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

PLAAT4

Recurrent heterozygous PLAAT4 missense variants (p.I14T, p.A96V) with a gain-of-function effect, driving demyelination in an oligodendrocyte-specific knock-in mouse model

This Chinese case series (4 tertiary referral hospitals of the China Alliance for Rare Diseases) combines exome sequencing, imaging and plasma lipidomics in patients with unexplained spastic paraplegia and white matter hyperintensities. Twenty-six individuals from 11 unrelated families carry recurrent heterozygous PLAAT4 variants (p.I14T and p.A96V), associated with a novel autosomal dominant leukoencephalopathy named SPDMLS. Onset ranges from 11 to 51 years (median 22 years), with predominant spastic paraplegia and, on MRI, a symmetric long-segment "girdle-like" spinal cord hyperintensity with atrophy; in presymptomatic carriers, spinal cord changes precede brain involvement. An oligodendrocyte-specific knock-in mouse model supports a role for PLAAT4 gain of function in demyelination, and accumulation of arachidonic acid-related plasma lipids correlates with disability stage.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A new dominant leukodystrophy gene, with two recurrent missense variants to look for first when interpreting an exome or genome in spastic paraplegia. The practical stake is the differential diagnosis with multiple sclerosis, highlighted by the authors to avoid unnecessary immunosuppression: the long "girdle-like" spinal cord hyperintensity is a red flag worth remembering. The series is exclusively Chinese and the same two variants recur: replication in other populations and validation of the lipid biomarker are awaited.

Analysis by Dr Thibaut Benquey