Complex Neurological Phenotype in Female Carriers of Mutations.

Mutations in (also termed ) 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 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 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 expression was correlated with greater tau deposition. Our study provides an examination of the phenotypic range in female carriers of mutations. The findings indicate that NHE6-related disease in females represents a new neurogenetic condition.