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

Background And Objectives: Variations in cause the X-linked neurologic disorder Christianson syndrome in males. Meanwhile, female carriers with variations may remain asymptomatic or develop intellectual disability, behavioral problems, and psychiatric illnesses. Only a few female carriers have been reported to have associated atypical parkinsonism in late life.

Methods: We present a Japanese family with a novel variation identified by quad whole-exome sequencing analysis and a reverse phenotyping strategy. The molecular and cellular impacts of the W89R variation in vitro were examined.

Results: The missense variation (c.265T>C, p.Trp89Arg) in cosegregated with atypical parkinsonism and intellectual disability in female carriers of this family. The female carriers in this family presented with bradykinesia, rigidity, and tremor, predominately on the right side. We found that the W89R variation changed membrane traffic of NHE6-harboring vesicles, indicating potential involvement in the disease pathogenesis.

Discussion: This study might have revealed an example of a monogenic origin of atypical parkinsonism in females with variations and draw attention to this understudied female-specific phenotype in clinical practice.