Novel PLA2G6 mutations and clinical heterogeneity in Chinese cases with phospholipase A2-associated neurodegeneration

Introduction Phospholipase A2-associated neurodegeneration (PLAN) is an autosomal recessive movement disorder with abnormal iron deposition in basal ganglia, substantial nigra and adjacent areas, and cerebellar atrophy. It is caused by PLA2G6 mutations and comprises three phenotypes. We aimed to investigate genetic mutations in patients with predominantly extrapyramidal symptoms. Methods Eighteen Chinese patients with early onset of extrapyramidal symptoms were identified and underwent targeted next-generation sequencing, followed by Sanger sequencing. Detailed clinical and radiological features are presented. Prediction software was used to evaluate the pathogenicity of the identified variants. Results We identified 7 PLA2G6 variants including five known variants (c.668C > T, c.991G > T, c.1117G > A, c.1982C > T, and c.2218G > A) and two novel variants (c.1511C > T, and c.1915G > A) in four index cases. Among them, three cases had initial symptoms of difficulty walking or gait disturbance around the age of 30, and one case and his sibling developed mental handicap at age 7. Two cases exhibited a phenotype of “early parkinsonism” and the other two cases mimicked a phenotype of “hereditary spastic paraplegia (HSP)”. Iron deposition in globus pallidus and substantia nigra was seen in three cases. Cerebellar atrophy was present in all four cases. Conclusions Our study expands the mutation spectrum of the PLA2G6 gene and further supports the hypothesis that PLA2G6 mutations are associated with a continuous clinical spectrum from PLAN to HSP.