French national reference center for intellectual disabilities and polyhandicaps of rare causes
The constituent site of Necker-
Enfants Malades university hospital has developed expertise in the care, teaching and research in polyhandicap linked to developmental encephalopathies such as Rett syndrome and related genetic syndromes (CDKL5, FOXG1, Aicardi syndrome, Angelman syndrome) and brain malformations.
The team also pays particular attention to the multidisciplinary care of polyhandicap, by combining a neurological assessment with gastroenterological, endocrinological, orthopedic and respiratory assessments of our patients. In the same way, it develops privileged relations with the medico-social sector in order to participate in the life project of the patients followed in the center.
Our center is one of the largest European centers for the care of patients with Rett’s syndromes and brain malformations.
Since the labeling in 2017, this rare disease reference center has relied on the national network of competence centers of the reference center for intellectual disabilities of rare causes, disseminated throughout the national territory including the French overseas departments and territories. This allows patients with these forms of polyhandicap an easy access to care and the most optimal use of skills and resources for each of them.
This reference center is affiliated with the DEFISCIENCE rare diseases healthcare network and the ITHACA European Reference Network (ERN).
Medical
team
Pr Nadia Bahi-Buisson
MD, PhD
In case of emergency
- Typical Rett syndrome is a developmental disease that affects girls almost exclusively. Only a few cases of boys are recorded. Children with Rett syndrome usually develop normally for 7-18 months after birth. At this stage, they lose their skills such as voluntary use of the hands and oral communication and develop microcephaly. Other signs appear such as a gait and balance disorder, stereotypes of the hands and autistic behavior. Rett syndrome progresses to multiple disabilities with an average lifespan of 50 years. The classic form of Rett syndrome is linked in more than 90% of cases to a mutation of MECP2, located on the X chromosome. In vitro experimental results from mice and human neurons have shown that even the most severe symptoms of Rett syndrome could be « reversed » by the reintroduction of an unmutated form of MecP2. Thus, all the efforts of academic and industrial research are now concentrated on the exploration for this treatment.
- Atypical and/or variants Rett syndromes and polyhandicap associated with microcephaly, FOXG1 and « FOXG1 plus » syndromes, encephalopathy linked to CDKL5 mutations
A number of developmental encephalopathies share symptoms with Rett syndrome, such as the CDKL5 or FOXG1 syndromes. Similarly, Rett syndrome has features in common with abnormalities in brain development such as congenital microcephaly. - Angelman syndrome
- Aicardi syndrome
- Polyhandicap linked to abnormalities in the development of the cerebral cortex (lissencephaly, polymicrogyria, microcephaly / megalencephaly, heterotopias)
- Dr Marie Hully, pediatric neurology
- Béatrice Gaschignard, health path coordinator
- Dr Cécile Talbotec, pediatric gastroenterology
- Pr Brigitte Fauroux and Dr Alessandro Amaddeo, pediatric pulmonology and ventilation unit – sleep specialists
- Dr. Robert Rubinsztajn, pediatric resuscitation
- Dr Hauviette Descamps, physical medicine and rehabilitation
- Dr Lotfi Miladi and Dr Alina Badina, pediatric orthopedics
- Prof. Dominique Bremond-Gignac, pediatric ophthalmology
- Dr Lisa Ouss, child psychiatry
- Camille Compte, social worker
The national diagnostic and care protocols (PNDS) are good practice guidelines for rare diseases. The objective of a PNDS is to explain to the concerned professionals the optimal diagnostic and therapeutic care and the course of care of a patient suffering from a given rare disease.
As provided for in the second national rare disease plan 2011-2014, they are drawn up by rare diseases reference and competence centers using a method proposed by the Haute Autorité de Santé (HAS).
PNDS prepared by the reference center
The Rett center team works in close collaboration with the research group led by Pr Bahi-Buisson in the team of Dr Alessandra Pierani – Genetics and brain development team Imagine Institute INSERM UMR-1163- Paris Descartes University.
