| Null (loss-of-function) mutations | Homozygous or compound heterozygous null alleles (frameshifts, nonsense, splice-site mutations) cause complete loss of PANK2 activity and are associated with the classic, severe form of PKAN . |
| Missense mutations | Point mutations that result in amino acid substitutions with residual enzyme activity are more commonly associated with atypical PKAN and later onset. |
| Common variants | The c.1561G>A (p.Gly521Arg) and c.1583C>T (p.Thr528Met) mutations are among the most frequently identified variants in European populations. |
| Genotype-phenotype correlations | Disease severity generally correlates with the degree of residual PANK2 enzyme activity. Patients with two null alleles typically exhibit earlier onset and more rapid decline . |
| Selective vulnerability | The globus pallidus and substantia nigra are particularly affected, likely because these regions have the highest baseline iron concentrations and are metabolically active. |
| Iron-mediated toxicity | Excess iron catalyzes the generation of hydroxyl radicals through the Fenton reaction, causing oxidative damage to lipids, proteins, and DNA . |
| Neuroaxonal dystrophy | Iron deposits are associated with swollen axons (spheroids) and neuroaxonal dystrophy, contributing to progressive neuronal dysfunction. |
| Age of onset | After age 10, typically in the teens to early twenties . |
| Gait disturbance | Usually the first symptom, with progressive difficulty walking due to dystonia and rigidity. |
| Corticospinal tract signs | Spasticity, hyperreflexia, and extensor plantar responses. |
| Pigmentary retinopathy | Present in approximately two-thirds of classic PKAN patients; may be detected before neurological symptoms. |
| Cognitive decline | Progressive intellectual deterioration, though often less prominent than motor disability. |
| Databases | OMIMOrphanetClinicalTrialsPubMed |
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