Abstract
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
Current Drug Targets
Title:Pantothenate Kinase-Associated Neurodegeneration
Volume: 13 Issue: 9
Author(s): Monika B. Hartig, Holger Prokisch, Thomas Meitinger and Thomas Klopstock
Affiliation:
Keywords: PANK2, CoA, iron, neurodegeneration, lipid metabolism, mitochondria, NBIA, mitochondrial localization, pantethine, retinitis pigmentosa, dysarthria
Abstract: 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.
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Cite this article as:
B. Hartig Monika, Prokisch Holger, Meitinger Thomas and Klopstock Thomas, Pantothenate Kinase-Associated Neurodegeneration, Current Drug Targets 2012; 13 (9) . https://dx.doi.org/10.2174/138945012802002384
DOI https://dx.doi.org/10.2174/138945012802002384 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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