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Diagnostic utility of the ATG9A ratio in AP-4-associated hereditary spastic paraplegia

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],...

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Main Authors: Agianda, Habibah (Author) , Kim, Hyo-Min (Author) , Battaglia, Nicole (Author) , Rong, Joshua (Author) , Tam, Amy (Author) , Gonzalez Saez-Diez, Enrique (Author) , Boerkoel, Cornelius F. (Author) , Saffari, Afshin (Author) , Quiroz, Vicente (Author) , Schierbaum, Luca (Author) , Zaman, Zainab (Author) , Bernardi, Katerina (Author) , Ebrahimi-Fakhari, Darius (Author)
Format: Article (Journal)
Language:English
Published: 05 January 2026
In: Annals of Clinical and Translational Neurology
Year: 2026, Pages: 1-6
ISSN:2328-9503
DOI:10.1002/acn3.70308
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/acn3.70308
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/acn3.70308
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Author Notes:Habibah A.P. Agianda, Hyo-Min Kim, Nicole Battaglia, Joshua Rong, Amy Tam, Enrique Gonzalez Saez-Diez, Cornelius F. Boerkoel, Afshin Saffari, Vicente Quiroz, Luca Schierbaum, Zainab Zaman, Katerina Bernardi, Darius Ebrahimi-Fakhari
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Summary: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
Item Description:Gesehen am 12.03.2026
Physical Description:Online Resource
ISSN:2328-9503
DOI:10.1002/acn3.70308

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