PLA2G6 – PLA2G6-associated Neurodegeneration with Brain Iron Accumulation

PLA2G6-associated neurodegeneration (PLAN) is an autosomal recessive disorder characterized by early-onset neuroaxonal dystrophy and iron deposition in the basal ganglia, classified under the umbrella of neurodegeneration with brain iron accumulation (NBIA). Clinical diagnosis relies on characteristic MRI findings such as the "eye-of-the-tiger" sign and progressive extrapyramidal symptoms including dystonia, rigidity, chorea, and dyskinesia.

Genetic evidence supports a definitive association between PLA2G6 and NBIA. A systematic review identified 391 patients, of whom 340 were included for detailed genotype–phenotype assessment, revealing biallelic PLA2G6 variants in all subtypes of PLAN (PMID:37285793). Segregation analyses in consanguineous families (e.g., R632W homozygosity co-segregating with dystonia-parkinsonism in an Iranian pedigree) confirm autosomal recessive inheritance (PMID:19087156).

The variant spectrum is broad, encompassing missense, loss-of-function, splice-site, and frameshift mutations. Recurrent alleles such as c.1894C>T (p.Arg632Trp) and c.1799G>A (p.Arg600Gln) have been observed across unrelated families, indicating potential mutational hotspots or founder effects (PMID:36790591). Loss-of-function mutations predominate in infantile presentations, whereas hypomorphic alleles often underlie later-onset parkinsonism.

Functional studies demonstrate that NBIA-associated PLA2G6 mutations abolish catalytic activity in phospholipid hydrolysis assays, with mutant proteins showing <20% of wild-type activity (PMID:20886109). Mouse and Drosophila models recapitulate key pathological features including axonal spheroids, motor impairment, and neurodegeneration, and have been used to validate pathomechanisms and therapeutic interventions (PMID:23467909; PMID:29440694).

Neuropathological analysis reveals widespread alpha-synuclein-positive Lewy bodies and hyperphosphorylated tau accumulation, linking PLAN to parkinsonian disorders and underscoring its clinical heterogeneity (PMID:20619503). Recent therapeutic studies demonstrate that dietary docosahexaenoic acid (DHA) supplementation rescues locomotor deficits in PLA2G6 mutant zebrafish and mice, highlighting potential avenues for clinical intervention (PMID:34520727).

Overall, the evidence for PLA2G6 in NBIA meets criteria for a definitive gene–disease relationship. Genetic testing for PLA2G6 variants is clinically useful for diagnosis, prognostication, and genetic counseling. Functional characterization and emerging therapeutic models pave the way for targeted interventions.

Key take-home: Biallelic PLA2G6 variants cause autosomal recessive NBIA with consistent neuroimaging, genetic, and functional hallmarks, supporting routine PLA2G6 testing in suspected PLAN cases.

References

• Parkinsonism & related disorders • 2023 • A systematic analysis of genotype-phenotype associations with PLA2G6. PMID:37285793
• European journal of neurology • 2009 • R632W mutation in PLA2G6 segregates with dystonia-parkinsonism in a consanguineous Iranian family. PMID:19087156
• PloS One • 2010 • Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. PMID:20886109
• Histology and histopathology • 2013 • Mouse models of human INAD by Pla2g6 deficiency. PMID:23467909
• Scientific reports • 2018 • Mutations in the Drosophila homolog of human PLA2G6 give rise to age-dependent loss of psychomotor activity and neurodegeneration. PMID:29440694
• Neurobiology of aging • 2012 • Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. PMID:20619503
• Experimental neurology • 2021 • PLA2G6 mutations cause motor dysfunction phenotypes of young-onset dystonia-parkinsonism type 14 and can be relieved by DHA treatment in animal models. PMID:34520727

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