The research team is formed of:
- Pr Nadia Bahi-Buisson, MD-PhD, group leader
- Dr Amandine Bery, post-doctoral fellow
- Dr. Mara Cavallin, MD, 3rd year doctoral student – genetics of Aicardi syndrome and brain malformations
- Sarah Farcy, 1st year doctoral student – dynéinopathies
- Camille Maillard, 1st year doctoral student – FOXG1 project
Old students :
- Nancy Vegas, MD, Master 2
- Marion Philbert, MD, Master 2
The main projects funded are:
- ANR 2016-2019 Elucidating molecular and cellular mechanisms underlying dyneinopathies
- EraNet Neuron 2015-2018 Stem cells aiding understanding of human malformations related to cortical development
- COST Action OC-2016-1-20862 European Network on Brain Malformations NeuroMIG (COST intergovernmental framework for European Cooperation in Science and Technology, allowing the coordination of nationally-funded research on a European level)
- Fondation Maladies Rares 2016: Identification of the genetic bases of Aicardi syndrome
- Fondation Maladies Rares 2015: Investigating Novel molecular basis for periventricular nodular heterotopia
- Role of FOXG1 / TLE1 in the proliferation-differentiation switch of neuronal progenitors
- AFSR 2017: Evaluation of stereotypes and their care in Rett syndrome
DIU pediatric neurology
Paris V –Paris VII – Paris XI – Amiens – Angers –Lille – Marseille – Montpellier- Reims – Toulouse -Tours
« Rett Syndrome » book for doctors, parents and carers AFSR editorial coordination; ed. 2016
AICARDI_Diseases_Childhood_3rd Chapter Brain Malformations
Atlas of epilepsy: Rett Syndrome chapter
Handbook of clinical Neurology: Rett syndrome chapter
Handbook of clinical Neurology: Cerebral Malformations chapter
Orphanet Handicap Encyclopedia: Rett Syndrome
Principles of Internal Medicine: 18th edition: Cortical malformations chapter
Flammarion Medicine-Sciences Pediatric Neurology: chapter: Rett syndrome
2021
– Deep phenotyping unstructured data mining in an extensive pediatric database to unravel a common KCNA2 variant in neurodevelopmental syndromes.
Marie Hully, Tommaso Lo Barco, Anna Kaminska, Giulia Barcia, Claude Cances, Cyril Mignot, Isabelle Desguerre, Nicolas Garcelon, Edor Kabashi, Rima Nabbout
Genet Med, 2021 May, PMID: 33500571 PMCID: PMC8105164 DOI: 10.1038/s41436-020-01039-z
– Human neuropathology confirms projection neuron and interneuron defects and delayed oligodendrocyte production and maturation in FOXG1 syndrome.
Nina-Maria Wilpert, Florent Marguet, Camille Maillard, Fabien Guimiot, Jelena Martinovic, Séverine Drunat, Tania Attié-Bitach, Ferechté Razavi, Aude Tessier, Yline Capri, Annie Laquerrière, Nadia Bahi-Buisson
Eur J Med Genet, 2021 Sep, PMID: 34284163 DOI: 10.1016/j.ejmg.2021.104282
– The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy.
Alexandre N. Datta,Nadia Bahi-Buisson,Thierry Bienvenu,Sarah E. Buerki,Fiona Gardiner,J. Helen Cross,Bénédicte Heron,Anna Kaminska,Christian M. Korff,Anne Lepine,Gaetan Lesca,Amy McTague,Heather C. Mefford,Cyrill Mignot,Matthieu Milh,Amélie Piton,Ronit M. Pressler,Susanne Ruf,Lynette G. Sadleir,Anne de Saint Martin,Koen Van Gassen,Nienke E. Verbeek,Dorothée Ville,Nathalie Villeneuve,Pia Zacher,Ingrid E. Scheffer,Johannes R. Lemke
Epilepsia, 2021 Feb, PMID: 33410528 PMCID: PMC7898319 DOI: 10.1111/epi.16761
– Heterogeneity in defining fetal corpus callosal pathology: systematic review.
