AP4S1 – Hereditary Spastic Paraplegia Type 52

Hereditary spastic paraplegia type 52 (SPG52) is a rare autosomal recessive neurodevelopmental disorder characterized by progressive lower-limb spasticity, delayed motor milestones, and exaggerated deep tendon reflexes. SPG52 arises from biallelic loss-of-function variants in AP4S1, which encodes the σ subunit of adaptor protein complex-4 critical for neuronal endosomal trafficking.

Genetic evidence includes two Rwandan siblings homozygous for a splice-site variant c.295-3C>A (PMID:40428364) and three unrelated probands with the canonical splice donor variant c.138+2T>G (PMID:32216065), all fitting an autosomal recessive inheritance pattern. No additional affected relatives were reported beyond these five probands. These biallelic splice variants disrupt AP-4 function, consistent with loss of function as the disease mechanism.

Functional studies demonstrate markedly reduced AP-4 complex formation in patient-derived fibroblasts and confirm abnormal splicing of exon 5 for c.295-3C>A via RNA-seq and RT-PCR (PMID:31660686). Morpholino-mediated knockdown of ap4s1 in zebrafish recapitulates key SPG52 phenotypes—altered CNS development, locomotor deficits, and neuronal hyperexcitability (PMID:32216065).

A cohort of 28 heterozygous carriers of the truncating variant c.289C>T (p.Arg97Ter) exhibited no neurological abnormalities (PMID:39865903), reinforcing that heterozygous AP4S1 variants are not sufficient to cause SPG52 and supporting a strictly recessive model.

Overall, the association between biallelic AP4S1 splice variants and SPG52 is rated as Strong based on five unrelated probands, clear autosomal recessive segregation, and concordant cellular and animal model data. Genetic evidence reaches Strong, and functional evidence is Moderate owing to patient cell assays and an in vivo zebrafish model.

Key take-home: Biallelic AP4S1 loss-of-function variants cause SPG52; early genetic testing facilitates timely diagnosis and targeted management.

References

• Genes • 2025 • A Rare Homozygous AP4S1 Variant in Rwandan Siblings with Autosomal Recessive Hereditary Spastic Paraplegia Type 52 (SPG52). PMID:40428364
• Annals of clinical and translational neurology • 2020 • Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52. PMID:32216065
• Human mutation • 2020 • Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia. PMID:31660686
• Annals of clinical and translational neurology • 2025 • Heterozygous variants in AP4S1 are not associated with a neurological phenotype. PMID:39865903

Evidence Based Scoring (AI generated)