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A novel gene mutation in PANK2 in a patient with an atypical form of pantothenate kinase-associated neurodegeneration
European Journal of Medical Genetics 56 (2013) 606e608
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short clinical report
A novel gene mutation in PANK2 in a patient with an atypical form of pantothenate kinase-associated neurodegeneration E.A. Pérez-González a, O.F. Chacón-Camacho b, J. Arteaga-Vázquez a, J.C. Zenteno b, O.M. Mutchinick a, * a b
Departamento de Genética, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, México, D.F., Mexico Unidad de Investigación, Instituto de Oftalmología Conde de Valenciana y Departamento de Bioquímica, Facultad de Medicina, UNAM, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 June 2013 Accepted 24 August 2013 Available online 25 September 2013
Pantothenate kinase-associated neurodegeneration (PKAN) disease is an autosomal recessive neurodegenerative disorder with iron storage in the brain due to PANK2 gene mutations. Brain magnetic resonance imaging (MRI) shows the typical “eye-of-the-tiger” sign. The aim of the present study was to describe clinical, MRI and molecular findings in a 26-year-old male with atypical PKAN disease in whom, brain MRI scans showed bilateral pallidal T2-hypointensity with a small central region of T2hyperintensity, resembling the “eye-of-the-tiger” typical image. Genetic analysis identified two mutations in PANK2: c.1561G>A and c.1663G>A, being the latter never described before. Due to limited phenotypeegenotype correlation among patients with movement disorders, if “eye-of-the-tiger” brain MRI is present, PANK2 mutations investigation are needed to confirm PKAN disease. Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords: PANK2 new mutation Atypical PKAN disease
1. Introduction
2. Clinical report
Pantothenate kinase-associated neurodegeneration (PKAN) is the most common autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA) in the basal ganglia, showing the characteristic “eye of the tiger” sign in MRI T2 sequences [1e3], though it may not be pathognomonic for PKAN [4,5]. Known causative genes of NBIA disorders include PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17 [6]. PANK2, that encodes pantothenate kinase-2, is located on chromosome 20p13. Mutations in this gene are present in approximately 50% of NBIA patients. PANK2 is the main regulatory enzyme in coenzyme A (CoA) biosynthesis. CoA deficiency affects cellular energy production, fatty acid metabolism and increase cysteine accumulation that in the presence of iron may cause oxidative stress [7e10]. Although two main clinical forms, classic and atypical exist for PKAN disease, specific genotypeephenotype correlations are unknown [11].
Herein we report a Mexican 26-year-old male with an atypical form of PKAN disease referred to us due to severe dystonia. No familial history of the disease was observed. He was the product of the third uneventful pregnancy from healthy non-consanguineous parents, having two older healthy brothers. Delivery and postnatal period was normal. Delayed language acquisition, frequent falls, attention difficulties and motor tics began at the age of 4. Symptoms remained stable until age 20 when he started to develop dysarthria, dysphagia, rigidity, dystonia in upper and lower limbs and oromandibular muscles, choreoathetoid movements, gait impairment, visual field reduction and progressive difficulties to write. Intellectual development, strength, tendon reflexes and sensitivity were normal. Fundus oculi showed retinitis pigmentosa and a brain MRI scan shown the “eye-of-the-tiger” typical sign (Fig. 1a and b). Blood smear was negative for acanthocytes and serum ferritin, ceruloplasmin, albumin and lipoproteins were within reference values. 3. Methods
* Corresponding author. Departamento de Genética, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Vasco de Quiroga 15, Sección XVI, Tlalpan, 14000 México, D.F., Mexico. E-mail addresses: [email protected], [email protected] (O.M. Mutchinick). 1769-7212/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmg.2013.08.007
After obtaining informed consent, genomic DNA of the proband, his parents and healthy brothers, were extracted from peripheral lymphocytes by standard methods. Mutation screening was performed by means of PCR amplification of the entire coding sequence of PANK2 followed by direct automated sequencing of the
E.A. Pérez-González et al. / European Journal of Medical Genetics 56 (2013) 606e608
607
Fig. 1. (a) T2 weighted brain MRI showing hypointensity with central hyperintensity in both globi pallidi, “eye-of-the-tiger” sign (dashed circle). (b) Fundus oculi with retinitis pigmentosa. (c) Electropherogram of the patient showing the nucleotide variants at residues c.1561G>A in exon 6 and c.1663G>A in exon 7. (d) and (e) Electropherograms of the father and mother that are heterozygous for the c.1561G>A and the c.1663G>A substitutions, respectively.
