomNXGA93 and e-4 linkslwwcomNXGA94)

Interesting data also came from the analysis of patients withrecurrent frameshift mutations c460dupG and c256dupCRemarkably among the patients with c460dupG we foundsignificant differences in clinical and imaging presentationsdemonstrating that genotype-phenotype correlation is notstraightforward in FOXG1 syndrome On MRI this mutationresulted in a spectrum of corpus callosum anomalies fromcomplete agenesis to global hypoplasia (figure e-5 linkslwwcomNXGA96) By contrast the 3 patients with the c256dupC had a more consistent phenotype

DiscussionFoxg1 is a transcription factor that plays nonredundant roles inbrain development such that loss of a single copy of the geneseverely affects brain formation and knock-out mice cannotsurvive after birth916 Consequently it is not surprising that allmutations identified in humans are heterozygous and result in

Figure 3 Changing appearance of the frontal cortex with age associated with increasing myelination

Representative images from 2 patients Im11 pGln86Profs35 (AndashD) and Im09 pGlu154Glyfs301 (EndashH) (A and B) Images obtained when the patient was 6months old T2-weighted image (A) shows normal thickness of both frontal lobes but delayedmyelination T1-weighted image (B) shows a pachygyric cortex inthe same region (C and D) Images obtained when the patient was 2 years 6months T2-weighted image (C) of the frontal lobe showsmildly thickened cortexprobably because of the poormyelination of the subcortical whitematter (E and F) Images obtainedwhen the patient was 1 year 8months In the frontal lobeT2-weighted (E) and T1-weighted (F) images show the same pattern of pachygyric cortex and severely delayed myelination (E) (G and H) At 3 years the T2-weighted image (G) shows significant improvement of myelination although still delayed in the frontal subcortical region the T1-weighted image (H) showsmildly simplified gyral pattern with no pachygyria

NeurologyorgNG Neurology Genetics | Volume 4 Number 6 | December 2018 9

Table 2 Clinical and neuroimaging features related to the FOXG1 genotype groups

N-terminaldomain variants

Forkhead domain frameshiftand nonsense variants

Forkhead domainmissense variants

C-terminal domainvariants Large deletions

Cases number n () 19 395 6 133 12 2560 3 7 5 116

Sex MF 109 526474 42 667333 66 5050 12 333667 14 2080

Median age at last follow-up (y) 48 15 55 71 38

Pregnancy and neonatal period

Problems in pregnancyscans 017 0 24 50 411 364 03 0 25 40

Mean gestation at delivery (GW)n 397 18 382 6 391 11 392 3 389 5

Neonatal issues 417 237 14 25 211 1820 13 333 45 80

Feeding difficulties at birth 317 176 14 25 111 91 13 333 25 40

Body measurements at birth

Length lt 22SD 016 0 05 0 110 10 03 0 05 0

Weight lt 22SD 017 0 05 0 011 0 03 0 05 0

HC lt 22SD 118 56 05 0 312 25 03 0 05 0

Body measurements at last evaluation

Median age (y)n 47 18 66 5 75 12 71 3 38 5

Height lt 22SD 114 71 13 333 39 333 02 0 25 40

Weight lt 22SD 417 235 13 333 411 364 13 333 35 60

HC lt 22SD 1819 947 55 100 810 80 33 100 55 100

HC lt 24SD 1419 737 35 60 410 40 13 333 45 80

Microcephaly score

0 = Normal at birth and at last evaluation 118 56 15 20 211 182 03 0 05 0

1 = Postnatal microcephaly 318 167 15 20 311 273 23 667 15 20

2 = Severe postnatal microcephaly 24 to 26 SD 1318 722 35 60 311 273 13 333 45 80

3 = Congenital and postnatal microcephaly 118 57 05 0 311 273 03 0 05 0

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Table 2 Clinical and neuroimaging features related to the FOXG1 genotype groups (continued)

N-terminaldomain variants

Forkhead domain frameshiftand nonsense variants

Forkhead domainmissense variants

C-terminal domainvariants Large deletions

Motor and speech development

Social interactions (eye contact and smiling intentionally) 1015 667 33 100 811 727 33 100 35 60

