Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome

Authors

  • Melissa B. Ramocki MD, PhD,

    1. Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX
    2. Texas Children's Hospital, Houston, TX
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    • These authors contributed equally to this study.

  • Sarika U. Peters PhD,

    1. Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX
    2. Texas Children's Hospital, Houston, TX
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    • These authors contributed equally to this study.

  • Y. Jane Tavyev MD,

    1. Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX
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    • These authors contributed equally to this study.

  • Feng Zhang PhD,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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  • Claudia M. B. Carvalho PhD,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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  • Christian P. Schaaf MD,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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  • Ronald Richman,

    1. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX
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  • Ping Fang PhD,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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  • Daniel G. Glaze MD,

    1. Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX
    2. Texas Children's Hospital, Houston, TX
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  • James R. Lupski MD, PhD,

    1. Texas Children's Hospital, Houston, TX
    2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
    3. Department of Pediatrics, Baylor College of Medicine, Houston, TX
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  • Huda Y. Zoghbi MD

    Corresponding author
    1. Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX
    2. Texas Children's Hospital, Houston, TX
    3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
    4. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX
    5. Department of Neuroscience, Baylor College of Medicine, Houston, TX
    • One Baylor Plaza, MS 225, BCM-T807, Houston, TX 77030
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  • Potential conflict of interest: Some of the authors are based in the Department of Molecular and Human Genetics at Baylor College of Medicine, which offers extensive genetic laboratory testing including use of arrays for genomic copy number analysis and derives revenue from this activity.

Abstract

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.

Interpretation

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

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