7 exons and exon/intron junctions of the gene, using pairs of primers (Supplementary Table) derived from the PANK2 wild type sequence (Ensembl transcript number 00000316562). 4. Results Sequencing the complete coding region of PANK2 revealed that the patient is a compound heterozygote for two missense mutations. The first one is a known c.1561G>A in exon 6, causing a glycine to arginine substitution at position 521 (p.G521R) of the enzyme. The second one is a novel mutation c.1663G>A causing a glycine to serine substitution at position 555 of the protein (p.G555S) (Fig. 1c). Sequencing of both parents DNA confirmed that the mother was the carrier of the p.G555S novel mutation, while the father carries the known p.G521R substitution (Fig. 1d and e). Genetic analysis in DNA from two healthy brothers revealed that one of them was a heterozygous carrier of the novel p.G555S mutation while the other one carried two wild type PANK2 alleles. The novel p.G555S mutation was not present in DNA from 100 ethnically matched unrelated healthy controls (200 alleles) and was not annotated at the Exome Variant Server (http://evs.gs.washington.edu/EVS/) and the 1000 Genomes Project databases (www.1000genomes.org). 5. Discussion PKAN disease has two phenotypic forms: classic and atypical. Classic form initiates at 3e4 years of age and have a rapid progression. Dystonia is the earliest manifestation, followed by extrapyramidal symptoms, dysarthria, rigidity, choreoathetosis,
corticospinal tract impairment, cognitive decline, and retinal changes [1,4]. Atypical PKAN initiate at the end of the second decade, shows a slow and more heterogeneous progression, usually losing independent ambulation within 15e40 years after disease onset [4]. Natural history of the disease in our patient has two distinct components, the early onset of the disease and the slow progression of the neuromuscular symptoms, speech difficulty and psychiatric disturbances. Early onset is characteristic of the classic type but the slow progression is more frequently observed in the atypical form [1,4]. The number of mutations identified to date in the PANK2 gene is close to 100. These include aberrant splicing, missense and nonsense mutations [5,11]. The diagnosis of PKAN disease should be suspected, as well in patients with clinical characteristics as those present in our patient or the classical form of the disease, but showing the typical “eye-ofthe-tiger” sign in a brain MRI. The hypointense area observed in this sign is due to the iron accumulation, whereas the central bright spot probably represents fluid collection or edema [12,13]. The neurological manifestations and neuroradiological findings observed in our patient fulfill the clinical diagnostic criteria of atypical PKAN disease. DNA sequencing of the patient confirmed to be a compound heterozygote for two different mutations in PANK2 gene, the c.1561G>A (p.G521R) in exon 6, which is the most frequently reported (z30%), and a novel mutation, the c.1663G>A (p.G555S) in exon 7, not described before. The first one encodes for a protein that does not fold properly and interferes with its catalytic activity, reducing completely its enzymatic activity [10,14]. Mutation c.1663G>A (p.G555S) is not located near to an exon/intron boundary so it is unlikely to affect RNA processing.
