neurogenetics

, Volume 11, Issue 2, pp 241–249

Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant

  • Nadia Bahi-Buisson
  • Juliette Nectoux
  • Benoit Girard
  • Hilde Van Esch
  • Thomy De Ravel
  • Nathalie Boddaert
  • Perrine Plouin
  • Marlene Rio
  • Yann Fichou
  • Jamel Chelly
  • Thierry Bienvenu
ORIGINAL ARTICLE

DOI: 10.1007/s10048-009-0220-2

Cite this article as:
Bahi-Buisson, N., Nectoux, J., Girard, B. et al. Neurogenetics (2010) 11: 241. doi:10.1007/s10048-009-0220-2

Abstract

The Forkhead box G1 (FOXG1) is a transcription factor that is critical for forebrain development, where it promotes progenitor proliferation and suppresses premature neurogenesis. Recently, the FOXG1 gene was implicated in the molecular aetiology of the congenital variant of Rett syndrome. So far, 15 FOXG1 molecular alterations, including only eight point mutations, have been reported. We screened the FOXG1 gene in a cohort of 206 MECP2 and CDKL5 mutation negative patients (136 females and 70 males) with severe encephalopathy and microcephaly. The screening was negative in all males, but two de novo mutations (c.1248C>G, p.Y416X and c.460_461dupG, p.E154GfsX300) were identified in two unrelated girls. Both patients showed neurological symptoms from the neonatal period with poor reactivity, hypotonia, and severe microcephaly. During the first year of life, both patients had feeding difficulties and made slow developmental progress. At 5 years old, the girls were significantly neurologically impaired with gross hypotonia, no language, convergent strabismus, and no voluntary hand use. Moreover, they presented a combination of jerky movements, hand-mouthing, and hand-washing stereotypies. Hence, FOXG1 mutation patients demonstrate severe encephalopathy compatible with the congenital variant, as well as additional features such as absent eye contact, inconsolable crying during the perinatal period, and delayed myelination with thin to hypoplastic corpus callosum. Although the overall frequency of mutations in FOXG1 in females with severe mental retardation and microcephaly appears to be low (1.5%), our findings suggest the requirement to investigate both point mutations and gene dosage in the FOXG1 gene in patients with severe encephalopathy with microcephaly and some Rett-like features.

Keywords

Rett syndrome Congenital variant Encephalopathy FOXG1 

Introduction

In 2005, Shoichet et al. reported a 7-year-old girl exhibiting severe cognitive disability associated with complete agenesis of the corpus callosum and microcephaly with a balanced de novo translocation t(2;14)(p22;q12) that disrupts the Forkhead box G1 (FOXG1) gene [1]. Later, three 14q12 interstitial deletion (3.1, 2.9, and 3.6 Mb) including FOXG1 (MIM 164874) were identified and characterised in two girls with psychomotor retardation, epilepsy, microcephaly, and unusual facial features and in a 10-month-old male patient with mental retardation, microcephaly, and facial dysmorphism, respectively [2, 3, 4]. The importance of the FOXG1 gene was reinforced in a recent publication by linking FOXG1-null mutations and the congenital variant of Rett syndrome (RTT) in two unrelated girls [5]. The congenital variant is one of the five subgroups of atypical RTT, and although up to 95% of classical RTT and 40–50% of atypical RTT are caused by mutations in the Methyl-CpG binding protein 2 (MECP2) gene, only four girls described as congenital variants have been reported as mutated in this gene [6, 7, 8].

As we did not find any mutations in the MECP2 gene in a cohort of patients with Rett-like features compatible with the diagnosis of the congenital variant, the aim of our study was to test these individuals for mutations in the FOXG1 gene. In addition, we aimed to refine the spectrum of these Rett variant patients. Here, we describe two novel pathogenic mutations in the FOXG1 gene and review the clinical features of the patients published to date to refine the spectrum of these FOXG1-related disorders.

Patients and methods

Patients

As part of the Rettsearch program (SYRENE program), 206 patients with a clinical diagnosis of severe congenital encephalopathy with microcephaly were selected for the study. This cohort included 136 girls and 70 boys from Caucasian or North-African origin. In all selected individuals, neither point mutations nor large rearrangements in the MECP2 and CDKL5 genes had been previously identified. Methylation studies for Angelman syndrome and chromosome analysis were also normal.

