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Pantothenate kinase-associated neurodegeneration (PKAN) is the most common subtype of Neurodegeneration with Brain Iron Accumulation (NBIA), a group of rare inherited neurodegenerative disorders characterized by abnormal iron deposition in the basal ganglia, leading to progressive movement disorders.

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Etiopathogenesis

Genetics:

Mutations in pantothenate kinase 2 (PANK2) and phospholipase A2, group VI (PLA2G6) may interfere with synthesis and remodelling of the mitochondrial inner membrane lipid cardiolipin (panel a), giving rise to characteristic loss of cristae as seen in electron micrographs of Pank2-knockout mice90 and Pla2g6-knockout mice (panel b).  a | PANK2 is needed for the formation of coenzyme A (CoA) from pantothenate . CoA condenses with fatty acids to form acyl-CoA, which crosses into the mitochondrial matrix using the carnitine carrier system (not shown). Acyl-CoA in the mitochondrial matrix either delivers fatty acids for incorporation into complex intra-mitochondrial lipids such as cardiolipin or may alternatively undergo oxidation by the mitochondrial respiratory chain to generate ATP (not shown). The matrix membrane contains cardiolipin, a flexible molecule in which two fatty acid-bearing glycerol molecules are bridged by a single glycerol. Cardiolipins enable the inner membrane to bend and turn. PLA2G6 may remove damaged fatty acids to allow incorporation of flexible unsaturated fatty acids, such as linoleic acid, from the acyl-CoA pool in the matrix.  b | The mitochondrial inner membranes form convoluted structures known as cristae, and loss of cristae is characteristic of mouse models of PANK2 and PLA2G6 loss. Enzymes involved in maturation of mammalian cardiolipins are incompletely characterized, and 'new players and functions' are needed to understand how cardiolipins are synthesized Part b reproduced Beck, G. et al. Neuroaxonal dystrophy in calcium-independent phospholipase A2β deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes. J. Neurosci. 31, 11411–11420 (2011) Rouault, T. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14, 551–564 (2013). https://doi.org/10.1038/nrn3453

Mutations in pantothenate kinase 2 (PANK2) and phospholipase A2, group VI (PLA2G6) may interfere with synthesis and remodelling of the mitochondrial inner membrane lipid cardiolipin (panel a), giving rise to characteristic loss of cristae as seen in electron micrographs of Pank2-knockout mice90 and Pla2g6-knockout mice (panel b).  a | PANK2 is needed for the formation of coenzyme A (CoA) from pantothenate . CoA condenses with fatty acids to form acyl-CoA, which crosses into the mitochondrial matrix using the carnitine carrier system (not shown). Acyl-CoA in the mitochondrial matrix either delivers fatty acids for incorporation into complex intra-mitochondrial lipids such as cardiolipin or may alternatively undergo oxidation by the mitochondrial respiratory chain to generate ATP (not shown). The matrix membrane contains cardiolipin, a flexible molecule in which two fatty acid-bearing glycerol molecules are bridged by a single glycerol. Cardiolipins enable the inner membrane to bend and turn. PLA2G6 may remove damaged fatty acids to allow incorporation of flexible unsaturated fatty acids, such as linoleic acid, from the acyl-CoA pool in the matrix.  b | The mitochondrial inner membranes form convoluted structures known as cristae, and loss of cristae is characteristic of mouse models of PANK2 and PLA2G6 loss. Enzymes involved in maturation of mammalian cardiolipins are incompletely characterized, and 'new players and functions' are needed to understand how cardiolipins are synthesized Part b reproduced Beck, G. et al. Neuroaxonal dystrophy in calcium-independent phospholipase A2β deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes. J. Neurosci. 31, 11411–11420 (2011) Rouault, T. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14, 551–564 (2013). https://doi.org/10.1038/nrn3453

Pathophysiology:

![**MRI, pathology and potential molecular basis of PKAN:

a** | MRI of a patient with pantothenate kinase deficiency-associated neurodegeneration (PKAN) shows the classical 'eye of the tiger' sign on axial T2 fast spin-echo imaging. Hyperintense (white) signals indicative of tissue rarefaction are seen (centre of red rectangle) surrounded by areas of hypointensity (black areas) attributable to iron accumulation. b | Pathological changes in the globus pallidus (GP) of patients with PKAN showing iron (Fe) accumulation and increased ferritin that are not present in the GP of a healthy control subject. Prussian blue staining in a patient with PKAN to detect ferric iron (top row) demonstrates that iron accumulates in perivascular areas, diffuse neuropile, some intact neurons (arrows) and some astrocytes (short arrows in middle panel and intensely blue stained accumulations in right panel, where arrows point to degenerating neurons). Normal controls do not show iron accumulation (middle row). High ferritin was detected in neuronal and astrocytic remnants in patients with PKAN (bottom row, left and middle) but not in controls (bottom row, right)103.

Image in part a courtesy of S. Hayflick, Oregon Health & Science University, Portland, USA Part b courtesy of Kruer, M. C. et al. Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration. Brain 134, 947–958 (2011). Rouault, T. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14, 551–564 (2013). https://doi.org/10.1038/nrn3453](attachment:7f48859a-9c55-4685-8744-eca7d8f3582a:image.png)

**MRI, pathology and potential molecular basis of PKAN:

a** | MRI of a patient with pantothenate kinase deficiency-associated neurodegeneration (PKAN) shows the classical 'eye of the tiger' sign on axial T2 fast spin-echo imaging. Hyperintense (white) signals indicative of tissue rarefaction are seen (centre of red rectangle) surrounded by areas of hypointensity (black areas) attributable to iron accumulation. b | Pathological changes in the globus pallidus (GP) of patients with PKAN showing iron (Fe) accumulation and increased ferritin that are not present in the GP of a healthy control subject. Prussian blue staining in a patient with PKAN to detect ferric iron (top row) demonstrates that iron accumulates in perivascular areas, diffuse neuropile, some intact neurons (arrows) and some astrocytes (short arrows in middle panel and intensely blue stained accumulations in right panel, where arrows point to degenerating neurons). Normal controls do not show iron accumulation (middle row). High ferritin was detected in neuronal and astrocytic remnants in patients with PKAN (bottom row, left and middle) but not in controls (bottom row, right)103.

Image in part a courtesy of S. Hayflick, Oregon Health & Science University, Portland, USA Part b courtesy of Kruer, M. C. et al. Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration. Brain 134, 947–958 (2011). Rouault, T. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14, 551–564 (2013). https://doi.org/10.1038/nrn3453

Clinical Features

Onset:

Classical PKAN: