Abstract
INTRODUCTION: Complex hereditary spastic paraplegias (HSPs) are defined by progressive spasticity with diverse neurological manifestations, complicating the diagnostic process. Pathogenic variants in genes encoding subunits of the adaptor protein complex-4 (AP4), including the AP4S1 gene, have been implicated in a subset of HSPs. CASE PRESENTATION: We report three siblings with complex HSP harboring pathogenic AP4S1 gene variants, focusing on the clinical characteristics and the diagnostic challenges and pitfalls. The patients exhibited common clinical features such as progressive spasticity, distinctive craniofacial features, and neurodevelopmental delays. Neuroimaging findings included agenesis of the corpus callosum and ventricular enlargement in two siblings, whereas one sibling demonstrated normal brain imaging. Initially, these cases were misdiagnosed as cerebral palsy, leading to unwarranted surgical interventions for tethered cord syndrome. Copy number variation analysis identified homozygous deletions in the AP4S1 gene. CONCLUSION: In patients with progressive spasticity, seizures, distinctive craniofacial features, and neuroimaging anomalies, AP4S1-related HSP should be considered in the differential diagnosis. Enhanced awareness and further studies are vital for improving diagnostic precision and management of these intricate neurogenetic disorders.