The Clinical, Radiological and Genetic Spectrum of PLA2G6-Associated Neurodegeneration: An Experience From a Tertiary Center

Abstract

Background: Despite being the second most common type of neurodegeneration with brain iron accumulation, there is limited literature on PLA2G6-associated neurodegeneration (PLAN) within the Asian ethnicity, particularly in the Indian context.

Methods: We conducted a retrospective observational study on patients with pathogenic/likely pathogenic PLA2G6 variants based on exome sequencing.

Results: We identified 26 patients (22 families, 15 males) of genetically-confirmed PLAN with a median age of 22.5 years and age at onset of 13.0 years, encompassing various subtypes: infantile neuroaxonal dystrophy (5/26;19.2%), atypical neuroaxonal dystrophy (3/26;11.5%), dystonia-parkinsonism (5/26;19.2%), dystonia-parkinsonism-myoclonus (n = 4, 15.38%), early-onset Parkinson's disease (2/26;7.7%), complex dystonia (2/26;7.7%), and complicated hereditary spastic paraparesis (cHSP; 5/26;19.2%). The common initial symptoms included walking difficulty (7/26;26.9%), developmental regression (6/26;23.1%), and slowness (4/26;15.4%). Dystonia (14/26;53.8%), followed by parkinsonism (11/26; 42.3%), was the most common motor symptom. Non-motor symptoms included cognitive decline (12/26;46.2%) and behavioral changes (6/26;23.1%). Neuroimaging revealed cerebellar atrophy in 23/26 (88.5%) patients and claval hypertrophy in 80% (4/5) of INAD patients. Levodopa responsiveness was noted in 12 of 14 patients with parkinsonism/dystonia who received levodopa, and dyskinesia was noted in 10/11 patients. Genetic analysis revealed a total of 19 unique variants in PLA2G6 gene, of which 11 were novel. Twelve patients harbored the c.2222G>A variant, which is predominantly seen in Asian subpopulations.

Conclusions: The study introduces 26 new patients of PLAN and 12 patients associated with the c.2222G>A variant, potentially forming the most extensive single center series to date. It also expands the phenotypic, neuroimaging, and genotypic spectrum of PLAN.

Keywords: ANAD; Dystonia; HSP; INAD; PLA2G6; PLAN; early-onset Parkinson’s disease.

Figure 1

Magnetic resonance imaging of the brain of selected patients. A: Patient of early-onset parkinsonism (Patient-22). T1 mid-sagittal image showing claval (gracile tubercle) hypertrophy (yellow arrow). B: Patient of infantile neuroaxonal dystrophy (Patient-12). T2 mid-sagittal image showing vertically oriented splenium of the corpus callosum (red dotted circle). C: Patient of atypical neuroaxonal dystrophy (Patient-16). T2 coronal (C-1) and axial (C-2) images showing bilateral optic nerve atrophy (red arrow). D: Patient of complicated hereditary spastic paraparesis (Patient-13). SWI image showing mineralization of bilateral caudate (D-1, yellow arrowhead), putamen, globus pallidi (D-2, red arrow head), and substantia nigra (D-3, green arrow head). E: Patient of complicated hereditary spastic paraparesis (Patient-19). Fluid attenuated inversion recovery (FLAIR) axial image showing atrophy of bilateral caudate and generalized cerebral atrophy (white arrow). It also shows FLAIR hypointensity of bilateral putamen and globus pallidi.

Figure 2

Overview of the variants identified in this cohort. Image depicting the location of the identified variants in the PLA2G6 gene (Transcript ID: NM_003560.4). Novel variants are in italics, pathogenic variants are in red, likely pathogenic variants are in black and variant of uncertain significance are in blue.