608
E.A. Pérez-González et al. / European Journal of Medical Genetics 56 (2013) 606e608
In silico analysis of the novel p.G555S mutation using the PolyPhen2 software (Polymorphism Phenotyping, http://genetics.bwh. harvard.edu/pph2/) to predict its impact on the structure and function of PANK2 protein, indicated that the novel substitution is deleterious. Glycine-555 is phylogenetically conserved among PANK2 proteins from distinct species. The novel p.G555S mutation affects the PANK2 catalytic core which is composed by residues 211570, and thus is predicted to reduce the catalytic function of the protein. The above, allows us to hypothesize that probably this mutation preserves some activity of the enzyme, explaining to some extent the atypical clinical evolution of the disease in our patient. Almost all null mutations resulting in truncated proteins occurred in patients with the classic form of the disease, whereas missense mutations that preserve partial PANK2 activity were associated with atypical forms showing milder symptoms of the disease [4]. This phenomenon, known as interallelic complementation occurs when mutations in interacting domains of protein subunits are able to preserve partial function. This novel mutation increase the pool of gene mutations for PKAN, contributing to the wide spectrum of phenotypes reported. Conflict of interest The authors have no financial or personal relations that could pose a conflict of interest. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ejmg.2013.08.007. References [1] A. Gregory, B.J. Polster, S.J. Hayflick, Clinical and genetic delineation of neurodegeneration with brain iron accumulation, J. Med. Genet. 46 (2009) 73e80.
[2] S. Hayflick, M. Hartman, J. Coryell, J. Gitschier, H. Rowley, Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutation, Am. J. Neuroradiol. 27 (2006) 1230e1233. [3] S.J. Hayflick, Unraveling the HallervordeneSpatz syndrome: pantothenate kinase associated neurodegeneration is the name, Curr. Opin. Pediatr. 15 (2003) 572e577. [4] S.J. Hayflick, S.K. Westaway, B. Levinson, B. Zhou, M.A. Johnson, K.H. Ching, et al., Genetic, clinical, and radiographic delineation of HallervordeneSpatz syndrome, N. Engl. J. Med. 348 (2003) 33e40. [5] M.B. Hartig, K. Hortnagel, B. Garavaglia, G. Zorzi, T. Kmiec, T. Klopstock, et al., Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation, Ann. Neurol. 59 (2006) 248e256. [6] A. Gregory, S. Hayflick, Neurodegeneration with brain iron accumulation disorders overview, in: R.A. Pagon, T.D. Bird, C.R. Dolan, et al. (Eds.), GeneReviewsÔ [Internet], University of Washington, Seattle, Seattle (WA), 2013 Feb 28, 1993e2013, Available from: http://www.ncbi.nlm.nih.gov/books/ NBK121988/. [7] B. Zhou, S.K. Westaway, B. Levinson, M.A. Johnson, J. Gitschier, S.J. Hayflick, A novel pantothenate kinase gene (PANK2) is defective in HallervordeneSpatz syndrome, Nat. Genet. 28 (2001) 345e349. [8] K. Hortnagel, H. Prokisch, T. Meitinger, An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria, Hum. Mol. Genet. 12 (2003) 321e327. [9] M.A. Johnson, Y.M. Kuo, S.K. Westaway, et al., Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase associated neurodegeneration, Ann. N. Y. Acad. Sci. 1012 (2004) 282e298. [10] P.T. Kotzbauer, A.C. Truax, J.Q. Trojanowski, V.M. Lee, Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2, J. Neurosci. 25 (2005) 689e 698. [11] M.T. Pellecchia, E.M. Valente, L. Cif, S. Salvi, A. Albanese, V. Scarano, et al., The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration, Neurology 64 (2005) 1810e1812. [12] K.D. Sethi, R.J. Adams, D.W. Loring, T. el Gammal, Hallervorden Spatz syndrome: clinical and magnetic resonance imaging correlations, Ann. Neurol. 24 (1988) 692e694. [13] M. Savoiardo, W.C. Halliday, N. Nardocci, L. Strada, L. D’Incerti, L. Angelini, et al., HallervordeneSpatz disease: MR and pathologic findings, Am. J. Neuroradiol. 14 (1993) 155e162. [14] Y.M. Zhang, C.O. Rock, S. Jackowski, Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase associated neurodegeneration, J. Biol. Chem. 281 (2006) 107e114.
