Objective: To characterize the spectrum of phenotypes of PLA2G6-associated neurodegeneration in a single patient.

Background: The phospholipase A2 Group VI (PLA2G6) gene encodes a cytosolic and mitochondrial enzyme involved in lipid metabolism. Loss of PLA2G6 function causes cell membrane instability and axonal damage. PLA2G6-associated neurodegeneration (PLAN) encompasses four distinct phenotypes: infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, dystonia-Parkinsonism, and early onset Parkinsonism. Classic imaging findings include cerebellar atrophy and hypointense globus pallidi, suggestive of brain iron accumulation.   However, many cases do not fit into the typical categories, which can make diagnosis challenging.

Method: We reviewed the chart of a person with genetically confirmed PLAN with video examination.

Results: A 43-year-old right-handed Caucasian man presented with five years of progressive walking difficulties. He had no significant birth history but had mild motor developmental delay and a speech impediment. Pertinent exam findings included swan-neck deformities in bilateral hands, mild cognitive impairment, dysarthria, saccadic vertical pursuits, no nystagmus, reduced sensation to vibration and proprioception in distal bilateral lower extremities, moderate hypomimia, mildly increased tone in the upper extremities, mild slowness of rapid alternating movements, appendicular and truncal ataxia, wide-based gait with internally rotated right foot, requiring a walker with one-person assistance. MRI brain showed mild cerebral atrophy, moderate cerebellar atrophy, and chronic right frontal strokes. DaT scan was positive with bilateral reduced uptake. The patient had initial good response to carbidopa/levodopa but developed early dyskinesias at higher doses. Ceruloplasmin, Fragile X PCR, TSH, Celiac panel, ANA, Vitamin B12 and folate were negative. Initial genetic testing was positive for variants of unknown significance in BIN1 and RYR1 genes, inconsistent with his phenotype. A comprehensive ataxia panel revealed a heterozygous pathogenic variant in the PLA2G6 gene.

Conclusion: Features of multiple PLAN phenotypes can present in an individual without evidence of iron accumulation on brain imaging. PLA2G6 mutations should be investigated for young-onset neurodegenerative disease characterized by ophthalmoparesis, dysarthria, ataxia, and Parkinsonism.

References: 1. Gregory A, Kurian MA, Maher ER, et al. PLA2G6-Associated Neurodegeneration. 2008 Jun 19 [Updated 2017 Mar 23]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1675/ 2. Guo YP, Tang BS, Guo JF. PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes. Front Neurol. 2018;9:1100. Published 2018 Dec 18. doi:10.3389/fneur.2018.01100 3. Wang ZB, Liu JY, Xu XJ, et al. Neurodegeneration with brain iron accumulation: Insights into the mitochondria dysregulation. Biomed Pharmacother. 2019;118:109068. doi:10.1016/j.biopha.2019.109068

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