Recurrent Heterozygous PLAAT4 Variants in Animal Models of Spinal Predominant Demyelinating Leukodystrophy
A study found recurrent heterozygous variants in the PLAAT4 gene in patients with unexplained spastic paraplegia and brain white matter hyperintensities (WMH). MRI scans showed slow disease progression, with distinctive spinal cord WMH patterns. Changes in spinal cord signal occurred before brain changes in presymptomatic carriers.
- Tags
- #MSResearch
- Most relevant to
- —
- Human efficacy
- Not established from this source
- Mechanism
- Not reported
- Evidence strength
- Not graded
- Outcome
- Not reported
Why it matters
Identifying PLAAT4 variants contributes to understanding genetic factors in spinal predominant demyelinating disorders. It highlights a novel autosomal dominant leukoencephalopathy and suggests possible biomarkers for tracking disease progression.
What this does not prove
The study is limited by its case series nature, lacking a control group or randomization, which restricts the ability to draw strong causal conclusions.
Next milestone
No next milestone was established from the available source.
Study facts
- Study design
- Not reported
- Participants / samples
- 26 · basis not reported
- Randomised
- Not reported
- Controlled
- Not reported
- Primary endpoint met
- Not reported
- Relevant MS type
- Not reported
- Publication date
- 2026-10-26
- Evidence reviewed
- Abstract only
- Regulatory approval
- Not reported
- Research areas
- Not classified
- Biological target
- PLAAT4
- Pathway
- Not reported
- Population
- patients with unexplained spastic paraplegia and central nervous system (CNS) WMH
- Size of effect
- Not reported
- Secondary endpoints
- Symbol Digit Modalities Test scores ranged from 11 to 70 in 6 patients.
- MRI endpoints
- Heterogeneous brain WMH and a stereotyped pattern of symmetric, long-segment "girdle-like" spinal cord WMH.
- Biomarkers
- Arachidonic acid-related lipids suggested as a candidate biomarker for disease progression.
- Safety
- Not reported
Original sources
- Primary evidenceGain-of-Function Variants in PLAAT4 and Spinal Predominant Demyelinating Leukodystrophy. ↗DOI: 10.1001/jamaneurol.2026.3658
Supporting passages (10)
sample sizeRESULTS: Twenty-six individuals from 11 unrelated families were included; 4 patients underwent longitudinal follow-up for up to 5 years.
publication date2026-10-26
populationpatients with unexplained spastic paraplegia and central nervous system (CNS) WMH
findingsRecurrent heterozygous PLAAT4 (phospholipase A and acyltransferase 4) variants (p.I14T and p.A96V) were associated with a novel autosomal dominant leukoencephalopathy, named SPDMLS.
biological targetsPLAAT4
secondary endpointsSymbol Digit Modalities Test scores ranged from 11 to 70 in 6 available patients.
mri endpointsMagnetic 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.
biomarkersArachidonic acid-related lipids represent a candidate biomarker for disease progression.
limitationsTitle: Gain-of-Function Variants in PLAAT4 and Spinal Predominant Demyelinating Leukodystrophy.
peer reviewedPublication types: Journal Article
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