Sit with support 619 316 26 40 712 583 23 667 15 20

Walked independently 019 0 06 0 112 83 23 667 05 0

Hand use 1019 526 35 60 412 333 13 333 15 20

Speech (at least bisyllabisms) 117 59 06 0 112 83 13 333 05 0

Sleep and behavior disturbances

Inappropriate laughingcryingscreaming spells 915 60 35 60 712 583 33 100 25 40

Impaired sleep pattern 1118 611 45 80 611 545 23 667 45 80

Feeding difficulties 1319 684 36 50 912 75 23 667 55 100

First concern and disease course

Median age at first concerns (mo)n 37 18 35 6 3 11 6 3 0 5

What were the first concerns

Microcephaly 719 368 16 50 412 333 13 333 25 40

Strabismuspoor eye contactabnormal ocular pursuit 619 316 26 333 612 50 03 0 25 40

Developmental Delay 819 421 46 667 412 333 23 667 15 20

Corpus callosum abnormalities 018 0 06 0 112 83 03 0 25 40

Seizures 219 105 06 0 212 167 03 0 05 0

Movement disorders 219 105 06 0 212 167 13 333 15 20

A period of regression 319 158 25 40 212 167 23 667 15 20

Clinical examination

Dysmorphic features 818 444 25 40 311 273 13 333 15 20

Axial hypotonia 1819 947 56 833 1111 100 33 100 55 100

Hypertoniaspasticity 1319 684 56 833 812 667 13 333 35 60

Continued

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Table 2 Clinical and neuroimaging features related to the FOXG1 genotype groups (continued)

N-terminaldomain variants

Forkhead domain frameshiftand nonsense variants

Forkhead domainmissense variants

C-terminal domainvariants Large deletions

Movement disorders 1919 100 66 100 1212 100 33 100 55 100

Stereotypic movements 1519 789 34 75 812 636 33 100 55 100

Strabismus 1618 889 44 100 1012 818 33 100 55 100

Scoliosis 519 263 15 20 111 91 13 333 15 20

Epilepsy

Seizure occurrence 1519 789 56 80 912 75 23 667 45 80

Median age at seizure onset (y) 1 14 1 5 13

Severity of epilepsy

0 = No seizures 419 21 16 167 312 25 13 333 15 20

1 = Seizure onset gt2 y and seizure free after withdrawal AE 215 133 15 167 19 111 02 0 04 0

2 = Seizure onset gt2 y and seizure free with AE 215 133 25 40 29 222 02 0 14 25

3 = Seizure onset lt2 y and continuing seizures with AE 615 40 25 40 39 333 12 50 14 25

4 = Severe infantile spasms or seizure onset lt6 mo 515 333 05 0 39 333 12 50 24 50

MRI pattern

Median age at examination (y) 34 23 56 79 395

Cortical anomalies

Normal or mild SIMP gyral pattern 819 417 25 40 511 455 23 667 45 80

Moderate SIMP gyral pattern 519 263 25 40 211 182 13 333 15 20

Severe and pseudopachygyric cortex 619 316 15 20 411 364 03 0 05 0

Cortical atrophy 1219 632 34 75 711 636 13 333 25 20

Myelination delay

Absent to mild myelination delay 619 316 24 50 310 30 23 667 25 40

Moderate myelination delay 219 105 14 25 510 50 13 333 35 60

Severe myelination delay or white matter loss 1119 579 14 25 210 20 03 0 05 0

Continued

12Neu

rologyG

enetics

|Volu

me4N

umber

6|

Decem

ber

2018NeurologyorgN

G

noticeable changes in brain size and mental development earlyin childhood To date FOXG1 has been linked to a wide rangeof human congenital brain disorders1ndash717ndash19 In this study wedescribe detailed clinical and neuroradiological data on 45patients with pathogenic single nucleotide variants and copynumber variations affecting FOXG1 This is one of the largestcohort of patients with FOXG1 syndrome and focuses onFOXG1 point mutations which affect both sexes equally Theaim of this study was to refine the phenotypic spectrum ofFOXG1 syndrome and its natural history and to further in-vestigate genotype-phenotype correlations In keeping withpreviously published FOXG1-associated clinical features wefound FOXG1 syndrome to be associated with severe postnatalmicrocephaly (minus4 to minus6 SD) dyskinetic-hyperkinetic movementdisorders visual impairment epilepsy stereotypies abnormalsleep patterns and unexplained episodes of crying135ndash81820ndash23

