Brain Advance Access originally published online on September 12, 2008
Brain 2008 131(10):2647-2661; doi:10.1093/brain/awn197
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Key clinical features to identify girls with CDKL5 mutations
1Pediatric Neurology, Department of Pediatrics, Necker Enfants Malades Hospital, AP-HP, Paris V, 2INSERM, U663; Paris Descartes University, 3Paris Descartes University, Paris V, 4Reference Centre for Epilepsies, Necker Enfants Malades Hospital, AP-HP, 5Cochin Institute, Paris Descartes University, CNRS (UMR 8104), 6INSERM, U567, 7Assistance Publique - Paris Hospitals, Cochin Hospital, Laboratory of Biochemistry and Molecular Genetics, Paris, 8Inmed, INSERM U29, Luminy Science Park, Marseille, 9Unit of Pediatric Neurology, Children's; Hospital, Toulouse, 10Pediatric Neurology, Centre Hospitalo-Universitaire de Lyon, Lyon, 11Pediatric Neurology, Trousseau Hospital, AP-HP, 12Genetics Department, Necker Enfants Malades Hospital, AP-HP, Paris V, 13Department of Genetics, Pitié Salpêtrière Hospital, Paris, 14Department of Paediatrics, Centre of Language and Learning Disorders, Centre Hospitalo-Universitaire, Grenoble and 15Laboratory of Medical Genetics, EA 4002, Nancy-Brabois University, Vandoeuvre the Nancy, France
Correspondence to: Dr Thierry Bienvenu, Laboratoire de Génétique et de Physiopathologie des Maladies Neuro-développementales, Institut Cochin, 24 rue du Faubourg Saint Jacques, 75014 Paris, France. E-mail: thierry.bienvenu{at}inserm.fr
Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause infantile spasms as well as Rett syndrome (RTT)-like phenotype. To date, less than 25 different mutations have been reported. So far, there are still little data on the key clinical diagnosis criteria and on the natural history of CDKL5-associated encephalopathy. We screened the entire coding region of CDKL5 for mutations in 183 females with encephalopathy with early seizures by denaturing high liquid performance chromatography and direct sequencing, and we identified in 20 unrelated girls, 18 different mutations including 7 novel mutations. These mutations were identified in eight patients with encephalopathy with RTT-like features, five with infantile spasms and seven with encephalopathy with refractory epilepsy. Early epilepsy with normal interictal EEG and severe hypotonia are the key clinical features in identifying patients likely to have CDKL5 mutations. Our study also indicates that these patients clearly exhibit some RTT features such as deceleration of head growth, stereotypies and hand apraxia and that these RTT features become more evident in older and ambulatory patients. However, some RTT signs are clearly absent such as the so called RTT disease profile (period of nearly normal development followed by regression with loss of acquired fine finger skill in early childhood and characteristic intensive eye communication) and the characteristic evolution of the RTT electroencephalogram. Interestingly, in addition to the overall stereotypical symptomatology (age of onset and evolution of the disease) resulting from CDKL5 mutations, atypical forms of CDKL5-related conditions have also been observed. Our data suggest that phenotypic heterogeneity does not correlate with the nature or the position of the mutations or with the pattern of X-chromosome inactivation, but most probably with the functional transcriptional and/or translational consequences of CDKL5 mutations. In conclusion, our report show that search for mutations in CDKL5 is indicated in girls with early onset of a severe intractable seizure disorder or infantile spasms with severe hypotonia, and in girls with RTT-like phenotype and early onset seizures, though, in our cohort, mutations in CDKL5 account for about 10% of the girls affected by these disorders.
Key Words: CDKL5; MECP2; Rett syndrome; seizures
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Received January 29, 2008. Revised July 26, 2008. Accepted July 28, 2008.
*These authors contributed equally to the study.
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