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The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome

From Laboratoire de Biochimie et Genetique Moleculaire (J.N., J. Chelly, T.B.) and Service de Biostatistiques et d'Informatique Médicale, AP-HP (J. Coste), Hopital Cochin, Paris; Institut Cochin (J.N., H.R., J. Chelly, T.B.), Université Paris Descartes, CNRS (UMR 8104), Inserm U567, Paris; Service de Neuropédiatrie (N.B.-B., I.G.), Hopital Necker-Enfants-Malades, AP-HP, Paris; Service de Biochimie et Genetique Moleculaire (N.D.R.), Hôpital Robert Debré, Paris; and Service de Neurologie (M.T.), CHU Bicêtre, Le Kremlin Bicêtre, France.

Address correspondence and reprint requests to Dr. Thierry Bienvenu, Laboratoire de Génétique et de Physiopathologie des Maladies Neurodéveloppementales, Institut Cochin, 24 rue du Faubourg Saint Jacques, 75014 Paris, France bienvenu{at}cochin.inserm.fr

Objective: X chromosome inactivation and the MECP2 genotype do not provide the full explanations for the clinical differences between patients with Rett syndrome (RTT), suggesting the involvement of other factors. One MeCP2 target is the brain-derived neurotrophic factor (BDNF) gene. We investigated, according to the MECP2 genotype, the role of the BDNF functional polymorphism (Val66Met) on the severity of RTT.

Methods: This polymorphism in BDNF was analyzed by PCR and dHPLC in 81 patients with RTT. We studied the association between the MECP2 and BDNF genotypes and the clinical features in each patient.

Results: We found that some RTT features can be correlated with MECP2 genotypes. Missense mutations are associated with a more severe epileptic phenotype (early onset and drug resistance) than other mutations. Non-sense and late truncating mutations lead to a less severe phenotype regarding walking. The distribution of the Val66Met polymorphism was not significantly different between the different groups in regard to the severity of all tested symptoms. However, girls with RTT bearing the Val66Val genotype tend to present earlier seizures than girls with RTT bearing the Met66 allele. No girls with RTT with the Met66 allele presented early seizures.

Conclusions: Early onset of seizures is linked to the combined MECP2 and BDNF genotypes. The BDNF Met66 allele may protect against seizures, whereas missense mutations in the MBD of MECP2 are more frequently associated with early seizures.

GLOSSARY: BDNF = brain-derived neurotrophic factor; dHPLC = denaturing high pressure liquid chromatography; MBD = methyl-binding domain; NLS = nuclear location signal; RTT = Rett syndrome; TRD = transcription repression domain; XCI = X-chromosome inactivation status.

Supplemental data at www.neurology.org

e-Pub ahead of print on April 23, 2008, at www.neurology.org.

*These authors contributed equally.

Supported by a grant from ANR-Maladies Rares (ANR-6-MRAR-003-01). J.N. is currently funded by Fondation pour la Recherche Medicale (FRM).

Disclosure: The authors report no disclosures.

Received July 6, 2007. Accepted in final form November 7, 2007.