Neurology · 15 h ago
PLAAT4 Variants Linked to Spinal-Predominant Demyelinating Leukodystrophy
A case series of 26 people from 11 families identified two recurrent PLAAT4 variants associated with a distinct leukodystrophy marked by leg spasticity and spinal cord abnormalities. The findings may help distinguish this disorder from multiple sclerosis, but the proposed lipid biomarker remains exploratory.
- Two PLAAT4 variants were linked to a distinct leukodystrophy.
- Spinal cord MRI abnormalities may precede brain involvement.
- Arachidonic acid–related lipids are candidate, not validated, biomarkers.
Researchers analyzed clinical, imaging and genetic data from 26 people in 11 unrelated families evaluated at four tertiary referral hospitals in China between July 2019 and August 2025. The case series included patients with unexplained spastic paraplegia and central nervous system white matter hyperintensities, as well as family members. Whole-exome sequencing identified recurrent heterozygous PLAAT4 variants, p.I14T and p.A96V; investigators also assessed plasma lipids and used an oligodendrocyte-specific knock-in mouse model to examine variant effects.
The variants were associated with a proposed autosomal dominant disorder termed spinal-predominant demyelinating leukodystrophy with leg spasticity. Onset ranged from 11 to 51 years (median 22). MRI showed variable brain white matter abnormalities and a more consistent pattern of symmetric, long-segment spinal cord lesions with atrophy. In presymptomatic carriers, spinal cord changes preceded brain involvement. Mouse-model findings supported a role for PLAAT4 gain-of-function in demyelination; patient lipidomics suggested arachidonic acid–related lipids as candidate markers associated with disability stage.
The authors suggest considering this diagnosis in people with unexplained spastic paraplegia and white matter abnormalities, including when multiple sclerosis is a diagnostic concern. The findings come from a relatively small case series, and the lipid findings do not establish a validated biomarker or clinical test.
In practice
For patients with unexplained spastic paraplegia and CNS white matter hyperintensities, the reported PLAAT4-associated phenotype may be a diagnostic consideration, particularly when spinal MRI shows symmetric, long-segment abnormalities with atrophy. The study describes 26 individuals from 11 families and does not establish prevalence, diagnostic test performance, or a treatment. Arachidonic acid–related lipid findings are exploratory and are not yet a validated biomarker for monitoring disease.
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JAMA Neurology: Gain-of-Function Variants in PLAAT4 and Spinal Predominant Demyelinating Leukodystrophy ↗This is an automated AI-condensed summary that has not yet been reviewed by an editor. Always consult the full item at the original source.