NDPACX: a newly defined X-linked Parkinsonian syndrome associated with <i>SLC9A6</i> hemizygote mutation.

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X-linked female-restricted neurodegenerative disorder with Parkinsonian syndrome and cognitive impairment (NDPACX) is a recently recognized clinical entity caused by heterozygous mutations in SLC9A6 on the X chromosome, which encodes the endosomal Na⁺/H⁺ exchanger NHE6 that contributes to endolysosomal trafficking and acidification. While hemizygous SLC9A6 mutations in males cause Christianson syndrome, a severe neurodevelopmental disorder, emerging evidence indicates that female carriers may develop progressive, adult-onset Parkinsonian syndrome variably accompanied by cognitive decline and psychiatric symptoms. These features often resemble those of corticobasal degeneration, progressive supranuclear palsy, and atypical Parkinson's disease. Although pathological data for NDPACX are currently lacking, mechanistic inferences drawn from Christianson syndrome and animal models implicate endosomal dysfunction, impaired receptor recycling, and tau accumulation, depending on the loss of function. Furthermore, recent findings have linked reduced SLC9A6 expression to the increased vulnerability of the substantia nigra in sporadic Parkinson's disease, suggesting a broader relevance beyond rare monogenic disorders. In particular, NDPACX represents a model of endolysosomal neurodegeneration that may be related to lysosomal storage diseases or autophagy-related mechanisms commonly implicated in Parkinsonian syndromes. In this review, we summarize the clinical, molecular, and emerging pathological insights into NDPACX and propose that targeting endolysosomal homeostasis may open new therapeutic avenues for both hereditary and idiopathic neurodegenerative diseases characterized by proteinopathies.

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