Our data clearly confirm that head circumference is usuallynormal to borderline small at birth and evolves during infancyto severe microcephaly below minus3 SD with normal somaticgrowth Although no longitudinal data on head circumferenceare available from our series it is interesting to note thatmicrocephaly was the first concern in one-third of the cohortat the mean age of 347 months suggesting that the slowdownin head growth occurs earlier than previously described Ofnote FOXG1-related postnatal microcephaly is characterizedby underdevelopment of the frontal lobes a unique patternthat does not occur in other causes of progressive micro-cephaly24 This underdevelopment of frontal lobes can beassociated with a mildly to moderately simplified gyral patternand reduced white matter or in the youngest patients witha pachygyric appearance We observed this pattern on T2-weighted images in infants who showed mild gyral simplifi-cation later in childhood The clue to the cause of the 2patterns came from studying serial MRI of patients Im09 andIm11 Frontal pachygyria which was observed at 6 months ofage changed into mild gyral simplification at 25 years of ageThis finding suggested that the 2 cortical patterns did notrepresent differences of morphology but instead differencesin the maturity of the subcortical white matter It is note-worthy that this changing appearance has been observedpreviously in polymicrogyria2526

Another imaging hallmark of FOXG1 disorder is the delayedmyelination While delayed myelination has a similar ap-pearance to hypomyelination on a single MRI especially ifdone at an early age sequential studies can distinguish be-tween them by demonstrating increasing myelin content indelayed myelination27 This evolution of delayed myelinationtoward normalization in childhood is not specific to FOXG1syndrome as it has been observed in other developmentaldisorders such as MCT8 deficiency and Xq28 duplicationinvolving MECP2 or SPTAN1 encephalopathy27ndash29

Taken together with the published literature we suggest thatFOXG1 syndrome is a disorder in which hypogenetic corpuscallosum is the most frequent finding More specifically corpusTa

ble

2Clin

ical

andneu

roim

agingfeaturesrelatedto

theFO

XG1ge

notypegroups(con

tinue

d)

N-term

inal

domain

variants

Fork

headdomain

framesh

ift

andnonse

nse

variants

Fork

headdomain

misse

nse

variants

C-term

inaldomain

variants

Larg

edeletions

Corp

usca

llosu

masp

ect

Norm

al

119

53

06

0011

023

667

05

0

Hyp

oplasicbutco

mplete

319

158

26

333

311

2730

13

333

35

60

Hyp

oge

neticwithabse

ntro

stru

m10

19

526

26

333

611

545

03

015

20

Partialo

rco

mplete

age

nesis

519

263

26

333

211

182

03

015

20

Cere

bellaratrophy

319

158

05

0111

91

03

015

20

Abbreviations

AE=an

tiep

ilepticdru

gCC=co

rpusca

llosu

mS

E=statusep

ilepticu

sSIMP=simplifiedgy

ration

NeurologyorgNG Neurology Genetics | Volume 4 Number 6 | December 2018 13

callosum malformations in FOXG1 syndrome are frontal pre-dominant similar to the gyral abnormality suggesting that thesame pathogenic mechanism operates for both the frontalcortical abnormalities and the callosal abnormalities Completeagenesis occurs occasionally and is likely to represent the mostsevere end of the spectrum of pathogenic mechanisms un-derlying hypoplasia This also illustrates that hypoplasia andagenesis are related to a similar mechanism and that geneticmodifiers influence the severity of the callosal phenotype30 Ofinterest the severity of corpus callosum anomaly does notcorrelate with the degree of microcephaly the degree of mye-lination abnormality or the degree of gyral abnormalities Thiscontrasts with data from congenital microcephaly that showeda correlation between the degree of microcephaly and the se-verity of the associated callosal anomaly31

