Clinical spectrum of the PLA2G6 gene

Background: The PLA2G6 gene encodes the enzyme A2-Phospholipase, responsible for phospholipid metabolism. This process is vital for the maintenance of the cell membrane. Disruption of this process leads to accumulation of cell products and development of spheroid bodies in the axons. This, in turn, leads to axonal loss and neuronal death. Pathogenic variants in the PLA2G6 can produce at least 3 distinct clinical entities: Infantile neuroaxonal dystrophy (NAD), atypical neuroaxonal dystrophy (aNAD), and the adult-onset PLA2G6-related dystonia-parkinsonism. These conditions are grouped under the term PLA2G6 associated neurodegeneration (PLAN), one type of NBIA (neurodegeneration with brain iron accumulation) syndromes. The NBIAs are a group of ultra-rare (less than 1 per million people) disease; their recognition is utmost importance in order to provide patients and caregivers adequate support and treatment. Objective: To describe the clinical spectrum of 4 cases PLA2G6-associated neurodegeneration in a neuromuscular center results of the 4 patients included in this study, 2 patients had a phenotype of PLA2G6- dystonia-parkinsonism. In addition to dystonia and parkinsonism, these patients presented with negative myoclonus and facial-faucial- finger myoclonus. The other 2 patients presented with a motor-neuron presentation. All patients had myoclonus and 3 of 4 patients had generalized epilepsy. Characteristic brain magnetic resonance imaging findings of low signal on T2/Flair weighted-imaging was observed in only one patient (the other 3 patients had cortical atrophy as the only imaging abnormality). None of the patients had attention deificts or a dysexecutive syndrome. Genetically, all patients were compound heterozygous for the condition. Conclusion: Pathogenic variants in the PLA2G6 can cause a devastating disease with varied clinical presentations and an unmet need of disease-modifying treatments. The present work aims to alert clinicians to these clinical features in order to provide prompt diagnosis and support to the patients and their caregivers.