Pantothenate kinase-associated neurodegeneration

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.