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      Natural history and genotype‐phenotype correlation of pantothenate kinase‐associated neurodegeneration


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          To investigate the natural history and genotype‐phenotype correlation of pantothenate kinase‐associated neurodegeneration.


          We collected data of patients with PKAN by searching from available publications in English and Chinese. Patients diagnosed in our center (Peking University First Hospital) were also included. The difference in natural history and genotype between early‐onset (<10 year of age at onset) and late‐onset patients (≥10 year of age at onset) with PKAN was compared.


          A total of 248 patients were included. The median age at onset was 3.0 years in the early‐onset group and 18.0 years in the late‐onset group. Dystonia in lower limbs was the most common initial symptom in both groups. In the early‐onset group, the median interval between the disease onset and occurrence of oromandibular dystonia, generalized dystonia, loss of independent ambulance was 6.0 years, 5.0 years, and 5.0 years. The corresponding values in late‐onset group were 1.0 year, 4.0 years, and 6.0 years. About 20.0% died at median age of 12.5 years and 9.5 years after the onset in early‐onset group. About 2.0% of the late‐onset patients died during the follow‐up. A total of 176 mutations were identified. Patients carrying two null alleles in PANK2 showed significantly earlier age of disease onset and progressed more rapidly to loss of independent ambulance.


          This study provided a comprehensive review on the natural history and genotype of 248 patients with PKAN. The results will serve as a historical control data for future clinical trial on PKAN.

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          Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study

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            Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.

            Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by magnetic resonance imaging (MRI) changes in basal ganglia. Both missense and nonsense mutations have been found in such patients in a gene encoding the mitochondrial pantothenate kinase (PANK2). We completed a mutation screen in 72 patients with the diagnosis NBIA based on clinical findings and radiological imaging. The entire coding region of the PANK2 gene (20p12.3) was investigated for point mutations and deletions. We uncovered both mutant alleles in 48 patients. Deletions accounted for 4% of mutated alleles. Patients with two loss-of-function alleles (n = 11) displayed symptoms always at an early stage of life. In the presence of missense mutations (n = 37), the age of onset correlated with residual activity of the pantothenate kinase. Progression of disease measured by loss of ambulation was variable in both groups. We did not observe a strict correlation between the eye-of-the-tiger sign and PANK2 mutations. In 24 patients, no PANK2 mutation was identified. Deletion screening of PANK2 should be part of the diagnostic spectrum. Factors other than enzymatic residual activity are determining the course of disease. There are strong arguments in favor of locus heterogeneity.
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              Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes.

              Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders characterized by the presence of radiologically discernible high brain iron, particularly within the basal ganglia. A number of childhood NBIA syndromes are described, of which two of the major subtypes are pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN). PKAN and PLAN are autosomal recessive NBIA disorders due to mutations in PANK2 and PLA2G6, respectively. Presentation is usually in childhood, with features of neurological regression and motor dysfunction. In both PKAN and PLAN, a number of classical and atypical phenotypes are reported. In this chapter, we describe the clinical, radiological, and genetic features of these two disorders and also discuss the pathophysiological mechanisms postulated to play a role in disease pathogenesis. © 2013 Elsevier Inc. All rights reserved.

                Author and article information

                CNS Neurosci Ther
                CNS Neurosci Ther
                CNS Neuroscience & Therapeutics
                John Wiley and Sons Inc. (Hoboken )
                11 February 2020
                July 2020
                : 26
                : 7 ( doiID: 10.1002/cns.v26.7 )
                : 754-761
                [ 1 ] Department of Pediatrics Peking University First Hospital Beijing China
                Author notes
                [*] [* ] Correspondence

                Ye Wu, Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing 100034, China.

                Email: dryewu@ 123456263.net

                Author information
                © 2020 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 06 November 2019
                : 27 January 2020
                : 27 January 2020
                Page count
                Figures: 3, Tables: 1, Pages: 8, Words: 4502
                Funded by: National Science and Technology Major Project of the Ministry of Science and Technology of China
                Award ID: 2017ZX09304029‐006
                Original Article
                Original Articles
                Custom metadata
                July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:17.06.2020

                genotypic spectrum,natural history,pank2,pantothenate kinase‐associated neurodegeneration disease


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