Hyperkinetic movement disorders have been recognized to bea key feature in FOXG1 syndrome since its originaldescription618 Our data show that movement disorder israrely the presenting feature of FOXG1 syndrome this hasnot been stressed previously It is important that the combi-nation of hand stereotypes mostly hand to mouth withgeneralized dyskinesia is one of the key characteristics ofFOXG1 syndrome that distinguishes it from other monogenichyperkinetic movement disorders or neurodegenerativediseases632 The hyperkinetic movement disorder althoughaffecting quality of life was stable over time never evolvedinto status dystonicus and did not lead to any of the com-plications of severe dystonia that can observed in other de-velopmental or degenerative neurologic disorders632

A previous report suggested that FOXG1 syndrome could beclassified as an epileptic-dyskinetic encephalopathy18 likeARX- and STXBP1-related encephalopathies Our data showthat epilepsy is not a consistent feature unlike dyskinetic-hyperkinetic movements Although epilepsy affected 79 ofpatients reported here which is within the range of previousreports (from 577 to 865) it did not show a particularseizure pattern that could help the clinician to define a specificepilepsy syndrome

Since the first report that FOXG1 mutations can be re-sponsible for congenital Rett variant a number of publicationshave emphasized the differences between these disorders33

Here by applying the congenital Rett variant criteria14 weconfirm that the majority of patients with the FOXG1 syn-drome do not meet the criteria for congenital Rett variant Atall ages FOXG1 syndrome is more severe with respect toambulation reciprocity and receptive language and has moredisordered sleep compared with Rett syndrome as well aslacking the regression observed in Rett syndrome Thesefindings further reinforce that FOXG1 disorder is clinicallyseparable from Rett syndrome with distinct clinical pre-sentation and natural history It is important that patients withFOXG1 disorder receive appropriate counseling about med-ical comorbidities and natural history related to their disorderavoiding the confusion with Rett syndrome

The number of reported FOXG1 mutations is now largeenough to search for genotype-phenotype correlations inFOXG1 syndrome We observed that patients carrying muta-tions in the N-terminal domain and large deletion of FOXG1which are the most common mutation types show the mostsevere presentation and MRI anomalies while those carryingmutations in the FBD or C-terminal domain were less severelyaffected In previous series a milder phenotype was observed inpatients with missense variants in the FBD conserved site7

However the differences were found in items related to sittingwalking and functional hand use which are commonly severelyimpaired in all FOXG1mutation patients7 Using covarianceand cluster analyses we highlighted relationships betweengyral and myelination patterns in patients with FOXG1disorder However identical hotspot mutations c256dupCand c406dupG can be associated with highly variable fea-tures such as variable epilepsy severity or degree of corpuscallosum anomalies underlining the importance of being cau-tious about predicting phenotype on the basis of genotype in thecontext of genetic counseling This suggests that factors beyondthe primary mutation can influence disease severity includinggenetic modifiers and epigenetic and environmental factors

The complexity and the poor reproducibility of genotype-phenotype relationships in FOXG1 syndrome probably reflectsthe pleiotropic and nonredundant roles of Foxg1 in vertebratebrain development

This study one of the largest to date provides evidence thatFOXG1 mutations are responsible for a specific and recogniz-able neurodevelopmental disorder with a high degree of vari-abilityWe have expanded the phenotypic spectrumby defining3 key brain imaging features of FOXG1 syndrome noting thatthe degree of cortical abnormality is not correlated with theseverity of the corpus callosum malformation Moreover ourdata confirm that mutations leading to the loss of the FBDdomain lead to themost severe clinical presentation of FOXG1syndrome The pathophysiology of such complex genotype-phenotype relationships reflects the pleiotropic and non-redundant roles of Foxg1 during development

AffiliationFrom the Imagine Institute (NV MC C Maillard ABNB-B) INSERM UMR 1163 Paris Descartes UniversityNecker Enfants Malades Hospital Paris France PediatricNeurology APHPmdashNecker Enfants Malades Hospital (MCMH NB-B) Paris France Pediatric Radiology (NB)APHPmdashNecker Enfants Malades Hospital Paris FranceImagemdashImagine Institute (NB) INSERMUMR 1163 ParisDescartes University Necker EnfantsMalades Hospital ParisFrance Department of Paediatric Clinical Epileptology (JT)Sleep Disorders and Functional Neurology University Hos-pitals of Lyon (HCL) France Service de Genetique medicale(ES) Hopitaux Universitaires de Strasbourg IGMA FrancePediatric Neurology (TL-S) Wolfson Medical Center TelAviv Israel Wolfson Molecular Genetics Laboratory (DL)Wolfson Medical Center Tel Aviv Israel Neurometabolism

