Natural history of Christianson syndrome

Schroer, Richard J.; Holden, Kenton R.; Tarpey, Patrick; Matheus, Maria G.; Griesemer, David A.; Friez, Michael J.; Fan, Jane Zheng; Simensen, Richard J.; Strømme, Petter; Stevenson, Roger E.; Stratton, Michael R.; Schwartz, Charles E.

doi:10.1002/ajmg.a.33093

Cited by 69 publications

(101 citation statements)

References 13 publications

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“…Although some female carriers in CS pedigrees have previously been reported with ID/DD, speech and language problems, truncal ataxia, hyperkinesis, and psychiatric illness [1-4, 7], we employed standardized neuropsychological measures across multiple CS pedigrees with inherited transmission to rigorously quantify performance across cognitive domains. Our findings suggest that female carriers of NHE6 mutations display a recognizable neurocognitive phenotype.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…NHE proteins are generally 12-transmembrane-domain proteins that exchange hydrogen ions for cations (e.g., Na + or K + ions). Affected CS males usually harbor loss-of-function mutations and present with intellectual disability (ID)/developmental delay (DD), epilepsy, postnatal microcephaly, and ataxia [1-4]. Notable neurological symptoms reported in a subset of CS patients include cerebellar/brainstem atrophy and eye movement problems (closest to Duane syndrome Type I, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Female carriers in these CS pedigrees exhibit heterogeneous phenotypes, ranging from unaffected to presenting with mild-moderate ID/DD, neuropsychiatric disorders including attentional difficulties, mild ataxia, and/or microcephaly [1-8]. Recurrent developmental features of female carriers include learning problems, difficulty in school, speech disorder, and/or behavioral problems [2-4, 7]. However, the full phenotypic spectrum in females with NHE6 mutations, particularly across the lifespan, is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

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Complex Neurological Phenotype in Female Carriers of NHE6 Mutations

et al. 2019

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Mutations in NHE6 (also termed SLC9A6) cause the X-linked neurological disorder Christianson syndrome (CS) in males. The purpose of this study was to examine the phenotypic spectrum of female carriers of NHE6 mutations. Twenty female carriers from 9 pedigrees were enrolled, ranging from approximately age 2 to 65. A subset of female carriers was assessed using standardized neuropsychological measures. Also, the association of NHE6 expression with markers of brain age was evaluated using 740 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). A majority, but not all, female carriers demonstrated a deficit in at least one neurocognitive domain (85%). A recognizable neuropsychological profile emerged, revealing impairments in visuospatial function, attention, and executive function. Common neuropsychiatric diagnoses included: intellectual disability/developmental delay (20%), learning difficulties (31%), speech/language delays (30%), and attention-deficit/hyperactivity disorder (20%). Notable neurological diagnoses in aging CS female carriers include corticobasal degeneration and atypical parkinsonism. In postmortem brains from the ROS/MAP dataset of normal and pathological aging, decreased NHE6 expression was correlated with greater tau deposition. Our study provides an examination of the phenotypic range in female carriers of NHE6 mutations. The findings indicate that NHE6-related disease in females represents a new neurogenetic condition.

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Section: Discussion/conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Complex Neurological Phenotype in Female Carriers of NHE6 Mutations

et al. 2019

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“…MowatWilson syndrome results from a de novo dominant mutation or deletions in ZEB2 . Individuals with Christianson syndrome have seizures, severe developmental delay, ataxia, microcephaly, and a happy disposition [Christianson et al, 1999;Gilfillan et al, 2008;Schroer et al, 2010]. Christianson syndrome is X-linked and is caused by mutations in the SLC9A6 gene.…”

Section: Differential Diagnosismentioning

confidence: 99%

Molecular and Clinical Aspects of Angelman Syndrome

2011

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The Angelman syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2–q13 genomic region identifies 75–80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5–10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman syndrome is a prototypical developmental syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity.

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“…Thus, NHE6 has an important role in the growth of dendritic spines, and also in the development of normal brain wiring. Thus far, five SLC9A6 mutations have been reported in six AS families; two nonsense mutations, one inframe deletion, one frameshift deletion, and one splicing mutation [Gilfillan et al, 2008;Schroer et al, 2010]. The precise pathogenesis by which these mutations produce disease remains to be clarified.…”

Section: Neuropsychiatric Geneticsmentioning

confidence: 99%

A loss‐of‐function mutation in the SLC9A6 gene causes X‐linked mental retardation resembling Angelman syndrome

Takahashi

Hosoki

Matsushita

et al. 2011

American J of Med Genetics Pt B

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SLC9A6 mutations have been reported in families in whom X-linked mental retardation (XMR) mimics Angelman syndrome (AS). However, the relative importance of SLC9A6 mutations in patients with an AS-like phenotype or XMR has not been fully investigated. Here, the involvement of SLC9A6 mutations in 22 males initially suspected to have AS but found on genetic testing not to have AS (AS-like cohort), and 104 male patients with XMR (XMR cohort), was investigated. A novel SLC9A6 mutation (c.441delG, p.S147fs) was identified in one patient in the AS-like cohort, but no mutation was identified in XMR cohort, suggesting mutations in SLC9A6 are not a major cause of the AS-like phenotype or XMR. The patient with the SLC9A6 mutation showed the typical AS phenotype, further demonstrating the similarity between patients with AS and those with SLC9A6 mutations. To clarify the effect of the SLC9A6 mutation, we performed RT-PCR and Western blot analysis on lymphoblastoid cells from the patient. Expression of the mutated transcript was significantly reduced, but was restored by cycloheximide treatment, indicating the presence of nonsense mediated mRNA decay. Western blot analysis demonstrated absence of the normal NHE6 protein encoded for by SLC9A6. Taken together, these findings indicate a loss-of-function mutation in SLC9A6 caused the phenotype in our patient.

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Natural history of Christianson syndrome

Cited by 69 publications

References 13 publications

Complex Neurological Phenotype in Female Carriers of <b><i>NHE6</i></b> Mutations

Complex Neurological Phenotype in Female Carriers of <b><i>NHE6</i></b> Mutations

Molecular and Clinical Aspects of Angelman Syndrome

A loss‐of‐function mutation in the SLC9A6 gene causes X‐linked mental retardation resembling Angelman syndrome

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