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short clinical report
A novel gene mutation in PANK2 in a patient with an atypical form of pantothenate kinase-associated neurodegeneration E.A. Pérez-González a, O.F. Chacón-Camacho b, J. Arteaga-Vázquez a, J.C. Zenteno b, O.M. Mutchinick a, * a b
Departamento de Genética, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, México, D.F., Mexico Unidad de Investigación, Instituto de Oftalmología Conde de Valenciana y Departamento de Bioquímica, Facultad de Medicina, UNAM, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 June 2013 Accepted 24 August 2013 Available online 25 September 2013
Pantothenate kinase-associated neurodegeneration (PKAN) disease is an autosomal recessive neurodegenerative disorder with iron storage in the brain due to PANK2 gene mutations. Brain magnetic resonance imaging (MRI) shows the typical “eye-of-the-tiger” sign. The aim of the present study was to describe clinical, MRI and molecular findings in a 26-year-old male with atypical PKAN disease in whom, brain MRI scans showed bilateral pallidal T2-hypointensity with a small central region of T2hyperintensity, resembling the “eye-of-the-tiger” typical image. Genetic analysis identified two mutations in PANK2: c.1561G>A and c.1663G>A, being the latter never described before. Due to limited phenotypeegenotype correlation among patients with movement disorders, if “eye-of-the-tiger” brain MRI is present, PANK2 mutations investigation are needed to confirm PKAN disease. Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords: PANK2 new mutation Atypical PKAN disease
1. Introduction
2. Clinical report
Pantothenate kinase-associated neurodegeneration (PKAN) is the most common autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA) in the basal ganglia, showing the characteristic “eye of the tiger” sign in MRI T2 sequences [1e3], though it may not be pathognomonic for PKAN [4,5]. Known causative genes of NBIA disorders include PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17 [6]. PANK2, that encodes pantothenate kinase-2, is located on chromosome 20p13. Mutations in this gene are present in approximately 50% of NBIA patients. PANK2 is the main regulatory enzyme in coenzyme A (CoA) biosynthesis. CoA deficiency affects cellular energy production, fatty acid metabolism and increase cysteine accumulation that in the presence of iron may cause oxidative stress [7e10]. Although two main clinical forms, classic and atypical exist for PKAN disease, specific genotypeephenotype correlations are unknown [11].
Herein we report a Mexican 26-year-old male with an atypical form of PKAN disease referred to us due to severe dystonia. No familial history of the disease was observed. He was the product of the third uneventful pregnancy from healthy non-consanguineous parents, having two older healthy brothers. Delivery and postnatal period was normal. Delayed language acquisition, frequent falls, attention difficulties and motor tics began at the age of 4. Symptoms remained stable until age 20 when he started to develop dysarthria, dysphagia, rigidity, dystonia in upper and lower limbs and oromandibular muscles, choreoathetoid movements, gait impairment, visual field reduction and progressive difficulties to write. Intellectual development, strength, tendon reflexes and sensitivity were normal. Fundus oculi showed retinitis pigmentosa and a brain MRI scan shown the “eye-of-the-tiger” typical sign (Fig. 1a and b). Blood smear was negative for acanthocytes and serum ferritin, ceruloplasmin, albumin and lipoproteins were within reference values. 3. Methods
* Corresponding author. Departamento de Genética, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Vasco de Quiroga 15, Sección XVI, Tlalpan, 14000 México, D.F., Mexico. E-mail addresses: [email protected], [email protected] (O.M. Mutchinick). 1769-7212/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmg.2013.08.007
After obtaining informed consent, genomic DNA of the proband, his parents and healthy brothers, were extracted from peripheral lymphocytes by standard methods. Mutation screening was performed by means of PCR amplification of the entire coding sequence of PANK2 followed by direct automated sequencing of the
E.A. Pérez-González et al. / European Journal of Medical Genetics 56 (2013) 606e608
607
Fig. 1. (a) T2 weighted brain MRI showing hypointensity with central hyperintensity in both globi pallidi, “eye-of-the-tiger” sign (dashed circle). (b) Fundus oculi with retinitis pigmentosa. (c) Electropherogram of the patient showing the nucleotide variants at residues c.1561G>A in exon 6 and c.1663G>A in exon 7. (d) and (e) Electropherograms of the father and mother that are heterozygous for the c.1561G>A and the c.1663G>A substitutions, respectively.