14 Neurology Genetics | Volume 4 Number 6 | December 2018 NeurologyorgNG

Department (BM) Angers Hospital and University FranceCentre de Genetique et Centre de Reference Maladies RaresAnomalies du Developpement (SM AM) CHU DijonFrance South Australian Clinical Genetics Service (EH)SA Pathology (at Royal Adelaide Hospital) and School ofMedicine University of Adelaide Australia Service deGenetique Medicale (BI MN MV BC) CHU NantesFrance Departement de Genetique et Centre de ReferenceDeficiences Intellectuelles de Causes Rares (DH C Mignot)Hopital de la Pitie-Salpetriere APHP Paris France GMGF(MM) INSERM UMR_S910 Aix-Marseille University Pe-diatric Neurology Unit Timone Children Hospital MarseilleFrance Department of Neonatal Medicine (SR) RouenUniversity Hospital Haute-Normandie France DepartmentofMedical Genetics (CMichot) Reference Center for SkeletalDysplasia INSERM UMR 1163 Laboratory of Molecular andPhysiopathological Bases of Osteochondrodysplasia ParisDescartes-Sorbonne Paris Cite University AP-HP InstitutImagine and Hopital Universitaire Necker-Enfants MaladesParis France APHP (SV) GHUEP Hopital TrousseauNeurologie Pediatrique Paris France GRC ConCer-LD(SV) Sorbonne Universites UPMCUniv 06 Paris FranceHopital Nord Franche Comte (SW) CH HNFCmdashSite deBelfort France Pediatrics (AD) University of Basel Child-rensrsquo Hospital Switzerland CHU Rennes (SO) Service deGenetique Clinique CNRS UMR6290 Universite Rennes1France Service de Pediatrie (LL) Centre Hospitalier dela Cote Basque Bayonne France Department of Genetics(GAM) Rouen University Hospital France Service deGenetique (AS) Hopital Bretonneau Tours France Servicede Neurologie Pediatrique (JMP) Hopital Pellegrin-EnfantsCHU de Bordeaux France Pediatrie generale (IC) Hopitalde Lorient France Genetique MedicalemdashCHU EstaingCLERMONT-FERRAND (BP BT) France Service deNeurologie Pediatrique (FR) Hopital Gui de ChauliacCHRU de Montpellier France Equipe Genetique desAnomalies du Developpement (CP) INSERM UMR1231Universite de Bourgogne-Franche Comte Dijon FranceLaboratoire de Genetique chromosomique moleculaire(CP) Plateau technique de Biologie CHU Dijon FranceLaboratory of Biochemistry and Molecular Genetics (TB)HUPC Paris Centre Cochin Hospital Paris France NationalRare Disease CentermdashCentre de Reference ldquodeficiences intel-lectuelles de causes raresrdquo (M-AS) Strasbourg UniversityHospital France and National Rare Disease CentermdashCentrede Reference ldquodeficiences intellectuelles de causes raresrdquo(NB-B) AP-HP Necker Enfants Malades Paris France

Author contributionsN Vegas M Cavallin C Maillard study concept and designanalysis and acquisition of clinical and molecular data NBoddaert analysis and acquisition of MRI data J Toulouse ESchaefer T Lerman-Sagie D Lev B Magalie S MouttonE Haan B Isidor D Heron M Milh S Rondeau C MichotS Valence S Wagner M Hully C Mignot A Masurel ADatta S Odent M Nizon L Lazaro M Vincent B Cogne

GA Marie A Stephanie JM Pedespan I Caubel B PontierB Troude F Rivier M-A Spitz acquisition of data andfollow-up of the patients C Philippe and T Bienvenuanalysis molecular data A Bery and N Bahi-Buisson studysupervision concept and critical revision of manuscript forintellectual content

