Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

Abstract

Background: Phospholipase A2 group VI (PLA2G6) mutations associated with neurodegeneration (PLAN) manifest as heterogeneous neurodegenerative disorders with variable ages of onset. The genotype-phenotype correlation is not well-established. We aim to describe three adult patients with PLAN and combined these data with results from previous studies to elucidate adult-onset PLA2G6 phenotype-genotype correlations. Case presentations: The first index patient presented with dystonia-parkinsonism starting at age 31 years, accompanied by major depression and cognitive decline. Genetic analysis using targeted next generation sequencing (NGS) panel, Sanger sequencing, and segregation analyses revealed a compound heterozygous mutation, c.991G > T (p.D331Y)/c.1077G > A (M358IfsX), in PLA2G6. The other two patients had levodopa-responsive, early-onset parkinsonism, starting in their late twenties. Both patients had homozygous c.991G > T (p.D331Y) mutations in PLA2G6. Patient characteristics of our reported 3 cases were compared to those of 32 previously described (2008 to 2019) patients with adult-onset PLAN. Among the combined cohort of 35 patients with adult-onset PLAN, 14 had dystonia-parkinsonism, 17 had early-onset Parkinson's disease, 3 had hereditary spastic paraparesis, and one had ataxia. The c.991G > T (p. D331Y) mutation was almost exclusively found in Chinese patients, suggesting a common founder effect. All patients with homozygous p.D331Y mutations had levodopa-responsive, early-onset PD (100%); while other mutations mostly led to dystonia-parkinsonism, ataxia, spasticity, and combine psychiatric comorbidities. Conclusions: We showed that adult-onset PLAN could present as purely parkinsonism features, without brain iron accumulation, particularly patients with homozygous p.D331Y mutations. Compound heterozygous mutations, including heterozygous p.D331Y, produced heterogeneous phenotypes, without obvious levodopa responsiveness.

Severe Early‐Onset Parkinsonian Syndrome Caused by PLA2G6 Heterozygous Variants

“…One such condition is the rare, neurodegeneration with brain iron accumulation (NBIA)/ hereditary dystonia (DYT)/designated genes involved in familial Parkinson's disease (PARK)-PLA2G6 or autosomal recessive parkinsonism type 14 (Online Mendelian Inheritance in Man #612953), characterized by parkinsonism and early-onset dystonia. 1,[3][4][5][6] The clinical spectrum of NBIA/DYT/PARK-PLA2G6 comprises severe cognitive decline, psychiatric disorders such as depression and hallucinations, dysarthria, dysphonia, dysphagia, rigid-akinetic syndrome, ataxia, and epilepsy. 4,7 Herein we describe a Brazilian patient with early-onset neurodegeneration, iron brain accumulation on imaging, and heterozygous PLA2G6 variants, compatible with the early-onset dystonia-parkinsonism phenotype.…”

Initial survey of PLA2G6 missense variant causing neuroaxonal dystrophy in Papillon dogs in North America and Europe

“…Recently, the genotype-phenotype associations in human patients with NAD and PLA2G6 variants (so called PLAN disorders) were reviewed [ 4 , 5 ]. Interestingly, missense variants were also commonly reported in human patients with PLAN.…”

“…Interestingly, missense variants were also commonly reported in human patients with PLAN. However, in humans, variants were found throughout the gene and were not associated with age of disease onset or clinical presentation of the four PLAN subtypes [ 4 , 5 ]. While the affected Papillons present similarly to children with infantile NAD, an analogous variant has not yet been identified in human patients, although similar missense variants in the same domain are observed [ 4 ].…”

“…Neuroaxonal dystrophy (NAD) represents a group of autosomal recessive degenerative neuropathies characterized histopathologically by ‘spheroids’ in the central nervous system and caused by one of a few dysfunctional genes in humans [ 2 ] and various animal species including dogs [ 1 , 3 ]. In humans, variants in the phospholipase A2 group VI ( PLA2G6 ) gene, which encodes a calcium-independent enzyme essential for membrane integrity, cause PLA2G6 -associated neurodegeneration (PLAN) [ 4 , 5 ].…”

New Insights of Phospholipase A2 Associated Neurodegeneration Phenotype Based on the Long-Term Follow-Up of a Large Hungarian Family

“…At this is not always feasible, use of the term PLAN spectrum disease is more appropriate ( Ozes et al, 2017 ). Recently the spectrum was further expanded with complicated hereditary spastic paraparesis ( Koh et al, 2019 ) and pure Parkinsonism without iron accumulation also ( Chu et al, 2020 ). Intrafamilial discordant clinical phenotype such as spastic paraplegia and dopa responsive Parkinsonism with claval hypertrophy ad without brain iron accumulation was reported by Park et al (2019) .…”