PMID- 25044251
OWN - NLM
STAT- MEDLINE
DCOM- 20141211
LR  - 20211021
IS  - 1531-8249 (Electronic)
IS  - 0364-5134 (Print)
IS  - 0364-5134 (Linking)
VI  - 76
IP  - 4
DP  - 2014 Oct
TI  - Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.
PG  - 581-93
LID - 10.1002/ana.24225 [doi]
AB  - 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.
CI  - (c) 2014 American Neurological Association.
FAU - Pescosolido, Matthew F
AU  - Pescosolido MF
AD  - Department of Molecular Biology, Cell Biology, and Biochemistry and Laboratory 
      for Molecular Medicine, Institute for Brain Science, Brown University, 
      Providence, RI; 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.
FAU - Stein, David M
AU  - Stein DM
FAU - Schmidt, Michael
AU  - Schmidt M
FAU - El Achkar, Christelle Moufawad
AU  - El Achkar CM
FAU - Sabbagh, Mark
AU  - Sabbagh M
FAU - Rogg, Jeffrey M
AU  - Rogg JM
FAU - Tantravahi, Umadevi
AU  - Tantravahi U
FAU - McLean, Rebecca L
AU  - McLean RL
FAU - Liu, Judy S
AU  - Liu JS
FAU - Poduri, Annapurna
AU  - Poduri A
FAU - Morrow, Eric M
AU  - Morrow EM
LA  - eng
GR  - P20GM103645/GM/NIGMS NIH HHS/United States
GR  - P20 GM103645/GM/NIGMS NIH HHS/United States
GR  - 1R01MH105442-01/MH/NIMH NIH HHS/United States
GR  - R01 MH105442/MH/NIMH NIH HHS/United States
GR  - T32 NS062443/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140919
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - 0 (SLC9A6 protein, human)
RN  - 0 (Sodium-Hydrogen Exchangers)
RN  - Mental Retardation, X-Linked, Syndromic, Christianson Type
SB  - IM
MH  - Adolescent
MH  - Ataxia/*complications/*genetics/pathology
MH  - Autistic Disorder/etiology/genetics
MH  - Brain/growth & development/pathology
MH  - Child
MH  - Child, Preschool
MH  - Developmental Disabilities/complications/*genetics/pathology
MH  - Disease Progression
MH  - Electroencephalography
MH  - Epilepsy/*complications/etiology/*genetics/pathology
MH  - Female
MH  - Genetic Diseases, X-Linked/*complications/*genetics/pathology
MH  - Genotype
MH  - Humans
MH  - Intellectual Disability/*complications/*genetics/pathology
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Microcephaly/*complications/*genetics/pathology
MH  - Mutation/*genetics
MH  - Ocular Motility Disorders/*complications/*genetics/pathology
MH  - Phenotype
MH  - Regression Analysis
MH  - Sodium-Hydrogen Exchangers/*genetics
MH  - Young Adult
PMC - PMC4304796
MID - NIHMS613728
COIS- None of the authors have a financial conflict of interest.
EDAT- 2014/07/22 06:00
MHDA- 2014/12/17 06:00
PMCR- 2015/10/01
CRDT- 2014/07/22 06:00
PHST- 2014/01/20 00:00 [received]
PHST- 2014/06/30 00:00 [revised]
PHST- 2014/07/10 00:00 [accepted]
PHST- 2014/07/22 06:00 [entrez]
PHST- 2014/07/22 06:00 [pubmed]
PHST- 2014/12/17 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - 10.1002/ana.24225 [doi]
PST - ppublish
SO  - Ann Neurol. 2014 Oct;76(4):581-93. doi: 10.1002/ana.24225. Epub 2014 Sep 19.