Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. Issue 4 (19th September 2014)

• Record Type: Journal Article
• Authors: Pescosolido, Matthew F.; Stein, David M.; Schmidt, Michael; El Achkar, Christelle Moufawad; Sabbagh, Mark; Rogg, Jeffrey M.; Tantravahi, Umadevi; McLean, Rebecca L.; Liu, Judy S.; Poduri, Annapurna; Morrow, Eric M.
• Is Part Of: Annals of neurology. Volume 76:Issue 4(2014:Oct.)
• Page Start: 581
• Page End: 593
• Publication Date: 2014-09-19
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24225
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24225-sec-0001" sec-type="section"> <title>Objective</title> <p>Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X‐linked Na<sup>+</sup>/H<sup>+</sup> exchanger 6 (<italic>NHE6</italic>). We aimed to determine the diagnostic criteria and mutational spectrum for CS.</p> </sec> <sec id="ana24225-sec-0002" sec-type="section"> <title>Methods</title> <p>Twelve independent pedigrees (14 boys, age = 4–19 years) with mutations in <italic>NHE6</italic> were administered standardized research assessments, and mutations were characterized.</p> </sec> <sec id="ana24225-sec-0003" sec-type="section"> <title>Results</title> <p>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 <italic>de novo</italic>, 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.</p> </sec> <sec id="ana24225-sec-0004" sec-type="section"> <title>Interpretation</title> <p>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</p> </sec> </abstract>