DNA mutation analysis

DNA was extracted from peripheral blood using standard methods. All blood samples were obtained after provision of informed consent. DNA samples were screened for mutations in FOXG1 using polymerase chain reaction (PCR) amplification and direct sequencing. Primer sequences and PCR conditions are available upon request to the corresponding author. Sequencing reactions were carried out with the BigDye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems, Courtaboeuf, France) and loaded on the ABI 3100 genetic analyser (PE Applied Biosystems, Foster city, CA, USA). Detection of large rearrangements of the FOXG1 gene was carried out by quantitative real-time PCR with the SYBR Green PCR Master Mix (Applied Biosystems) according to the manufacturer’s instructions. Primers were designed with Primer Express software and are available upon request to the corresponding author. After PCR amplification, purity of products was determined by a melting-curve analysis. Reactions with melting-curves indicating a single amplification product were considered positive for further analysis. The identity and size of the single PCR product were also confirmed by agarose gel electrophoresis. For each cycle, a relative quantification of the amount of each individual gene was calculated by the ΔCt method as described by the manufacturer, providing a relative measure of FOXG1 copy number, which was normalised with the albumin gene as the calibrator sample on an ABI Prism 7000 sequence detection system.

Results

The whole coding sequence of the FOXG1 gene was screened for mutations and/or polymorphisms by direct sequencing in the 206 patients with severe encephalopathy and microcephaly. All males tested were negative. No large rearrangements in the coding region of the FOXG1 gene have been identified by quantitative real-time PCR. The analysis revealed the presence of two novel mutations in two unrelated affected girls (Fig. 1), which were observed neither in their parents nor in more than 200 normal chromosomes 14. Both mutations disrupt the protein at different levels. In case 1, a stop codon mutation p.Y416X (c.1248C>G) affects the C-terminal part of the FOXG1 protein but maintains the three known functional domains (Forkhead binding, Groucho binding, and JARID1B-interacting domains). Conversely, case 2 showed a 1-bp duplication (c.460_461dupG, p.E154GfsX300) resulting in the loss of these three domains.
Fig. 1

Mutations identified in the FOXG1 gene in two patients with severe encephalopathy and microcephaly (patients 1 and 2). The arrows indicate the position of the mutation

Clinical description of case 1

Case 1 is a French female who was born by spontaneous delivery after uneventful pregnancy of unrelated parents. She has a healthy brother. Her birth weight was 3,230 g (median M), her height was 51 cm (+1 SD), and her head circumference (occipital-frontal circumference (OFC)) was 34 cm (−1 SD). The neonatal period was apparently normal. At 2 months of age, she presented with feeding difficulties, excessive crying, and poor eye contact. On examination, she had a convergent strabismus, axial hypotonia, and evidence of deceleration of head growth. Subsequently, microcephaly became evident with OFC measured at 40 cm at 9 months (−3 SD), at 43 cm at 2 years (−4 SD), and 44 cm at 5 years (−4 SD).

Seizures started at 4 months of age with generalised tonic seizures followed by spontaneous and reflex audiogenic myoclonic seizures. These myoclonia affected mainly upper limbs or were more generalised with repeated axial anteflexion and elevation of upper limbs. Interictal electroencephalogram (EEG) showed slow background activity but no epileptiform discharges (Fig. 2a, b). At 2 years old, she became seizure-free on a combination of sodium valproate and clonazepam.
Fig. 2

a Interictal electroencephalogram (EEG) showed slow background activity—theta rhythmic activity—without physiological developmental features but no epileptiform discharges. b EEG recording of axial myoclonia on electromyogram (arrow), with simultaneous discharges of high amplitudes of spikes and slow waves. Age, 2 years old; amplitude, 10 μV/mm; speed, 15 mm/s

Significant developmental delay was apparent from 6 months old and, in addition, she developed a hyperkinetic movement disorder with intermixed erratic myoclonia. At 1 year old, she had hand stereotypies with hand-to-mouth, midline stereotypies, and intermittent teeth grinding. Video EEG performed at 2 years old recorded abnormal dyskinetic and non-epileptic movement disorder (see video in Supplemental data 1). Because of feeding difficulties and severe gastro-oesophageal reflux, she was predominantly gastrostomy fed. She also had recurrent chest infections. At 3 years old, her eye contact had improved and she was babbling. At 4 years old, she was able to hold her head. She never developed intentional hand use. At re-evaluation at 5 years old, the patient weighed 17 kg (−1 SD), her height was 106 cm (−1 SD), and her head circumference was 44 cm (−4 SD). She was visually alert, seeking to make eye contact, and had smooth ocular pursuit. She had severe generalised hypotonia with poor head control and severe thoracic kyphoscoliosis and limb hyperextensibility. She had a prominent dyskinetic movement disorder with erratic and massive myoclonias, hand stereotypies, and tongue protrusion. Extremities were cold and hypotrophic. No spasticity was found. She had severe constipation with intrabdominal gas. Her respiratory pattern was normal. Neither sleep disturbances nor excessive crying or laughing was reported. Additional examination including computed tomography (CT) scan, ophthalmological and hearing testing, routine blood analysis, and metabolic testing were normal. Brain magnetic resonance imaging (MRI) performed at 22 months of age showed significant delayed myelination with thin corpus callosum combined with frontal and temporal atrophy with gyral simplification (Fig. 3a–d).
Fig. 3

