AP-4関連遺伝性痙縮性対麻痺におけるATG9A比の診断的有用性

Adaptor protein complex 4-associated hereditary spastic paraplegia (AP-4-HSP), a childhood-onset neurogenetic disorder and frequent mimic of cerebral palsy, is caused by biallelic variants in the adaptor protein complex 4 (AP-4) subunit genes (AP4B1 [for SPG47], AP4M1 [for SPG50], AP4E1 [for SPG51], and AP4S1 [for SPG52]). Diagnosis is often confounded by variants of uncertain significance. We evaluated the ATG9A ratio, a measure of ATG9A mislocalization in patient-derived fibroblasts, as a functional assay of AP-4 deficiency. In six of eight individuals with suspected AP-4-HSP, the assay demonstrated loss of AP-4 function, establishing pathogenicity of novel variants. These findings support the ATG9A ratio as a clinically useful diagnostic tool for confirming AP-4-HSP and aiding the classification of novel variants. Trial Registration: ClinicalTrials.gov identifier: NCT06948019, NCT05518188, NCT06692712, NCT04712812.