Fetal and Perinatal Brain MRI Findings in Adaptor Protein Complex 4–Associated Hereditary Spastic Paraplegia

Abstract

Purpose

Adaptor protein complex 4–associated hereditary spastic paraplegia (AP-4-HSP) is a rare childhood-onset neurogenetic disorder. With gene replacement therapies advancing, early—potentially prenatal—diagnosis holds significant clinical promise. We aimed to characterize fetal and perinatal brain MRI features of AP-4-HSP to assess whether early imaging can prompt timely diagnosis, counseling, and interventions.

Methods

In this retrospective analysis, we reviewed prenatal imaging from 303 individuals with genetically confirmed AP-4-HSP enrolled in the Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (NCT04712812). Four patients (covering SPG47, SPG50, SPG52) with fetal, perinatal, or early postmortem imaging available were selected for detailed neuroradiologic evaluation. Systematic assessment documented several structural anomalies, correlated with genotype and clinical progression.

Results

Fetal imaging between 22 and 38 weeks' gestation revealed ventriculomegaly, corpus callosum hypoplasia, reduced periventricular white matter, and hippocampal under-rotation across all subtypes. The SPG52 patient exhibited additional severe features, including gyral immaturity and pontine/vermis hypoplasia. Postnatal follow-up demonstrated progressive white matter volume reduction and delayed myelination.

Conclusions

This study demonstrates that fetal and perinatal brain MRI can detect early, consistent neurodevelopmental abnormalities in AP-4-HSP, reinforcing its classification as both a neurodevelopmental and neurodegenerative disorder. Integration of prenatal neuroimaging with molecular diagnostics could enable earlier recognition, family counseling, and access to emerging gene therapies. These findings support the incorporation of fetal brain MRI into diagnostic protocols for suspected neurogenetic conditions.