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Susanne A. Schneider - One of the best experts on this subject based on the ideXlab platform.
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Pantothenate Kinase-Associated NeurodeGeneration
Movement Disorders Curricula, 2017Co-Authors: Susanne A. SchneiderAbstract:Pantothenate kinase-associated neurodeGeneration (PKAN) is a rare clinically complex autosomal recessive Genetic disorder due to PANK2 Gene mutations. It is one of the syndromes with neurodeGeneration with brain iron accumulation (NBIA). Onset is usually in early childhood. Typical clinical features that comprise dystonia, spasticity, retinitis pigmentosa, and pallidal hypointensities with a central area (eye of the tiger sign) on magnetic resonance imaging may be the diagnostic clue. Diagnostic Genetic testing is available. Therapy remains symptomatic including drugs, deep brain stimulation, and supportive therapies. Reports on chelating therapies are controversial. A placebo-controlled randomized trial is on the way.
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7 Tesla MRI for brain iron quantification in homozygous and heterozygous PANK2 mutation carriers
2014Co-Authors: Petr Dusek, Elena Maria Tovar Martinez, Vince I. Madai, Robert Jech, Jan Sobesky, Friedemann Paul, Thoralf Niendorf, Jens Wuerfel, Susanne A. SchneiderAbstract:Pantothenate-kinase–associated neurodeGeneration (PKAN) is an autosomal recessive disorder characterized by iron deposits in basal ganglia. The aim of this study was to quantify iron concentrations of deep gray matter structures in heterozygous PANK2 mutation carriers and in PKAN patients using quantitative susceptibility mapping MRI. By determining iron concentration, we intended to find mutation-specific brain parenchymal stigmata in heterozygous PANK2 mutation carriers in comparison to age-matched healthy volunteers. We studied 11 heterozygous PANK2 Gene mutation carriers (mean age: 43.4 years; standard deviation [SD]: 10.5), who were found to be clinically asymptomatic by neurological examination. These carriers were compared to 2 clinically affected PKAN patients 21 and 32 years of age and to 13 age-matched, healthy controls (mean age: 39.7; SD, 13.6). Scanning was performed on a 7.0-Tesla whole-body scanner applying three-dimensional susceptibility-weighted gradient echo acquisitions. Susceptibility maps were calculated by threshold-based k-space division with single-orientation acquisition. Magnetic susceptibility values, relative to the occipital white matter, were determined for the following regions of interest (ROI): globus pallidus (GP), thalamus, putamen, internal capsule (IC), caudate nucleus, substantia nigra (SN), and red nucleus. Heterozygous PANK2 mutation carriers did not show increased brain iron concentrations, compared to healthy controls (P > 0.05), in any of the examined ROIs. In PKAN patients, more than 3 times higher concentrations of iron were found in the GP, SN, and IC. Our results suggest that heterozygous mutations in PANK2 Gene do not cause brain iron accumulation nor do they cause movement disorders.
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7‐Tesla Magnetic Resonance Imaging for Brain Iron Quantification in Homozygous and Heterozygous PANK2 Mutation Carriers
Movement disorders clinical practice, 2014Co-Authors: Petr Dusek, Elena Maria Tovar Martinez, Vince I. Madai, Robert Jech, Jan Sobesky, Friedemann Paul, Thoralf Niendorf, Jens Wuerfel, Susanne A. SchneiderAbstract:Pantothenate-kinase–associated neurodeGeneration (PKAN) is an autosomal recessive disorder characterized by iron deposits in basal ganglia. The aim of this study was to quantify iron concentrations of deep gray matter structures in heterozygous PANK2 mutation carriers and in PKAN patients using quantitative susceptibility mapping MRI. By determining iron concentration, we intended to find mutation-specific brain parenchymal stigmata in heterozygous PANK2 mutation carriers in comparison to age-matched healthy volunteers. We studied 11 heterozygous PANK2 Gene mutation carriers (mean age: 43.4 years; standard deviation [SD]: 10.5), who were found to be clinically asymptomatic by neurological examination. These carriers were compared to 2 clinically affected PKAN patients 21 and 32 years of age and to 13 age-matched, healthy controls (mean age: 39.7; SD, 13.6). Scanning was performed on a 7.0-Tesla whole-body scanner applying three-dimensional susceptibility-weighted gradient echo acquisitions. Susceptibility maps were calculated by threshold-based k-space division with single-orientation acquisition. Magnetic susceptibility values, relative to the occipital white matter, were determined for the following regions of interest (ROI): globus pallidus (GP), thalamus, putamen, internal capsule (IC), caudate nucleus, substantia nigra (SN), and red nucleus. Heterozygous PANK2 mutation carriers did not show increased brain iron concentrations, compared to healthy controls (P > 0.05), in any of the examined ROIs. In PKAN patients, more than 3 times higher concentrations of iron were found in the GP, SN, and IC. Our results suggest that heterozygous mutations in PANK2 Gene do not cause brain iron accumulation nor do they cause movement disorders.
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early onset l dopa responsive parkinsonism with pyramidal signs due to atp13a2 pla2g6 fbxo7 and spatacsin mutations
Movement Disorders, 2010Co-Authors: Coro Paisanruiz, Rocio Guevara, Monica Federoff, Hasmet Hanagasi, Fardaz Sina, Nin Bajaj, Susanne A. Schneider, Elahe Elahi, Petra Schwingenschuh, Murat EmreAbstract:Seven autosomal recessive Genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. NeurodeGeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 Gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other Genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified Genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The Genetic heteroGeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN Gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four Genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome. © 2010 Movement Disorder Society.
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Early‐onset L‐dopa‐responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations
Movement disorders : official journal of the Movement Disorder Society, 2010Co-Authors: Coro Paisán-ruiz, Rocio Guevara, Monica Federoff, Hasmet Hanagasi, Fardaz Sina, Nin Bajaj, Susanne A. Schneider, Elahe Elahi, Petra Schwingenschuh, Murat EmreAbstract:Seven autosomal recessive Genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. NeurodeGeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 Gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other Genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified Genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The Genetic heteroGeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN Gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four Genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome. © 2010 Movement Disorder Society.
Murat Emre - One of the best experts on this subject based on the ideXlab platform.
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early onset l dopa responsive parkinsonism with pyramidal signs due to atp13a2 pla2g6 fbxo7 and spatacsin mutations
Movement Disorders, 2010Co-Authors: Coro Paisanruiz, Rocio Guevara, Monica Federoff, Hasmet Hanagasi, Fardaz Sina, Nin Bajaj, Susanne A. Schneider, Elahe Elahi, Petra Schwingenschuh, Murat EmreAbstract:Seven autosomal recessive Genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. NeurodeGeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 Gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other Genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified Genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The Genetic heteroGeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN Gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four Genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome. © 2010 Movement Disorder Society.
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Early‐onset L‐dopa‐responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations
Movement disorders : official journal of the Movement Disorder Society, 2010Co-Authors: Coro Paisán-ruiz, Rocio Guevara, Monica Federoff, Hasmet Hanagasi, Fardaz Sina, Nin Bajaj, Susanne A. Schneider, Elahe Elahi, Petra Schwingenschuh, Murat EmreAbstract:Seven autosomal recessive Genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. NeurodeGeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 Gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other Genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified Genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The Genetic heteroGeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN Gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four Genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome. © 2010 Movement Disorder Society.
Suzanne Jackowski - One of the best experts on this subject based on the ideXlab platform.
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Proposed Therapies for Pantothenate-Kinase-Associated NeurodeGeneration.
Journal of experimental neuroscience, 2019Co-Authors: Suzanne JackowskiAbstract:Multiple approaches to therapy have been proposed for the rare inherited neurodeGenerative disease associated with mutations in the PANK2 Gene, called pantothenate-kinase-associated neurodeGenerati...
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Proposed Therapies for Pantothenate-Kinase-Associated NeurodeGeneration
SAGE Publishing, 2019Co-Authors: Suzanne JackowskiAbstract:Multiple approaches to therapy have been proposed for the rare inherited neurodeGenerative disease associated with mutations in the PANK2 Gene, called pantothenate-kinase-associated neurodeGeneration (PKAN). Penetration of the blood-brain barrier for treatment of a central nervous system (CNS) disorder is a major challenge in drug discovery. Evaluation of the biochemistry and medicinal chemistry of the proposed therapies reveals potential liabilities among several compounds under consideration for clinical development
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Correction of a Genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy.
Molecular genetics and metabolism, 2015Co-Authors: Stephen P. Zano, Caroline Pate, Matthew W. Frank, Charles O. Rock, Suzanne JackowskiAbstract:Coenzyme A (CoA) is a ubiquitous cofactor involved in numerous essential biochemical transformations, and along with its thioesters is a key regulator of intermediary metabolism. Pantothenate (vitamin B5) phosphorylation by pantothenate kinase (PanK) is thought to control the rate of CoA production. Pantothenate kinase associated neurodeGeneration is a hereditary disease that arises from mutations that inactivate the human PANK2 Gene. Aryl phosphoramidate phosphopantothenate derivatives were prepared to test the feasibility of using phosphopantothenate replacement therapy to bypass the Genetic deficiency in the Pank1(-/-) mouse model. The efficacies of candidate compounds were first compared by measuring the ability to increase CoA levels in Pank1(-/-) mouse embryo fibroblasts. Administration of selected candidate compounds to Pank1(-/-) mice corrected their deficiency in hepatic CoA. The PanK bypass was confirmed by the incorporation of intact phosphopantothenate into CoA using triple-isotopically labeled compound. These results provide strong support for PanK as a master regulator of intracellular CoA and illustrate the feasibility of employing PanK bypass therapy to restore CoA levels in Genetically deficient mice.
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Targeting the PANK2 Gene for deletion in mice.
2013Co-Authors: Matthew Garcia, Roberta Leonardi, Yong-mei Zhang, Jerold E. Rehg, Suzanne JackowskiAbstract:(A) A selection cassette containing cDNA encoding thymidine kinase (TK) and neomycin resistance (NEO) was inserted into the intron between exons 2 (Ex2) and 3 (Ex3) of the PANK2 Gene. The cassette was flanked by loxP (▸) sites. A third loxP site was inserted between exons 3 (Ex3) and 4 (Ex4). Cre-recombinase-mediated deletion of the DNA between the outermost loxP sites resulted in a knockout (KO) allele which lacked Ex3 and lacked the selection cassette. Locations of the primers (arrows) for PCR genotyping are shown. PCR products and sizes are indicated (bars), and B indicates the presence of a BamHI site. (B) A PCR product of 618 bp using primers F and R1 indicated a wild-type (WT) allele. A PCR product of 526 bp using primers F and R2 indicated a deleted (KO) allele. Heterozygous (Hz) mice had both alleles.
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Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism.
PloS one, 2012Co-Authors: Matthew R. Garcia, Roberta Leonardi, Yong-mei Zhang, Jerold E. Rehg, Suzanne JackowskiAbstract:Pantothenate kinase (PanK) phosphorylates pantothenic acid (vitamin B5) and controls the overall rate of coenzyme A (CoA) biosynthesis. Pank1 Gene deletion in mice results in a metabolic phenotype where fatty acid oxidation and gluconeoGenesis are impaired in the fasted state, leading to mild hypoglycemia. Inactivating mutations in the human PANK2 Gene lead to childhood neurodeGeneration, but PANK2 Gene inactivation in mice does not elicit a phenotype indicative of the neuromuscular symptoms or brain iron accumulation that accompany the human disease. Pank1/PANK2 double knockout (dKO) mice were derived to determine if the mild phenotypes of the single knockout mice are due to the ability of the two isoforms to compensate for each other in CoA biosynthesis. Postnatal development was severely affected in the dKO mice. The dKO pups developed progressively severe hypoglycemia and hyperketonemia by postnatal day 10 leading to death by day 17. Hyperketonemia arose from impaired whole-body ketone utilization illustrating the requirement for CoA in energy Generation from ketones. dKO pups had reduced CoA and decreased fatty acid oxidation coupled with triglyceride accumulation in liver. dKO hepatocytes could not maintain the NADH levels compared to wild-type hepatocytes. These results revealed an important link between CoA and NADH levels, which was reflected by deficiencies in hepatic oleate synthesis and gluconeoGenesis. The data indicate that PanK1 and PANK2 can compensate for each other to supply tissue CoA, but PanK1 is more important to CoA levels in liver whereas PANK2 contributes more to CoA synthesis in the brain.
Bi Hongyan - One of the best experts on this subject based on the ideXlab platform.
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Bilateral Striatal Necrosis in a chinese family, a new type? (P2.247)
Neurology, 2015Co-Authors: Bi HongyanAbstract:OBJECTIVE: To report the clinical characteristics, Gene mutation of bilateral striatal necrosis in a Chinese family. BACKGROUND: Bilateral striatal necrosis(BSN) is a kind of clinical syndrome including a group of nervous system functional disorders caused by various factors. The etiology is roughly divided into two categories including Genetic cause and secondary one. There are no effective therapies by now. Most patients finally lose the ability to work, a heavy financial burden and mental pressure to both the family and society. DESIGN/METHODS: A family with BSN in the remote northwest mountain areas was collected. The proband was a 20 year old woman with dystonia, the elder and younger sister had the similar symptoms(Figure 1). The head MRI was performed for two patients and CT for one patient, what’s more, muscle biopsy was performed for the proband. The NUP62,SLC19A3,SLC25A19,PANK2 Gene and mitochondrial Gene were examined. RESULTS: Three patients manifested Generalized dystonia and the MRI or CT image showed bilateral striatal necrosis(Figure 2). There were no evident pathologic findings in the skeletal muscle. In the NUP62 Gene, we found a cDNA337G-A heterozygous mutation(pG113S mutation). The same mutation was found in the other two patients, the normal sister, the father and the grandmother. The other Genes(PANK2,SLC25A19,SLC19A3 and mitochondrial Gene) were normal. CONCLUSIONS: The clinical features of BSN in this family were summarized. The correlation between BSN and some known Genes was ruled out. We deduce that the disease may be a new type and further study need to be done. Study Supported by: National natural science foudation of China Disclosure: Dr. hongyan has nothing to disclose.