AcknowledgmentThe authors would like to thank the affected individuals andtheir families for participation in this study as well as theclinicians in charge of these patients who may not be citedThe authors would like to sincerely thank Prof AlessandraPierani for her critical reading of the manuscript and helpfulcomments on our findings

Study fundingResearch reported in this publication was supported by theAgence Nationale de la Recherche (ANR-16-CE16-0011 MCAB NBB) the Fondation Maladies Rares and DESIRE (grantagreement 602531) The project was also supported by theEuropean Network on Brain Malformations (COST ActionCA16118) The authors have no conflict of interest to declare

DisclosureN Vegas M Cavallin C Maillard N Boddaert J ToulouseE Schaefer report no disclosures T Lerman-Sagie has servedon the editorial boards of the Journal of Child NeurologyHarefuah and the European Journal of Paediatric Neurology DLev has received research support from the Sackler School ofMedicine (Tel Aviv University) M Barth and S Mouttonreport no disclosures E Haan has received research supportfrom the Lipedema Foundation (USA) B Isidor and DHeron report no disclosures M Milh has received speakerhonoraria from Shire and Cyberonics S Rondeau C MichotS Valence S Wagner M Hully C Mignot A Masurel ADatta S Odent M Nizon L Lazaro M Vincent B CogneAM Guerrot S Arpin JM Pedespan I Caubel B PontierB Troude F Rivier C Philippe T BienvenuM Spitz and ABery report no disclosures N Bahi-Buisson has received re-search support from Agence Nationale de la rechercheFondation pour la Recherche Medicale Fondation NRJmdashInstitut de France and the EU-FP7 project GENECODYSFull disclosure form information provided by the authors isavailable with the full text of this article at NeurologyorgNG

Received March 24 2018 Accepted in final form July 12 2018

References1 Ariani F Hayek G Rondinella D et al FOXG1 is responsible for the congenital

variant of Rett syndrome Am J Hum Genet 20088389ndash932 Mencarelli MA Spanhol-Rosseto A Artuso R et al Novel FOXG1 mutations asso-

ciated with the congenital variant of Rett syndrome J Med Genet 20104749ndash533 Kortum F Das S Flindt M et al The core FOXG1 syndrome phenotype consists of

postnatal microcephaly severe mental retardation absent language dyskinesia andcorpus callosum hypogenesis J Med Genet 201148396ndash406

4 Ellaway CJ Ho G Bettella E et al 14q12 Microdeletions excluding FOXG1 give riseto a congenital variant Rett syndrome-like phenotype Eur J Hum Genet 201321522ndash527

5 Seltzer LE MaM Ahmed S et al Epilepsy and outcome in FOXG1-related disordersEpilepsia 2014551292ndash1300

6 Papandreou A Schneider RB Augustine EF et al Delineation of the movementdisorders associated with FOXG1 mutations Neurology 2016861794ndash1800

NeurologyorgNG Neurology Genetics | Volume 4 Number 6 | December 2018 15

7 Mitter D Pringsheim M Kaulisch M et al FOXG1 syndrome genotype-phenotypeassociation in 83 patients with FOXG1 variants Genet Med 20182098ndash108

8 Bahi-Buisson N Nectoux J Girard B et al Revisiting the phenotype associated withFOXG1 mutations two novel cases of congenital Rett variant Neurogenetics 201011241ndash249

9 Kumamoto T Hanashima C Evolutionary conservation and conversion of Foxg1function in brain development Dev Growth Differ 201759258ndash269

10 Krishnaraj R Ho G Christodoulou J RettBASE Rett syndrome database updateHum Mutat 201738922ndash931

11 Le Guen T Bahi-Buisson N Nectoux J et al A FOXG1 mutation in a boy withcongenital variant of Rett syndrome Neurogenetics 2011121ndash8

12 Diebold B Delepine C Nectoux J Bahi-Buisson N Parent P Bienvenu T Somaticmosaicism for a FOXG1mutation diagnostic implication ClinGenet 201485589ndash591

13 Sanger TD Chen D Fehlings DL et al Definition and classification of hyperkineticmovements in childhood Mov Disord 2010251538ndash1549

