A novel CDKL5 mutation in a 47,XXY boy with the early‐onset seizure variant of Rett syndrome

• Published in: American journal of medical genetics. Part A Vol. 149A; no. 2; pp. 232 - 236
• Main Authors: Sartori, Stefano, Di Rosa, Gabriella, Polli, Roberta, Bettella, Elisa, Tricomi, Giovanni, Tortorella, Gaetano, Murgia, Alessandra
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2009; Wiley-Liss
• Subjects: 47,XXY karyotype; Age of Onset; Biological and medical sciences; CDKL5; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Developmental Disabilities; early‐onset epileptic encephalopathy; Follow-Up Studies; Gynecology. Andrology. Obstetrics; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Infant; Klinefelter syndrome; Male; Male and female genital diseases. Gonadal dysgenesis. Hermaphroditism. Sex hormones resistance; Medical genetics; Medical sciences; Mutation; Nervous system (semeiology, syndromes); Neurology; Protein-Serine-Threonine Kinases - genetics; Rett Syndrome - genetics; Rett syndrome variant; Seizures - genetics; Sex Chromosome Disorders; X Chromosome Inactivation; Chromosomal aberration; Endocrinopathy; early-onset epileptic encephalopathy; mutation; Rett syndrome variant; Klinefelter syndrome; X-chromosome inactivation; 47,XXY karyotype; Epilepsy; Aneuploidy; Male; Supernumerary X chromosome; Inactivation; Encephalopathy; Degenerative disease; X-Chromosome; Neurological disorder; Male genital diseases; Child; Human; Nervous system diseases; CDKL5; Sexual differentiation disorder; Genetic disease; Cerebral disorder; Variant; Convulsion; Malformation; Central nervous system disease; Rett syndrome; Cytogenetics; Early; Mutation; Karyotype
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.32606

Mutations of the cyclin‐dependent kinase‐like 5 gene (CDKL5), reported almost exclusively in female subjects, have been recently found to be the cause of a phenotype overlapping Rett syndrome with early‐onset epileptic encephalopathy. We describe the first CDKL5 mutation detected in a male individual with 47,XXY karyotype. This previously unreported, de novo, mutation truncates the large CDKL5 COOH‐terminal region, thought to be crucial for the proper sub‐cellular localization of the CDKL5 protein. The resulting phenotype is characterized by a severe early‐onset epileptic encephalopathy, global developmental delay, and profound intellectual and motor impairment with features reminiscent of Rett syndrome. In light of the data presented we discuss the possible phenotypic modulatory effects of the supernumerary wild type X allele and pattern of X chromosome inactivation and stress the importance of considering the causal involvement of CDKL5 in developmentally delayed males with early‐onset seizures. © 2009 Wiley‐Liss, Inc.