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Article History

Received: 26 March 2026

Accepted: 5 July 2026

First Online: 8 August 2026

Declarations

Ethics approval: Ethical approval was not required for this narrative review of previously published literature.

Competing interests: The authors declare no competing interests.

Consent to participate: Not applicable.

What is already known about this topic: Biallelic PPP1R21 variants cause a severe autosomal-recessive neurodevelopmental disorder (OMIM#619383) linked to the FERRY endosomal complex. Published case reports and small series describe global developmental delay, epilepsy, coarse facial features, and white-matter abnormalities, but no systematic phenotypic synthesis exists. Functional studies in patient fibroblasts suggest disrupted endo-lysosomal trafficking and altered proteasome activity

What this study adds: First comprehensive review of all 25 molecularly confirmed individuals, with phenotypic frequencies, standardized denominators, and individual-level data in Online Resources , , and . Description of a recurrent neuroimaging pattern combining supratentorial white-matter volume loss, thin corpus callosum, and cerebellar atrophy. A proposed pathophysiological model linking endosomal mRNA transport, proteostasis, and mTOR signaling, with a structured research agenda for preclinical validation