Gain-of-Function Variants in PLAAT4 and Spinal Predominant Demyelinating Leukodystrophy

Importance: Leukoencephalopathies are clinically and etiologically heterogeneous disorders, and establishing a specific diagnosis remains challenging. Patients with unexplained spastic paraplegia and brain white matter hyperintensities (WMH) may be misdiagnosed as having multiple sclerosis, potentially exposing them to unnecessary immunosuppressive therapy. Objective: To define the clinical, radiological, and genetic features of spinal predominant demyelinating leukodystrophy with leg spasticity (SPDMLS). Design, Setting, and Participants: This case series involved participants from 4 tertiary referral hospitals within the China Alliance for Rare Diseases during the period July 2019 to August 2025. The study design integrated clinical evaluations and whole-exome sequencing (WES), as well as targeted plasma lipidomics correlated with SPATAX-EUROSPA disability stages. Variant pathogenicity was evaluated using an oligodendrocyte-specific knock-in mouse model. Participants were patients with unexplained spastic paraplegia and central nervous system (CNS) WMH and available family members, including presymptomatic carriers. Exposures: WES, genetic characterization, testing. Main Outcomes and Measures: Identification of disease-associated gene and characterization of clinical, radiological, and genetic features of SPDMLS. Results: Twenty-six individuals from 11 unrelated families were included; 4 patients underwent longitudinal follow-up for up to 5 years. Recurrent heterozygous PLAAT4 (phospholipase A and acyltransferase 4) variants (p.I14T and p.A96V) were associated with a novel autosomal dominant leukoencephalopathy, named SPDMLS. Age at onset was 11 to 51 years (median [IQR], 22 [15-29] years), with patients predominantly developing spastic paraplegia. Symbol Digit Modalities Test scores ranged from 11 to 70 in 6 available patients. Magnetic resonance imaging (MRI) demonstrated slow progression with heterogeneous brain WMH and a stereotyped pattern of symmetric, long-segment "girdle-like" spinal cord WMH accompanied by atrophy. Somatosensory- and motor-evoked potentials indicated dysfunction of the dorsal columns and corticospinal tracts, respectively. In presymptomatic carriers, spinal cord signal alterations preceded brain involvement. An oligodendrocyte-specific knock-in mouse model provided in vivo functional evidence supporting a role of PLAAT4 gain-of-function in driving demyelination, informing SPDMLS pathogenesis. Patient plasma lipidomics suggested accumulation of arachidonic acid-related lipids correlating with disability stage. Conclusions and Relevance: This study found that PLAAT4 variants delineated SPDMLS, a clinically distinct leukodystrophy that should be considered in patients with unexplained spastic paraplegia and CNS WMH. Arachidonic acid-related lipids represent a candidate biomarker for disease progression.