Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome.
OBJECTIVE
There have been no objective assessments to determine whether boys with MECP2 duplication have autism or whether female carriers manifest phenotypes. This study characterizes the clinical and neuropsychiatric phenotypes of affected boys and carrier females.


METHODS
Eight families (9 males and 9 females) with MECP2 duplication participated. A detailed history, physical examination, electroencephalogram, developmental evaluation, Autism Diagnostic Observation Schedule, and Autism Diagnostic Interview-Revised were performed for each boy. Carrier females completed the Symptom Checklist-90-R, Wechsler Abbreviated Scale of Intelligence, Broad Autism Phenotype Questionnaire, and detailed medical and mental health histories. Size and gene content of each duplication were determined by array comparative genome hybridization. X-chromosome inactivation patterns were analyzed using leukocyte DNA. MECP2 and IRAK1 RNA levels were quantified from lymphoblast cell lines, and western blots were performed to assess MeCP2 protein levels.


RESULTS
All of the boys demonstrated mental retardation and autism. Poor expressive language, gaze avoidance, repetitive behaviors, anxiety, and atypical socialization were prevalent. Female carriers had psychiatric symptoms, including generalized anxiety, depression, and compulsions that preceded the birth of their children. The majority exhibited features of the broad autism phenotype and had higher nonverbal compared to verbal reasoning skills.


CONCLUSIONS
Autism is a defining feature of the MECP2 duplication syndrome in boys. Females manifest phenotypes despite 100% skewing of X-inactivation and normal MECP2 RNA levels in peripheral blood. Analysis of the duplication size, MECP2 and IRAK1 RNA levels, and MeCP2 protein levels revealed that most of the traits in affected boys are likely due to the genomic region spanning of MECP2 and IRAK1. The phenotypes observed in carrier females may be secondary to tissue-specific dosage alterations and require further study. Ann Neurol 2009;66:771-782.
Ramocki
Melissa B
MB
Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Peters
Sarika U
SU
Tavyev
Y Jane
YJ
Zhang
Feng
F
Carvalho
Claudia M B
CM
Schaaf
Christian P
CP
Richman
Ronald
R
Fang
Ping
P
Glaze
Daniel G
DG
Lupski
James R
JR
Zoghbi
Huda Y
HY
D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D005192:Family Health; D005260:Female; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D009483:Neuropsychological Tests; D012333:RNA, Messenger / Q000235:genetics; D012727:Sex Characteristics; D049951:X Chromosome Inactivation / Q000235:genetics
C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases