Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most
frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive
movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients
exhibit the pathognonomic “eye of the tiger” sign in the globus pallidus which corresponds to iron accumulation and
gliosis as shown in neuropathological examinations. The discovery of the disease causing mutations in PANK2 has linked
the disorder to coenzyme A (CoA) metabolism. PANK2 is the only one out of four PANK genes encoding an isoform
which localizes to mitochondria. At least two other NBIA genes (PLA2G6, C19orf12) encode proteins that share with
PANK2 a mitochondrial localization and all are suggested to play a role in lipid homeostasis.
With no causal therapy available for PKAN until now, only symptomatic treatment is possible. A multi-centre retrospective
study with bilateral pallidal deep brain stimulation in patients with NBIA revealed a significant improvement of
dystonia. Recently, studies in the PANK Drosophila model “fumble” revealed improvement by the compound pantethine
which is hypothesized to feed an alternate CoA biosynthesis pathway. In addition, pilot studies with the iron chelator deferiprone
that crosses the blood brain barrier showed a good safety profile and some indication of efficacy. An adequately
powered randomized clinical trial will start in 2012.
This review summarizes clinical presentation, neuropathology and pathogenesis of PKAN.
Keywords: PANK2, CoA, iron, neurodegeneration, lipid metabolism, mitochondria, NBIA, mitochondrial localization, pantethine, retinitis pigmentosa, dysarthria
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Published on: 18 July, 2012
Page: [1182 - 1189]