American Journal of Medical Genetics 126A:129–140 (2004) Phenotypic Manifestations of MECP2 Mutations in Classical and Atypical Rett Syndrome Carolyn Schanen, 1,2,3 * Elisa J.F. Houwink, 2,4 Naghmeh Dorrani, 2 Jane Lane, 5 Ruth Everett, 2,6 Alice Feng, 2 Rita M. Cantor, 2,3 and Alan Percy 5,7 1 Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 2 Department of Human Genetics, University of California, Los Angeles, California 3 Department of Pediatrics, University of California, Los Angeles, California 4 Department of Obstetrics and Gynaecology, Vrije Universiteit, The Netherlands 5 Department of Pediatrics, University of Alabama, Birmingham, Alabama 6 Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 7 Civitan International Research Center, Birmingham, Alabama Since the identification of mutations in MECP2 in girls and women with apparent Rett syndrome, numerous efforts have been made to develop phenotype-genotype corre- lations. These studies have produced con- flicting results in part related to use of different clinical severity scales, different diagnostic criteria, and different strati- fication by age and mutation group as well as the possible effects of unbalanced X- chromosome inactivation. The present study applied a revised ordinal scoring system that allowed for correction for patient ages. We analyzed 85 patients with mutation in MECP2. Sixty-five (76%) had one of eight common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the methyl-binding domain (MBD) and the transcriptional repression domain (TRD). However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation including better overall score, later regression, and better language with less motoric impair- ment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups. Thus, the impact of specific muta- tions coupled with possible variation in X-chromosome inactivation must be consid- ered carefully in the derivation of pheno- type-genotype correlations. These results emphasize the limitations of such analyses in larger mutation groups, either by type or position. ß 2003 Wiley-Liss, Inc. KEY WORDS: methyl binding protein; X-linked mental retardation; Rett syndrome; epigenetic INTRODUCTION Rett syndrome (RTT) is an X-linked neurodevelop- mental disorder [Rett, 1966], a leading cause of mental retardation, affecting about 1 in 15,000 females world- wide [Hagberg, 1985; Kerr and Stephenson, 1985; Kozinetz et al., 1993; Hagberg and Hagberg, 1997]. The disorder is most often recognized between 6 and 18 months in girls who show a plateau in developmental progress followed by loss of purposeful hand skills coincident with the onset of hand stereotypies that are the hallmark behavioral manifestation of the disorder. Growth of the head slows and neurological signs in- cluding mixed tone abnormalities, motor and language apraxia, and seizures evolve. Other frequent symptoms are waking respiratory irregularities, constipation, and peripheral vasomotor disturbances [Hagberg, 2002] as well as a general decline in somatic growth [Motil et al., 1994]. While classic RTT is defined based on strict adherence to the diagnostic criteria introduced in 1988 by the Rett Syndrome Diagnostic Workgroup, atypical Grant sponsor: National Institute of Health; Grant numbers: RO1-HD 37874, MO1-RR00032; Grant sponsor: University of Alabama at Birmingham GCRC; Grant sponsor: The Nemours Foundation; Grant sponsor: International Rett syndrome Association. *Correspondence to: Carolyn Schanen, M.D., Ph.D., Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Room H3B-337, P.O. Box 269, Wilmington, DE 19899. E-mail: cschanen@nemours.org Received 14 April 2003; Accepted 31 August 2003 DOI 10.1002/ajmg.a.20571 ß 2003 Wiley-Liss, Inc.