PLAN is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in the PLA2G6 gene on chromosome 22q13.1, which encodes a calcium-independent phospholipase A2 enzyme involved in phospholipid remodeling and membrane homeostasis. The condition follows an autosomal recessive inheritance pattern. Genotype-phenotype correlations are present to a limited degree: individuals with two null (loss-of-function) alleles consistently develop INAD, while the less severe atypical NAD phenotype is caused almost exclusively by pathogenic missense variants. Certain pathogenic variants impair the catalytic activity of the PLA2G6 protein, while others are associated with alternative molecular mechanisms. The precise pathway by which PLA2G6 dysfunction leads to brain iron accumulation and neurodegeneration is an active area of investigation.

Diagnosis of PLAN is confirmed through molecular genetic testing demonstrating biallelic pathogenic variants in PLA2G6. Clinical suspicion for INAD arises in infants presenting with psychomotor regression, particularly when accompanied by elevated aspartate aminotransferase to alanine aminotransferase ratio and elevated lactate dehydrogenase. Neuroimaging, including MRI demonstrating cerebellar atrophy and, in older individuals, features such as the eye of the tiger sign in the globus pallidus, supports diagnosis. Electroencephalography is performed to evaluate for unrecognized seizure activity. Electromyography and nerve conduction studies may reveal peripheral neuropathy. Ophthalmologic examination assesses for optic atrophy. The differential diagnosis for INAD includes other conditions that present with early psychomotor regression and neurological progression, and laboratory findings in combination with neuroimaging help narrow the differential prior to molecular confirmation.

No disease-modifying pharmacological agent has received regulatory approval specifically for NBIA2A or PLAN. Available interventions are palliative and directed at specific manifestations. Pharmacological treatment of spasticity and seizures represents a primary supportive approach. For individuals with atypical INAD who have significant dystonia, oral or intrathecal baclofen has been utilized; deep brain stimulation has been reported in at least one individual with atypical NAD. Multidisciplinary evaluation at the time of diagnosis encompasses thorough ophthalmologic assessment, neurophysiological evaluation, and consultative input across relevant subspecialties. Periodic assessment of vision and hearing in nonverbal children is part of ongoing monitoring given the risk of progressive sensory deficits.

PLAN is a progressive neurodegenerative condition. INAD, the most severe phenotype, is characterized by relentless neurological deterioration following onset in infancy. The disease course in INAD is marked by progressive loss of motor and cognitive function, with affected individuals typically becoming nonverbal and nonambulatory. The atypical NAD phenotype and PLA2G6-related dystonia-parkinsonism generally have a slower rate of progression compared with INAD, with onset in later childhood or early adulthood. The overall prognosis varies with phenotype, though all three forms of PLAN are currently associated with significant progressive neurological disability.

One active clinical trial is registered addressing PLAN, investigating RT001 (a deuterated linoleic acid formulation) for infantile neuroaxonal dystrophy in a Phase 2 study (NCT03570931, sponsor: Biojiva LLC). The rationale for iron chelation in NBIA conditions, including PLAN, has been explored; the chelator deferiprone is under investigation for the PKAN form of NBIA, and results from these studies may inform potential future trials in PLAN. A proof-of-concept gene therapy strategy has also been described in the research literature. The published research base includes 76 classified articles, with case reports and case series representing the dominant publication type (21 case reports; 14 review articles), consistent with the rarity of the condition. Publications addressing gene therapy approaches and biomarkers are also represented.