Comparison of brain magnetic resonance imaging (MRI) features in FOXG1 mutation patients; patient 1 (ad), investigated at 22 months old by MRI, shows significant delayed myelination, severe atrophy that predominates in both frontal lobes (cd), with simplified gyration, atrophy of both temporal poles (b), and thin corpus callosum on sagittal section (a); patient 2 (eh) investigated at 5 years old shows delayed myelination with white matter hyperintensity in periventricular zones (g), normal corpus callosum (e), and normal gyral pattern without atrophy (f, h); patient 3 (il) investigated at 22 months old by MRI shows a more severe pattern with severe frontal atrophy and simplified gyral pattern, combined with ventricular dilatation and delayed myelination. Control (mp)

Clinical description of case 2

Case 2 is the first child of unrelated parents. Pregnancy and delivery at 39.5 weeks were uneventful with Apgar scores of 9 and 10 at 1 and 5 min, respectively. Her birth weight was 3,270 g (M), her height was 51 cm (+1 SD), and her head circumference was 31.7 cm (less than −2 SD). Between 3 and 6 months old, severe developmental delay became apparent with marked axial hypotonia and mild spasticity of all four limbs with hand fisting. She was however visually alert and responsive. Bayley Scales of Infant Development II carried out at 12 months old indicated a score below 55, equivalent to a 7-month-old developmental age. By the age of 3 years and 10 months, she had obvious repetitive hand movements, pill-rolling, involuntary movements, and grimacing. When last examined at the age of 5 years and 10 months, her height was 104 cm (−2 SD), her weight was 14.5 kg (−2 SD), and her head size was 45 cm (−3 SD). She maintained good eye contact, was friendly, and appeared keen on communicating but had inappropriate laughing. She had an alternating convergent strabismus. Peripheral spasticity was noted with small, blue, and cold feet. She was continually fiddling with her hands, displaying thumb adduction, and unpurposefully grasping objects. Feeding with solids has remained an issue.

Brain imaging comprising CT scan and two MRI performed at 7 months and at 5 years old showed mildly delayed myelination (Fig. 3e–h).

Discussion

This study describes the characterization of novel FOXG1 mutations in two unrelated girls with severe congenital encephalopathy accounting for a total number of ten published point mutations and 15 cases with FOXG1 molecular abnormalities (including translocation and large deletions) [1, 2, 3, 4, 5, 9, 10, 11]. Our data both confirm and expand the phenotype of FOXG1-associated encephalopathy. These observations, taken together with the previously reported cases, suggest that FOXG1 mutations are responsible for a wide range of clinical features that are reminiscent of the congenital variant of RTT.

The two girls reported here, combined with a third patient [10], but re-evaluated at 3 years old with FOXG1 point mutations, have a similar course of severe congenital encephalopathy with very limited cognitive and motor development combined with Rett-like features including microcephaly, hand apraxia, generalised hypotonia, scoliosis, feeding difficulties, and hand stereotypies. Up to now, clinical evidences suggest that these patients share several common specific features (Table 1).
Table 1

Rett variant criteria of the two cases reported in this paper and a third re-evaluated case [10] (according to Hagberg and Skjeldal) with FOXG1 mutations

 

Patient 1

Patient 2

Patient 3

Basic inclusion (A criteria)

A1 Loss of acquired finger skill

Never acquired

Never acquired

Never acquired

A2 Loss of words/nuanced babble

Never acquired

Never acquired

Never acquired

A3 RS hand stereotypies +

Present

Present

No

A4 Early deviant communication + (improved)

No

No

No

A5 Deceleration of OFC +

Present

Present (congenital microcephaly)

Present (congenital microcephaly)

A6 The RS disease profile +

No

No

No

Rett variant supportive manifestations (B criteria)

