Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

Authors

  • Matthew F. Pescosolido BA,

    1. Department of Molecular Biology, Cell Biology, and Biochemistry and Laboratory for Molecular Medicine, Institute for Brain Science, Brown University, Providence, RI
    2. Developmental Disorders Genetics Research Program, Emma Pendleton Bradley Hospital and Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, East Providence, RI
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  • David M. Stein BSc,

    1. Department of Molecular Biology, Cell Biology, and Biochemistry and Laboratory for Molecular Medicine, Institute for Brain Science, Brown University, Providence, RI
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  • Michael Schmidt BSc,

    1. Department of Molecular Biology, Cell Biology, and Biochemistry and Laboratory for Molecular Medicine, Institute for Brain Science, Brown University, Providence, RI
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  • Christelle Moufawad El Achkar MD,

    1. Epilepsy Genetics Program, Division of Epilepsy and Child Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA
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  • Mark Sabbagh BSc,

    1. Department of Molecular Biology, Cell Biology, and Biochemistry and Laboratory for Molecular Medicine, Institute for Brain Science, Brown University, Providence, RI
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  • Jeffrey M. Rogg MD,

    1. Department of Diagnostic Imaging, Warren Alpert Medical School of Brown University, Providence, RI
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  • Umadevi Tantravahi PhD,

    1. Division of Genetics, Department of Pathology, Woman and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI
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  • Rebecca L. McLean PhD,

    1. Developmental Disorders Genetics Research Program, Emma Pendleton Bradley Hospital and Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, East Providence, RI
    2. Neurodevelopmental Center, Department of Pediatrics, Memorial Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Pawtucket, RI
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  • Judy S. Liu MD, PhD,

    1. Center for Neuroscience Research, Children's National Medical Center, Washington, DC
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  • Annapurna Poduri MD, MPH,

    1. Epilepsy Genetics Program, Division of Epilepsy and Child Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA
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  • Eric M. Morrow MD, PhD

    Corresponding author
    1. Department of Molecular Biology, Cell Biology, and Biochemistry and Laboratory for Molecular Medicine, Institute for Brain Science, Brown University, Providence, RI
    2. Developmental Disorders Genetics Research Program, Emma Pendleton Bradley Hospital and Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, East Providence, RI
    • Address correspondence to Dr Morrow, Brown University, Lab for Molecular Medicine, 70 Ship Street, Providence, RI 02912. E-mail: eric_morrow@brown.edu

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Abstract

Objective

Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na+/H+ exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS.

Methods

Twelve independent pedigrees (14 boys, age = 4–19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized.

Results

The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold.

Interpretation

This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression. Ann Neurol 2014;76:581–593

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