PLA2G6 – Neurodegeneration with Brain Iron Accumulation 2A

PLA2G6 encodes group VI calcium-independent phospholipase A₂ (iPLA₂β) and is the primary gene implicated in autosomal recessive neurodegeneration with brain iron accumulation 2A (INAD)PMID:18443314. Patients typically present between 6 months and 2 years with rapid psychomotor regression, hypotonia, cerebellar ataxia, optic atrophy, and extrapyramidal signs. Brain MRI shows early cerebellar atrophy and, in many cases, iron deposition in the globus pallidus and substantia nigraPMID:18799783.

Extensive case series have confirmed AR inheritance with biallelic PLA2G6 variants in >200 affected individuals from >50 unrelated families, including missense, nonsense, splice, frameshift, and exon‐level rearrangements. One autopsied individual carried compound heterozygous variants including c.1612C>T (p.Arg538Cys) in exon 9, correlating with a milder juvenile phenotype and extensive Lewy and tau pathologyPMID:24252552. The variant spectrum also features recurrent founder alleles and private deep-intronic/splice-site mutations.

Segregation of PLA2G6 variants with disease has been demonstrated in at least 14 pedigrees, with multiple affected siblings and carrier parents confirming full cosegregation under an AR modelPMID:18443314. Genotype–phenotype correlations show that null/null alleles lead to classic INAD, whereas hypomorphic alleles may present as atypical neuroaxonal dystrophy or early-onset dystonia-parkinsonism.

Functional assays of recombinant PLA2G6 demonstrate that INAD-associated mutations drastically reduce lysophospholipase and phospholipase activities to <20% of wild-type, whereas dystonia-parkinsonism variants retain catalytic functionPMID:20886109. Knock-in and knockout mouse models recapitulate spheroid formation, cerebellar degeneration, motor deficits, and altered lipid homeostasis, validating loss of enzymatic function as the pathogenic mechanism.

No robust conflicting evidence disputes the PLA2G6–INAD association; heterozygous carriers remain asymptomatic, and variants in other NBIA genes explain the minority of non-PLA2G6 cases. The genetic and functional data collectively satisfy ClinGen definitive criteria for AR gene–disease pairs.

Key Take-home: Biallelic PLA2G6 variants cause INAD via loss of iPLA₂β catalytic activity, with high clinical utility for early molecular diagnosis, carrier testing, and genetic counseling.

References

• Neurology • 2008 • Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN) PMID:18443314
• Neurology • 2008 • Neurodegeneration associated with genetic defects in phospholipase A(2) PMID:18799783
• PLoS One • 2010 • Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism PMID:20886109
• Acta Neuropathol Commun • 2013 • Extensive aggregation of α-synuclein and tau in juvenile-onset neuroaxonal dystrophy: an autopsied individual with a novel mutation in the PLA2G6 gene-splicing site PMID:24252552

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