B1 Episodic hyperventilation/breath holding +

No

No

No

B2 Bloating/marked air swallowing

Yes

No

Yes

B3 RS type tooth grinding

Present

Present

Present

B4 Gait dyspraxia

Non-testable

Non-testable

Non-testable

B5 Neurogenic scoliosis

Present

Present

Present

B6 Abnormal appearing lower limb signs (dystonic toes)

Absent

Absent

Absent

B7 Impaired feet: small/blue/very cold

Present

Present

Present

B8 RS EEG abnormalities/pattern

No

No

No

B9 Inappropriate laughing/screaming

Present

Inappropriate laughing only

Inappropriate screaming

B10 Impaired/delayed nociperception

Present

Present

Present

B11 Intense eye “pointing”

Eye contact

Eye contact, smiling, and attention seeking

Absent

According to this model, a girl with mental retardation of unexplained origin and with at least 3/6 primary criteria and, in addition, at least 5/11 supportive manifestations meets the criteria of atypical Rett. The three girls fulfil at least one of the six primary criteria and, respectively, 7, 6, and 6 of the 11 supporting B criteria [15, 16]

Combining the clinical data of the ten patients with FOXG1 point mutations [2] and those with 14q12 deletion and translocation reported in the literature (one translocation and three deletions) [1, 3, 4], the most consistent features are severe presentation excluding the classic period of regression of typical RTT patients after a period of normal development, very limited motor development, congenital microcephaly (or early onset deceleration of head growth progressively resulting in absolute microcephaly before 4 months old), relative preservation of eye contact though not as intense eye gaze as the eye pointing of classical RTT, and no language (if any, limited to babbling). They also demonstrate features of autonomic origin, such as hypotrophic extremities and abdominal bloating, but no breathing disturbances [1, 2, 3, 4, 5].

More specifically, the ten patients with FOXG1-point mutations show intense hyperkinetic movement disorders with polymorphic midline stereotypies and jerky-like movements that represent myoclonia. The pattern of these stereotypies, however, differs from those of classic RTT with no hair-pulling, rare hand-washing, and a predominance of hand-pulling and pill-rolling [5, 12]. Moreover, they have bruxism and repetitive protrusive tongue movements. Another striking feature in FOXG1-related encephalopathy is the high prevalence of strabismus in these patients, which is usually not observed in other RTT variants.

Epilepsy is also a frequent feature with generalised tonic and myoclonic seizures, with a highly variable age of onset ranging from 4 months to 14 years. The EEG pattern does not suggest any specific epilepsy syndrome. In the great majority of cases and in contrast with CDKL5-related disorders, seizures were easily controlled by antiepileptic drugs [13, 14].

Moreover, a fine analysis of MRI data from our two FOXG1 mutation patients after 2 years old highlights myelination defects that range from delayed myelination to global hypomyelination, combined atrophy of both frontal lobes with gyral disorganisation, and a hypoplastic corpus callosum. A previous study also described that FOXG1 mutations are associated with either corpus callosum abnormalities or in few cases, poor development of frontal and parietal lobes [1].

It is of interest to note that although these features are quite homogeneous, FOXG1-related encephalopathy demonstrates variable degree of severity. Indeed, the more severely affected patient (patient 3, Table 2) carrying the c.551_552dupC mutation had congenital microcephaly, virtually no visual contact, and poor head control. Consistent with this severe phenotype, MRI performed at 22 months old showed atrophy of both frontal lobes with simplified gyral pattern and significantly delayed myelination with a development of myelin estimated at 3 months old combined with a hypoplastic corpus callosum (Fig. 3i–l). This severe form is reminiscent from two patients with an interstitial deletion within 14q12 with clinical features of tetraplegia, microcephaly, intractable seizures, and prominent stereotypies combined with dysmorphic features and on MRI corpus callosum agenesis. Unfortunately, in these latter, brain MRIs are not available to evaluate the degree of myelin maturation accurately [1, 3]. At the other end of the spectrum, the less severely affected patient (patient 2, Table 2) carrying the c.460_461dupG mutation had significant eye contact and babbling, no epilepsy, developed some purposeful hand function, and was able to take some steps with support. Consistent with this, myelination was mildly delayed in the centrum semi-ovale. Consistent with our findings, Philippe et al. recently reported a patient with a classical RTT presentation carrying the late truncating mutation p.Tyr400X [11]. Although genotype–phenotype correlation is difficult to establish with the few number of FOXG1 mutated cases, our data combined with the recent literature suggest that that the mutation does not predict the severity of the phenotype [1, 2, 3, 4, 5, 9, 10, 11]. Indeed, the patient with the p.Tyr400X presented the mildest phenotype [11], while our patient with the p.Tyr416X mutation (patient 1, Table 2) showed one of the most severe phenotype, suggesting that additional factors might contribute to the severity of the FOXG1-related disorders.
Table 2

