PPP1R21-Related neurodevelopmental disorder: Phenotypic delineation, variant spectrum, and pathophysiological...

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Rare Diseases

Background:

• PPP1R21-related neurodevelopmental disorder (PPP1R21-NDD) is an ultra-rare autosomal-recessive encephalopathy.
• It stems from the dysfunction of the Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY (FERRY) complex.

Purpose of the Study:

• To delineate the clinical, neuroimaging, and molecular spectrum of PPP1R21-NDD.
• To outline diagnostic and research priorities for this condition.

Main Methods:

• Conducted targeted literature searches across major scientific databases (PubMed, EMBASE, Scopus, Web of Science, Google Scholar).
• Included molecularly confirmed biallelic PPP1R21 cases and related functional studies.
• Performed independent data extraction by two researchers following narrative review quality criteria.

Main Results:

• Analyzed 25 individuals from 21 families with 17 distinct PPP1R21 variants (15 loss-of-function, 2 missense), all homozygous.
• Universal findings included profound global developmental delay/intellectual disability and near-universal hypotonia (88%).
• Observed a characteristic facial gestalt, delayed/ataxic ambulation, minimal expressive language, feeding dysfunction, respiratory morbidity, and 17% mortality.
• Neuroimaging revealed callosal thinning, white-matter volume loss, ventricular enlargement, and vermian hypoplasia.
• Fibroblast studies indicated delayed transferrin clearance and elevated proteasome activity, suggesting endosomal dysfunction and proteasome hyperactivation.

Conclusions:

• PPP1R21-NDD presents as a severe recessive encephalopathy with a convergent phenotype and evidence of endo-lysosomal dysfunction.
• Diagnosis warrants exome/genome sequencing in patients with characteristic features, especially in consanguineous families.
• Research priorities include natural history studies, standardized MRI protocols, neural disease models, and therapeutic strategies targeting endosomal trafficking.