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

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.

Novel SLC9A6 Variation in Female Carriers With Intellectual Disability and Atypical Parkinsonism

“… 2 Moreover, it was found in postmortem brain tissues that decreased NHE6 expression was correlated with greater tau deposition. 10 Our study further suggests that SLC9A6 variations might be associated with tau-related syndromes in females in late life.…”

Case Report: Christianson Syndrome Caused by SLC9A6 Mutation: From Case to Genotype-Phenotype Analysis

“…Moreover, deposition of tau may be mediated by the interaction with the mutant SLC9A6 protein (Garbern et al, 2010). After using a conservative genome-wide correction, it was found that the low expression of SLC9A6 was significantly related to increased tau deposition (Pescosolido et al, 2019). The most obvious pathological event in several neurodegenerative diseases is the aggregation of tau subtypes into the filamentous content of neurons, resulting in hyperphosphorylation of tau proteins (Buée et al, 2000).…”

Christianson syndrome: A novel splicing variant of SLC9A6 causes exon skipping in a Chinese boy and a literature review

“…Contrast to male, female variant carriers show milder phenotypes with variable penetrance 4,10 . Affected CS patients show a remarkable neurological symptom may be due to high‐level expression of mutant SLC9A6 gene in the central nervous system 11,12 …”

“… 4 , 10 Affected CS patients show a remarkable neurological symptom may be due to high‐level expression of mutant SLC9A6 gene in the central nervous system. 11 , 12 …”