H Mahallati, A Sotiriadis, C Celestin, A E Millischer, P Sonigo, D Grevent, N O’Gorman, N Bahi-Buisson, T Attié-Bitach, Y Ville, L J Salomon
Ultrasound Obstet Gynecol, 2021 Jul, PMID: 32798278 DOI: 10.1002/uog.22179
– Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.
Silvia Masnada, Anna Pichiecchio, Manuela Formica, Filippo Arrigoni, Paola Borrelli, Patrizia Accorsi, Paolo Bonanni, Renato Borgatti 1, Bernardo Dalla Bernardina, Alberto Danieli, Francesca Darra, Nicolas Deconinck Valentina De Giorgis, Olivier Dulac, Svetlana Gataullina, Lucio Giordano, Renzo Guerrini, Francesca La Briola, Massimo Mastrangelo, Martino Montomoli, Marzia Mortilla, Elisa Osanni, Pasquale Parisi, Emilio Perucca, Lorenzo Pinelli, Romina Romaniello, Mariasavina Severino, Federico Vigevano, Aglaia Vignoli, Nadia Bahi-Buisson et al.
Neurology, 2021 Mar 2, PMID: 33277420 PMCID: PMC8055324 DOI: 10.1212/WNL.0000000000011237
– Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans.
Thuy-Linh Le, Louise Galmiche, Jonathan Levy, Pim Suwannarat, Debby Mei Hellebrekers, Khomgrit Morarach, Franck Boismoreau, Tom Ej Theunissen, Mathilde Lefebvre, Anna Pelet, Jelena Martinovic, Antoinette Gelot, Fabien Guimiot, Amanda Calleroz, Cyril Gitiaux, Marie Hully, Olivier Goulet, Christophe Chardot, Severine Drunat, Yline Capri, Christine Bole-Feysot et al.
J Clin Invest, 2021 Mar 15, PMID: 33497358 PMCID: PMC7954599 DOI: 10.1172/JCI145837
– Inherited glycosylphosphatidylinositol defects cause the rare Emm-negative blood phenotype and developmental disorders.
Romain Duval, Gaël Nicolas, Alexandra Willemetz, Yoshiko Murakami, Mahmoud Mikdar, Cedric Vrignaud, Hisham Megahed, Jean-Pierre Cartron, Cecile Masson, Samer Wehbi, Bérengere Koehl, Marie Hully, Karine Siquier, Nicole Chemlay, Agnes Rotig, Stanislas Lyonnet, Yves Colin, Giulia Barcia, Vincent Cantagrel, Caroline Le Van Kim, Olivier Hermine, Taroh Kinoshita, Thierry Peyrard, Slim Azouzi
Blood, 2021 Jul 1, PMID: 33763700 DOI: 10.1182/blood.2020009810
– High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.
Mehdi Benkirane, Cecilia Marelli, Claire Guissart, Agathe Roubertie, Elizabeth Ollagnon, Ariane Choumert, Frédérique Fluchère, Fabienne Ory Magne, Yosra Halleb, Mathilde Renaud, Lise Larrieu, David Baux, Olivier Patat, Idriss Bousquet, Jean-Marie Ravel, Danielle Cuntz-Shadfar, Catherine Sarret, Xavier Ayrignac et al.
Genet Med, 2021 Nov, PMID: 34234304 DOI: 10.1038/s41436-021-01250-6
– Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.
Alice Lepelley, Erika Della Mina, Erika Van Nieuwenhove, Lise Waumans, Sylvie Fraitag, Gillian I Rice, Ashish Dhir, Marie-Louise Frémond, Mathieu P Rodero, Luis Seabra, Edwin Carter, Christine Bodemer, Daniela Buhas, Bert Callewaert, Pascale de Lonlay et al.
J Exp Med, 2021 Oct 4, PMID: 34387651 PMCID: PMC8374862 DOI: 10.1084/jem.20201560
2020
– Palliative Care in SMA Type 1: A Prospective Multicenter French Study Based on Parents » Reports.