Clinical summary of patients 1, 2, and 3 with FOXG1 mutations compared with the features of previously reported cases with FOXG1 mutations and patients with classic Rett (MECP2 mutations)

 

Classic Rett

FOXG1 Case 1 [5]

FOXG1 Case 2 [5]

FOXG1 [3]

Patient 1

Patient 2

Patient 3 Case 3 (#RTT01158) [10]

Case 1 (#1091) [10]

Case 2 (#RTT00967) [10]

Case 4 (60719368) [10]

Patient 1 [11]

Patient 2 [11]

Sex

F

F

F

F

F

F

F

F

F

F

F

F

Age (years)

Any

22

7

7

4

5.8

3

17

8.5

3 years 2 months

22 years

10 years

Normal pre- and perinatal period

Yes

Yes

Yes

Yes

Yes

Yes

Yes

N/A

Yes, inconsolable crying

Yes

Yes

Yes

Near normal early development

Yes

Yes

Yes

No

No

No

No

N/A

No

Sleepiness, cries only if hungry

Yes

Yes

Normal OFC at birth

Usually (less than −2 SD)

Yes

Yes

−1 SD

34 cm (−1 SD)

31.7 cm (−2 SD)

32.5 cm (−2 SD)

N/A

(34 cm) 50–75° cnt

(33.5 cm) 25–50° cnt

34 cm (−1 SD)

34 cm (−1 SD)

Deceleration of head growth from birth

Yes

Yes

Yes

Yes

Yes

No

Yes

N/A

Yes

Yes

Yes

Yes

Current OFC centile

Varies (usually less than third p)

49 cm (22 years)

47 cm (7 years)

45.5 cm less than third

44 cm (−4 SD)

45 cm (−3 SD)

42 cm (−4 SD)

46 cm (−6 SD)

(48 cm) −2.24 SD

(42 cm) −5 SD

N/A

48.5 cm (−2 SD)

Regression

Yes

N/A

N/A

Yes

No

No

No

6 months

6 months

3 months

4 months

6 months

Severe intellectual disability

Yes

Yes

Yes

Yes

Profound

Profound

Profound

Profound

Profound

Profound

Profound

Yes

Good eye contact

Yes

N/A

N/A

No

Yes

Yes

No

N/A

No

Yes

N/A (autistic features?)

No

Hypotonia

Yes

Yes

Yes

Yes

Yes

Yes

Yes

N/A

No (kyphosis)

Severe (kyphosis)

Yes

No

Scoliosis

Yes

Severe

Mild

Mild

Severe

No

Severe

Severe

No

No

No

No

Best motor skills

Varies

Sit unstable

Sit unstable

Head control

Head control

Sit with support, can step when supported

Poor head control

Head control?

Sit with support

Head control?

Sit?

Walk (2.5 years)

Voluntary hand use

Absent

Poor to absent

Poor to absent

Absent

Poor to absent

Poor to absent

Absent

N/A

Poor

Poor

Yes

Absent

Ophthalmological abnormalities

No

N/A

N/A

Hypermetropia

Convergent strabismus

Alternating convergent strabismus

Strabismus

N/A

Strabismus

Strabismus

Strabismus

Strabismus

Seizures (age of onset)

50% after regression (mean 4 years)

Yes (14 years)

Yes (2.5 years)

Yes (6 months)

Yes (4 months), easily controlled by AED

No

18 months (easily controlled by AED)

N.A (not controlled by therapy)

No

No epilepsy (3 years)

Yes (second year)

No

Hand stereotypies

++ midline

Complex intermixed with wringing movements of fingers, hand mouthing, and hand washing

Complex intermixed with wringing movements of fingers, hand mouthing, and hand washing

Hand not midline, rocking, waving, scratching

Complex intermixed with wringing movements of fingers, hand mouthing

Complex intermixed with wringing movements of fingers pill-rolling, and hand mouthing

Few

N/A

Intermittent: hand-mouth, washing

Constant hand to mouth

Yes

Yes with hand biting

Jerky movement of the upper limbs

Occasional

Yes

Yes

N/A

Yes

Yes

Occasional

N/A

Yes

Occasional

Probable (choreic movements)