14 Neul JL Kaufmann WE Glaze DG et al Rett syndrome revised diagnostic criteriaand nomenclature Ann Neurol 201068944ndash950

15 Adachi Y Poduri A Kawaguch A et al Congenital microcephaly with a simplifiedgyral pattern associated findings and their significance AJNR Am J Neuroradiol2011321123ndash1129

16 Xuan S Baptista CA Balas G Tao W Soares VC Lai E Winged helix transcriptionfactor BF-1 is essential for the development of the cerebral hemispheres Neuron1995141141ndash1152

17 Striano P Paravidino R Sicca F et al West syndrome associated with 14q12 dupli-cations harboring FOXG1 Neurology 2011761600ndash1602

18 Cellini E Vignoli A Pisano T et al The hyperkinetic movement disorder of FOXG1-related epileptic-dyskinetic encephalopathy Dev Med Child Neurol 20165893ndash97

19 Mariani J Coppola G Zhang P et al FOXG1-dependent dysregulation of GABAglutamate neuron differentiation in autism spectrum disorders Cell 2015162375ndash390

20 De Bruyn C Vanderhasselt T Tanyalcin I et al Thin genu of the corpus callosumpoints to mutation in FOXG1 in a child with acquired microcephaly trigonocephalyand intellectual developmental disorder a case report and review of literature Eur JPaediatr Neurol 201418420ndash426

21 De Filippis R Pancrazi L Bjorgo K et al Expanding the phenotype associated withFOXG1mutations and in vivo FoxG1 chromatin-binding dynamics Clin Genet 201282395ndash403

22 Florian C Bahi-Buisson N Bienvenu T FOXG1-Related disorders from clinicaldescription to molecular genetics Mol Syndromol 20122153ndash163

23 Van der Aa N Van den Bergh M Ponomarenko N Verstraete L Ceulemans B StormK Analysis of FOXG1 is highly recommended in male and female patients with Rettsyndrome Mol Syndromol 20111290ndash293

24 Seltzer LE Paciorkowski AR Genetic disorders associated with postnatal micro-cephaly Am J Med Genet C Semin Med Genet 2014166C140ndash155

25 Takanashi J Barkovich AJ The changing MR imaging appearance of polymicrogyriaa consequence of myelination AJNR Am J Neuroradiol 200324788ndash793

26 Bahi-Buisson N Poirier K Boddaert N et al GPR56-related bilateral frontoparietalpolymicrogyria further evidence for an overlap with the cobblestone complex Brain20101333194ndash3209

27 van der Knaap MS Wolf NI Hypomyelination versus delayed myelination AnnNeurol 201068115

28 El Chehadeh S Faivre L Mosca-Boidron AL et al Large national series of patientswith Xq28 duplication involving MECP2 delineation of brain MRI abnormalities in30 affected patients Am J Med Genet A 2016170A116ndash129

29 Syrbe S Harms FL Parrini E et al Delineating SPTAN1 associated phenotypes fromisolated epilepsy to encephalopathy with progressive brain atrophy Brain 20171402322ndash2336

30 Edwards TJ Sherr EH Barkovich AJ Richards LJ Clinical genetic and imagingfindings identify new causes for corpus callosum development syndromes Brain 20141371579ndash1613

31 Barkovich AJ Kjos BO Normal postnatal development of the corpus callosum asdemonstrated by MR imaging AJNR Am J Neuroradiol 19889487ndash491

32 Carecchio M Mencacci NE Emerging monogenic complex hyperkinetic disordersCurr Neurol Neurosci Rep 20171797

33 Ma M Adams HR Seltzer LE Dobyns WB Paciorkowski AR Phenotype differen-tiation of FOXG1 and MECP2 disorders a new method for characterization ofdevelopmental encephalopathies J Pediatr 2016178233ndash240 e210

16 Neurology Genetics | Volume 4 Number 6 | December 2018 NeurologyorgNG

DOI 101212NXG000000000000028120184 Neurol Genet

Nancy Vegas Mara Cavallin Camille Maillard et al encephalopathy

syndrome From congenital microcephaly to hyperkineticFOXG1Delineating

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