Marie Hully, Christine Barnerias, Delphine Chabalier, Sophie Le Guen, Virginie Germa, Elodie Deladriere, Catherine Vanhulle, Jean-Marie Cuisset, Brigitte Chabrol, Claude Cances, Carole Vuillerot, Caroline Espil, Michele Mayer, Marie-Christine Nougues, Pascal Sabouraud, Jeremie Lefranc, Vincent Laugel, Francois Rivier, Ulrike Walther Louvier, Julien Durigneux, Sylvia Napuri, Catherine Sarret, Michel Renouil, Alice Masurel, Marcel-Louis Viallard, Isabelle Desguerre
Front Pediatr, 2020 Feb 18, PMID: 32133329 PMCID: PMC7039815 DOI: 10.3389/fped.2020.00004
– JAK Inhibition in the Aicardi-Goutières Syndrome.
Bénédicte Neven, Buthaina Al Adba, Marie Hully, Isabelle Desguerre, Claire Pressiat, Natalie Boddaert, Darragh Duffy, Gillian I Rice, Luis Seabra, Marie-Louise Frémond, Stéphane Blanche, Yanick J Crow
N Engl J Med, 2020 Nov 26, PMID: 33252884 DOI: 10.1056/NEJMc2031081
– Expanding the phenotype of mitochondrial disease: Novel pathogenic variant in ISCA1 leading to instability of the iron-sulfur cluster in the protein.
E Lebigot, M Hully, L Amazit, P Gaignard, T Michel, M Rio, M Lombès, P Thérond, A Boutron, M P Golinelli-Cohen
Mitochondrion, 2020 May, PMID: 32092383 DOI: 10.1016/j.mito.2020.02.008
2017
– Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.
Broix L, Asselin L, Silva CG, Ivanova EL, Tilly P, Gilet JG, Lebrun N, Jagline H, Muraca G, Saillour Y, Drouot N, Reilly ML, Francis F, Benmerah A, Bahi-Buisson N, Belvindrah R, Nguyen L, Godin JD, Chelly J, Hinckelmann MV.
Hum Mol Genet. 2017 Oct 25.
– Lower incidence of fracture after IV bisphosphonates in girls with Rett syndrome and severe bone fragility.
Lambert AS, Rothenbuhler A, Charles P, Brailly-Tabard S, Trabado S, Célestin E, Durand E, Fontaine I, Miladi L, Wicart P, Bahi-Buisson N, Linglart A.
PLoS One. 2017 Oct 26;12(10):e0186941.
– WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells.
Cavallin M, Rujano MA, Bednarek N, Medina-Cano D, Bernabe Gelot A, Drunat S, Maillard C, Garfa-Traore M, Bole C, Nitschké P, Beneteau C, Besnard T, Cogné B, Eveillard M, Kuster A, Poirier K, Verloes A, Martinovic J, Bidat L, Rio M, Lyonnet S, Reilly ML, Boddaert N, Jenneson-Liver M, Motte J, Doco-Fenzy M, Chelly J, Attie-Bitach T, Simons M, Cantagrel V, Passemard S, Baffet A, Thomas S, Bahi-Buisson
Brain. 2017 Oct 1;140(10):2597-2609.
– Genetics and mechanisms leading to human cortical malformations.
Romero DM, Bahi-Buisson N, Francis F.
Semin Cell Dev Biol. 2017 Oct 10.
– Cryo-EM Reveals How Human Cytoplasmic Dynein Is Auto-inhibited and Activated.
Zhang K, Foster HE, Rondelet A, Lacey SE, Bahi-Buisson N, Bird AW, Carter AP.
Cell. 2017 Jun 15;169(7):1303-1314.e18. doi: 10.1016/j.cell.2017.05.025. Epub 2017 Jun 8.
– Neuropathological Hallmarks of Brain Malformations in Extreme Phenotypes Related to DYNC1H1 Mutations.