7 exons and exon/intron junctions of the gene, using pairs of primers (Supplementary Table) derived from the PANK2 wild type sequence (Ensembl transcript number 00000316562). 4. Results Sequencing the complete coding region of PANK2 revealed that the patient is a compound heterozygote for two missense mutations. The first one is a known c.1561G>A in exon 6, causing a glycine to arginine substitution at position 521 (p.G521R) of the enzyme. The second one is a novel mutation c.1663G>A causing a glycine to serine substitution at position 555 of the protein (p.G555S) (Fig. 1c). Sequencing of both parents DNA confirmed that the mother was the carrier of the p.G555S novel mutation, while the father carries the known p.G521R substitution (Fig. 1d and e). Genetic analysis in DNA from two healthy brothers revealed that one of them was a heterozygous carrier of the novel p.G555S mutation while the other one carried two wild type PANK2 alleles. The novel p.G555S mutation was not present in DNA from 100 ethnically matched unrelated healthy controls (200 alleles) and was not annotated at the Exome Variant Server (http://evs.gs.washington.edu/EVS/) and the 1000 Genomes Project databases (www.1000genomes.org). 5. Discussion PKAN disease has two phenotypic forms: classic and atypical. Classic form initiates at 3e4 years of age and have a rapid progression. Dystonia is the earliest manifestation, followed by extrapyramidal symptoms, dysarthria, rigidity, choreoathetosis,
corticospinal tract impairment, cognitive decline, and retinal changes [1,4]. Atypical PKAN initiate at the end of the second decade, shows a slow and more heterogeneous progression, usually losing independent ambulation within 15e40 years after disease onset [4]. Natural history of the disease in our patient has two distinct components, the early onset of the disease and the slow progression of the neuromuscular symptoms, speech difficulty and psychiatric disturbances. Early onset is characteristic of the classic type but the slow progression is more frequently observed in the atypical form [1,4]. The number of mutations identified to date in the PANK2 gene is close to 100. These include aberrant splicing, missense and nonsense mutations [5,11]. The diagnosis of PKAN disease should be suspected, as well in patients with clinical characteristics as those present in our patient or the classical form of the disease, but showing the typical “eye-ofthe-tiger” sign in a brain MRI. The hypointense area observed in this sign is due to the iron accumulation, whereas the central bright spot probably represents fluid collection or edema [12,13]. The neurological manifestations and neuroradiological findings observed in our patient fulfill the clinical diagnostic criteria of atypical PKAN disease. DNA sequencing of the patient confirmed to be a compound heterozygote for two different mutations in PANK2 gene, the c.1561G>A (p.G521R) in exon 6, which is the most frequently reported (z30%), and a novel mutation, the c.1663G>A (p.G555S) in exon 7, not described before. The first one encodes for a protein that does not fold properly and interferes with its catalytic activity, reducing completely its enzymatic activity [10,14]. Mutation c.1663G>A (p.G555S) is not located near to an exon/intron boundary so it is unlikely to affect RNA processing.