No

Bruxism

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes, teeth chattering

Yes

No

Mood lability inconsolable crying

Yes

Yes

Yes

N/A

Yes

No

Yes

N/A

N/A

N/A

Yes

Inappropriate laughing

Sleep disturbance

Yes

No

No

No

No

No

Yes

N/A

Yes

No

Night screaming

No

Gastro-oesophageal reflux

Often

N/A

N/A

Present

Yes

Yes

Severe

N/A

Yes

No

Yes

No

MRI features myelination

No

N/A

N/A

N/A

Significant delayed

Mildly delayed

Severely delayed, hypomyelination

N/A

N/A

N/A

Severely delayed with decreased white matter volume

No

Corpus callosum

No

Hypoplastic

Hypoplastic

Agenesis

Thin

Normal

Hypoplastic

N/A

Normal

Thin

Hypoplastic

Normal

Gyral pattern

    

Frontal and temporal atrophy with gyral simplification

Normal

Severe frontal atrophy and simplified gyral pattern

N/A

N/A

N/A

Simplified gyral pattern

Normal

Our data, taken together with previous findings, indicate that patients with FOXG1 mutations, except one case described as a classic RTT [11], fulfil most of the criteria for the congenital variant of RTT as defined by Hagberg and Skjeldal, although the clinical delineation of this variant of RTT is not precise [15]. Indeed, as highlighted by Hagberg, the model proposed to delineate Rett variants is particularly suitable for identifying mild protracted and initially indistinct Rett clinical phenotypes, the forme fruste, and the late regression variants [16]. Congenital onset phenotypes with early severe motor disabilities remain more difficult to distinguish according to these criteria [15, 16]. In fact, the most consistent Rett-like features observed in patients with FOXG1-related encephalopathy are absolute microcephaly, either of congenital onset or secondary to early postnatal deceleration of head growth, hand stereotypies, neurogenic scoliosis, and some autonomic features including hypotrophic feet, bloating, and impaired nociperception. On the contrary, some signs usually observed in typical RTT such as the disease profile, consisting of a period of normal development followed by regression, breathing disturbance with either episodic hyperventilation and/or breath holding, and typical RTT EEG pattern, have never been reported in FOXG1-mutated patients. Moreover, simplified gyral pattern and delayed myelination as well as the hypoplastic corpus callosum (or callosal agenesis) are usually not observed in patients with classic RTT, while they appear to be frequent in FOXG1 mutation patients.

Our data suggest that the overall frequency of point mutations in the FOXG1 gene in females with severe mental retardation and microcephaly is low (1.5%). Combination of mutations screening and gene dosage in the FOXG1 gene in patients with severe encephalopathy, microcephaly, and some Rett-like features will help to identify additional patients with FOXG1 abnormalities.

Acknowledgements

We thank the patients, clinicians, and families who helped the study. This work was supported by the Institut National de la Santé et de la Recherche Médicale (ANR e-RARE EURORett).

Supplementary material

Supplemental data 1

Video electroencephalogram showing abnormal dyskinetic and non-epileptic movement disorder. (WMV 1857 kb)

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Nadia Bahi-Buisson
    • 1
    • 2
    • 3
  • Juliette Nectoux
    • 1
    • 2
  • Benoit Girard
    • 4
  • Hilde Van Esch
    • 5
  • Thomy De Ravel
    • 5
  • Nathalie Boddaert
    • 6
  • Perrine Plouin
    • 7
  • Marlene Rio
    • 8
  • Yann Fichou
    • 1
    • 2
  • Jamel Chelly
    • 1
    • 2
    • 4
  • Thierry Bienvenu
    • 1
    • 2
    • 4
  1. 1.Université Paris DescartesInstitut Cochin, CNRS (UMR8104)ParisFrance
  2. 2.InsermParisFrance
  3. 3.Service de Neuropédiatrie, AP-HPHôpital Necker-Enfants-MaladesParisFrance
  4. 4.Laboratoire de Biochimie et Génétique Moléculaire, AP-HPHôpital CochinParisFrance
  5. 5.Centre for Human GeneticsLeuvenBelgium
  6. 6.Service de Radiologie Pédiatrique, AP-HPHôpital Necker-Enfants-MaladesParisFrance
  7. 7.Service d’Electroencéphalographie, AP-HPHôpital Necker-Enfants-MaladesParisFrance
  8. 8.Service de GénétiqueHôpital Necker-Enfants-MaladesParisFrance

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