General description

Phospholipase A2-Associated Neurodegeneration (PLAN) is a rare autosomal recessive disorder classified under Neurodegeneration with Brain Iron Accumulation (NBIA), a group of conditions marked by excessive iron deposits in the deep basal ganglia and extrapyramidal symptoms. PLAN is caused by mutations in the PLA2G6 gene, which encodes a calcium-independent phospholipase A2 enzyme crucial for maintaining cell membrane homeostasis and regulating lipid metabolism. These mutations result in disrupted phospholipid metabolism, mitochondrial dysfunction, oxidative stress, iron accumulation in specific brain regions such as the globus pallidus and substantia nigra, and subsequent neuronal loss and axonal degeneration.

PLAN manifests in two main clinical forms depending on the age of onset. Infantile Neuroaxonal Dystrophy (INAD) typically begins before the age of three and is characterized by rapid psychomotor regression, hypotonia that progresses to spasticity, cerebellar ataxia, optic atrophy leading to visual impairment, seizures, and dystonia. A slower-progressing form, known as Atypical Neuroaxonal Dystrophy (aNAD), usually presents in later childhood or adolescence. This variant includes symptoms such as gait disturbances, cerebellar ataxia, dystonia, parkinsonism, cognitive decline, speech difficulties including dysarthria, and persistent hypotonia.