608
E.A. Pérez-González et al. / European Journal of Medical Genetics 56 (2013) 606e608
In silico analysis of the novel p.G555S mutation using the PolyPhen2 software (Polymorphism Phenotyping, http://genetics.bwh. harvard.edu/pph2/) to predict its impact on the structure and function of PANK2 protein, indicated that the novel substitution is deleterious. Glycine-555 is phylogenetically conserved among PANK2 proteins from distinct species. The novel p.G555S mutation affects the PANK2 catalytic core which is composed by residues 211570, and thus is predicted to reduce the catalytic function of the protein. The above, allows us to hypothesize that probably this mutation preserves some activity of the enzyme, explaining to some extent the atypical clinical evolution of the disease in our patient. Almost all null mutations resulting in truncated proteins occurred in patients with the classic form of the disease, whereas missense mutations that preserve partial PANK2 activity were associated with atypical forms showing milder symptoms of the disease [4]. This phenomenon, known as interallelic complementation occurs when mutations in interacting domains of protein subunits are able to preserve partial function. This novel mutation increase the pool of gene mutations for PKAN, contributing to the wide spectrum of phenotypes reported. Conflict of interest The authors have no financial or personal relations that could pose a conflict of interest. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.ejmg.2013.08.007. References [1] A. Gregory, B.J. Polster, S.J. Hayflick, Clinical and genetic delineation of neurodegeneration with brain iron accumulation, J. Med. Genet. 46 (2009) 73e80.
[2] S. Hayflick, M. Hartman, J. Coryell, J. Gitschier, H. Rowley, Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutation, Am. J. Neuroradiol. 27 (2006) 1230e1233. [3] S.J. Hayflick, Unraveling the HallervordeneSpatz syndrome: pantothenate kinase associated neurodegeneration is the name, Curr. Opin. Pediatr. 15 (2003) 572e577. [4] S.J. Hayflick, S.K. Westaway, B. Levinson, B. Zhou, M.A. Johnson, K.H. Ching, et al., Genetic, clinical, and radiographic delineation of HallervordeneSpatz syndrome, N. Engl. J. Med. 348 (2003) 33e40. [5] M.B. Hartig, K. Hortnagel, B. Garavaglia, G. Zorzi, T. Kmiec, T. Klopstock, et al., Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation, Ann. Neurol. 59 (2006) 248e256. [6] A. Gregory, S. Hayflick, Neurodegeneration with brain iron accumulation disorders overview, in: R.A. Pagon, T.D. Bird, C.R. Dolan, et al. (Eds.), GeneReviewsÔ [Internet], University of Washington, Seattle, Seattle (WA), 2013 Feb 28, 1993e2013, Available from: http://www.ncbi.nlm.nih.gov/books/ NBK121988/. [7] B. Zhou, S.K. Westaway, B. Levinson, M.A. Johnson, J. Gitschier, S.J. Hayflick, A novel pantothenate kinase gene (PANK2) is defective in HallervordeneSpatz syndrome, Nat. Genet. 28 (2001) 345e349. [8] K. Hortnagel, H. Prokisch, T. Meitinger, An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria, Hum. Mol. Genet. 12 (2003) 321e327. [9] M.A. Johnson, Y.M. Kuo, S.K. Westaway, et al., Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase associated neurodegeneration, Ann. N. Y. Acad. Sci. 1012 (2004) 282e298. [10] P.T. Kotzbauer, A.C. Truax, J.Q. Trojanowski, V.M. Lee, Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2, J. Neurosci. 25 (2005) 689e 698. [11] M.T. Pellecchia, E.M. Valente, L. Cif, S. Salvi, A. Albanese, V. Scarano, et al., The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration, Neurology 64 (2005) 1810e1812. [12] K.D. Sethi, R.J. Adams, D.W. Loring, T. el Gammal, Hallervorden Spatz syndrome: clinical and magnetic resonance imaging correlations, Ann. Neurol. 24 (1988) 692e694. [13] M. Savoiardo, W.C. Halliday, N. Nardocci, L. Strada, L. D’Incerti, L. Angelini, et al., HallervordeneSpatz disease: MR and pathologic findings, Am. J. Neuroradiol. 14 (1993) 155e162. [14] Y.M. Zhang, C.O. Rock, S. Jackowski, Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase associated neurodegeneration, J. Biol. Chem. 281 (2006) 107e114.