Mohammad Rohani - One of the best experts on this subject based on the ideXlab platform.
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A novel homozygous variation in the PANK2 Gene in two Persian siblings with atypical pantothenate kinase associated neurodeGeneration.
Neurology international, 2019Co-Authors: Amir Hasan Habibi, Saeed Razmeh, Omid Aryani, Mohammad Rohani, Laleh Taghavian, Elham Alizadeh, Karim Moradian Kokhedan, Maryam ZaribafianAbstract:Pantothenate Kinase-associated NeurodeGeneration (PKAN) is an autosomal recessive disorder that is caused by variation in pantothenate kinase-2 Gene (PANK2) Gene on chromosome 20. The common presentation of this disease includes progressive dystonia, Parkinsonism, retinopathy, cognitive impairment, and spasticity. The typical magnetic resonance imaging finding is eye of the tiger sign in globus pallidus and not pathogenic and not found in all patients. In the present study, we describe two siblings who have a novel variation of the PANK2 Gene. These patients with the same genotype, have different ages at the onset of disease and also the various severity of the disease. The description of these cases helps to understand this disease, its symptoms, pathoGenesis, and its treatment.
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Tremor‐Dominant Pantothenate Kinase‐associated NeurodeGeneration
Movement disorders clinical practice, 2017Co-Authors: Mohammad Rohani, Afagh Alavi, Gholam Ali Shahidi, Anthony E. Lang, Niloufar Yousefi, Said Razme, Alfonso FasanoAbstract:Background NeurodeGeneration with brain iron accumulation (NBIA) includes rare and heteroGeneous group of disorders characterized by iron deposition in the basal ganglia. Pantothenate kinase-associated neurodeGeneration (PKAN), is the most common NBIA and has two main presentations: typical and atypical, the latter rarely presenting with tremor. Method Reported patients underwent full neurologic examination, a standard brain MRI and Genetic testing for PKAN. Results Three cases of ‘tremor-dominant’ PKAN with a relatively benign course were reported: dystonic tremor was seen in one patient and Parkinsonian tremor in remaining ones. All of them had homozygous mutations in PANK2 Gene and typical eye of the tiger sign on brain MRI. Conclusions PKAN (and NBIA in General) might be a potential cause of tremor, thus emphasizing the need to consider this diagnosis even in patients with a clinical diagnosis of essential, dystonic or Parkinsonian tremor. This article is protected by copyright. All rights reserved.
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Pantothenate kinase 2 mutation with eye-of-the-tiger sign on magnetic resonance imaging in three siblings
Iranian journal of neurology, 2012Co-Authors: Mitra Ansari Dezfouli, Elahe Elahi, Elham Jaberi, Afagh Alavi, Mohammad Reza Rezvani, Gholam Ali Shahidi, Mohammad RohaniAbstract:Background: Pantothenate kinase associated neurodeGeneration (PKAN) is the most prevalent type of neurodeGeneration with brain iron accumulation (NBIA) disorders characterized by extrapyramidal signs, and ‘eyeof-the-tiger’ on T2 brain magnetic resonance imaging (MRI) characterized by hypointensity in globus pallidus and a hyperintensity in its core. All PKAN patients have homozygous or compound heterozygous mutation in PANK2 Gene. Methods: Three sibling patients were diagnosed based on clinical presentations especially extrapyramidal signs and brain MRI. The exons and flanking intronic sequences of PANK2 were sequenced from DNA of leukocytes of the affected individuals. Results: All patients were homozygous for c.C1069T, p.R357W in PANK2 Gene. This mutation is well conserved in the homologous protein of distally related spices. Conclusion: In the current study we identified three siblings affected with PKAN, all of them have mutations in PANK2 Gene. In MRI of all patients with PANK2 mutation eye-of-the-tiger sign was apparent.
