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. 2019 Apr;5(2):98-108.
doi: 10.1159/000496341. Epub 2019 Mar 6.

Complex Neurological Phenotype in Female Carriers of NHE6 Mutations

Affiliations

Complex Neurological Phenotype in Female Carriers of NHE6 Mutations

Matthew F Pescosolido et al. Mol Neuropsychiatry. 2019 Apr.

Abstract

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.

Keywords: Christianson syndrome; Female carriers; Na+/H+ exchanger 6 (NHE6); X-chromosome inactivation (XCI).

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Figures

Fig. 1
Fig. 1
Neurocognitive profile of female carriers of NHE6 mutations from Christianson syndrome (CS) pedigrees. a Neuropsychological assessments were performed on 13 female carriers from 7 CS pedigrees. Mean female carrier age was 30.1 ± 15.9 years, with a range of approximately 3 years to 55 years. Domains with mean z-scores less than −1.5 in female carriers were visuospatial function, attention, and executive function. Individual z-scores are represented by red dots and mean z-scores per domain are denoted by a black bar. The z-score range from 1.5 to −1.5 is shaded in light gray to represent a non-clinical range. b Distribution of visuospatial, attention, and executive function deficits across individual female carriers (n = 12 participants with impairments in at least one of these domains). Impairment spanning all domains was the most common.
Fig. 2
Fig. 2
Neurocognitive profile of pediatric (i.e., < 18 years old) and adult (i.e., ≥18 years old) female carriers of NHE6 mutations. a Age distribution of all enrolled female carriers (i.e., age at enrollment). b Age distribution of female carriers with neurocognitive assessments (i.e., age at testing). c–i Comparison of pediatric versus adult female carriers across neurocognitive domains. Pearson correlation analyses were conducted to examine the association between age (i.e., pediatric or adult) and neurocognition. There were no statistically significant age effects found in any domain. Ages of pediatric female carriers (n = 4) ranged from approximately 4–17 years (average age 10.3 ± 4.6 years); ages of adult female carriers (n = 9) ranged from approximately 25–55 years (average age 38.9 ± 9.3 years). All neurocognitive domains were assessed in the 4 pediatric participants, except for language (n = 3). Neurocognitive data are reported as mean ± SEM.
Fig. 3
Fig. 3
a, b MRI scans of a female heterozygous for NHE6 mutation at approximately age 65 years show frontoparietal atrophy; the individual was diagnosed with corticobasal degeneration (CBD). Axial FLAIR (a) and T2-weighted (b) images show asymmetrical atrophy of the left frontal and parietal lobes.
Fig. 4
Fig. 4
a–g MRI scans of a female heterozygous for NHE6 mutation at approximately age 51 show cerebellar atrophy; the individual was diagnosed with atypical parkinsonism. a The sagittal T1-weighted image demonstrates cerebellar atrophy. Axial FLAIR (b–d) and T2-weighted (e–g) images through the cerebellar hemispheres further highlight diffuse cerebellar volume atrophy.

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