Molecular characteristics

Pathophysiology
PLAA functions as a ubiquitin adaptor protein essential for endolysosomal degradation of synaptic membrane proteins. Loss of PLAA function leads to accumulation of K63-polyubiquitylated proteins and synaptic membrane proteins, disrupting synaptic vesicle recycling and neurotransmission. Additionally, PLAA loss impairs prostaglandin E synthesis, contributing to white matter pathology.

Diagnosis
Diagnosis is established through whole-exome or genome sequencing (trio-WES is particularly useful), identifying biallelic pathogenic variants in PLAA, in the context of the characteristic clinical and neuroimaging phenotype. No specific metabolic biomarker exists.