Laquerriere A, Maillard C, Cavallin M, Chapon F, Marguet F, Molin A, Sigaudy S, Blouet M, Benoist G, Fernandez C, Poirier K, Chelly J, Thomas S, Bahi-Buisson
J Neuropathol Exp Neurol. 2017 Mar 1;76(3):195-205.
2016
– Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia.
Broix L, Jagline H, L Ivanova E, Schmucker S, Drouot N, Clayton-Smith J, Pagnamenta AT, Metcalfe KA, Isidor B, Louvier UW, Poduri A, Taylor JC, Tilly P, Poirier K, Saillour Y, Lebrun N, Stemmelen T, Rudolf G, Muraca G, Saintpierre B, Elmorjani A; Deciphering Developmental Disorders study., Moïse M, Weirauch NB, Guerrini R, Boland A, Olaso R, Masson C, Tripathy R, Keays D, Beldjord C, Nguyen L, Godin J, Kini U, Nischké P, Deleuze JF, Bahi-Buisson N, Sumara I, Hinckelmann MV, Chelly J.
Nat Genet. 2016 Nov;48(11):1349-1358. doi: 10.1038/ng.3676.
– Tubulinopathies Overview.
Bahi-Buisson N, Cavallin M. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors.
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.2016 Mar 24.
2014
– Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.
Fallet-Bianco C, Laquerrière A, Poirier K, Razavi F, Guimiot F, Dias P, Loeuillet L, Lascelles K, Beldjord C, Carion N, Toussaint A, Revencu N, Addor MC, Lhermitte B, Gonzales M, Martinovich J, Bessieres B, Marcy-Bonnière M, Jossic F, Marcorelles P, Loget P, Chelly J, Bahi-Buisson
Acta Neuropathol Commun. 2014 Jul 25;2:69.
– The wide spectrum of tubulinopathies: what are the key features for the diagnosis?
Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Bianco CF, Boddaert N, Elie C, Lascelles K, Souville I; LIS-Tubulinopathies Consortium, Beldjord C,
Chelly J.2014 Jun;137(Pt 6):1676-700.
– Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.
Kielar M, Tuy FP, Bizzotto S, Lebrand C, de Juan Romero C, Poirier K, Oegema R, Mancini GM, Bahi-Buisson N, Olaso R, Le Moing AG, Boutourlinsky K, Boucher D, Carpentier W, Berquin P, Deleuze JF, Belvindrah R, Borrell V, Welker E, Chelly J, Croquelois A, Francis F
Nat Neurosci. 2014 Jul;17(7):923-33.
Five hospital neuropediatrics departments – including Necker Hospital with Pr Isabelle Desguerre, Pr Nadia Bahi-Buisson and Dr Marie Hully – and nine medico-social establishments which welcome children with polyhandicaps participated in a pilot telemedicine experiment .
This film presents the strong benefits of this experience which has strengthened the link and the network of professionals, better interaction between the teams, for a single objective: the well-being of the patient!
Hoping that this experiment will continue and unfold!
- Association française du syndrome d’Angelman (AFSA)
- Association française du syndrome de Rett (AFSR)
- Rett Syndrome Europe
- Association FOXG1 France
- CDKL5 alliance francophone
- Association Syndrome Aicardi (ASA)
- Association de défense des polyhandicapés (ADEPO)
- Association Tous ensemble pour agir (TEPA)
- Au Clair de Lune
- Handy Rare et Poly
- Groupe Polyhandicap France (GPF)
- Comité d’études, d’éducation et de soins auprès des personnes polyhandicapées (CESAP)
- Association Les Tout Petits (LTP)
- Fast France
- Fondation Saint-Jean de Dieu
- Association Notre Dame de Joye
- Envoludia
- Alliance Maladies Rares
My child won’t be like the others
Le Monde | 12.15.2016
> Read more
Contact information
Necker-Enfants malades university hospital
> Pediatric neurology department
149 rue de Sèvres
75743 PARIS Cedex 15
In Necker, the reference center for intellectual disabilities and polyhandicaps of rare causes in brief …
* data valid for 2022