Elevated serum autotaxin levels and multiple system atrophy-like presentation in a patient with PLA2G6-associated neurodegeneration

Abstract

PLA2G6-associated neurodegeneration (PLAN) encompasses a spectrum of phenotypes caused by biallelic pathogenic variants in PLA2G6. Initially linked to infantile and atypical neuroaxonal dystrophy, PLAN now includes adult-onset conditions such as dystonia-parkinsonism, ataxia, and spastic paraplegia. We report a female patient presenting young-onset parkinsonism with pyramidal tract signs, cerebellar atrophy, and autonomic dysfunction, mimicking multiple system atrophy (MSA). Neuroimaging showed decreased dopamine uptake and cerebellar hypoperfusion. Genetic analysis identified a homozygous pathogenic variant in PLA2G6 (c.967G>A, p.Val323Met), confirming a diagnosis of PLAN. Interestingly, elevated serum autotaxin levels (4.67 ng/mL) without liver abnormalities. Bilateral brachymetatarsia was also observed, which may indicate an association with the PLA2G6 variant. This case underscores the importance of considering PLAN in cases of young-onset parkinsonism with multisystem involvement. Genetic testing is crucial for accurate diagnosis and management of such cases. Elevated serum autotaxin levels may be associated with decreased phospholipase activity in PLAN and warrants further investigation.

Fig. 1

Imaging studies of the patient. a Plain radiographs of both feet. b Magnetic resonance imaging of the brain. Sagittal view of T1-weighted imaging (left) shows cerebellar atrophy. Fluid-attenuated inversion recovery (top right) shows no abnormal high-intensity lesions. T2*-weighted imaging (bottom right) shows no evidence of iron deposition. c Single-photon emission computed tomography with ¹²³I-labeled iofetamine. Cerebellar blood flow is decreased. d Dopamine transporter scintigraphy. Decreased uptake, predominantly on the right side, was observed. The uptake was bean-shaped, not the dot-shaped uptake typically observed in Parkinson’s disease

Fig. 2

Electropherograms of the direct nucleotide sequencing analysis of the proband and both parents. The c.967G>A variant was homozygous in the proband, and heterozygous in both parents

Fig. 3

Schematic overview of the lysophosphatidic acid (LPA) signaling pathway. Changes associated with decreased PLA2G6 activity in our proposed hypothesis are shown in red. LPA lysophosphatidic acid, LPC lysophosphatidylcholine, PLA₂ phospholipase A₂