{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T03:12:22Z","timestamp":1773976342644,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U2005201"],"award-info":[{"award-number":["U2005201"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>PLA2G6-associated neurodegeneration (PLAN) is a rare autosomal recessive disorder caused by PLA2G6 mutations. This study aimed to investigate the clinical characteristics and mutation spectrum of PLAN and to investigate the founder effects in Chinese PLAN patients. Six Chinese PLAN families were clinically examined in detail and whole-exome sequencing was performed in the probands. Haplotype analysis was performed in five families with the PLA2G6 c.991G &gt; T mutation using 23 single nucleotide polymorphism markers. Furthermore, all previously reported PLA2G6 mutations and patients in China were reviewed to summarize the genetic and clinical features of PLAN. Interestingly, we found that one patient had hereditary spastic paraplegia and showed various atypical clinical characteristics of PLAN, and five patients had a phenotype of parkinsonism. All probands were compound heterozygotes for PLA2G6 variants, including four novel pathogenic\/likely pathogenic mutations (c.967G &gt; A, c.1450G &gt; T, c.1631T &gt; C, and c.1915delG) and five known pathogenic mutations. Haplotype analyses revealed that patients carrying PLA2G6 c.991G &gt; T mutations shared a haplotype of 717 kb. The frequencies of psychiatric features, cognitive decline, and myoclonus in Chinese patients with PLA2G6-related parkinsonism were significantly different from those in European patients. Thus, our study expands the clinical and genetic spectrum of PLAN and provides an insightful view of the founder effect to better diagnose and understand the disease.<\/jats:p>","DOI":"10.3390\/brainsci12050517","type":"journal-article","created":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T22:07:26Z","timestamp":1650406046000},"page":"517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Clinical Characterization and Founder Effect Analysis in Chinese Patients with Phospholipase A2-Associated Neurodegeneration"],"prefix":"10.3390","volume":"12","author":[{"given":"Hao-Ling","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Neurology, Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Yan","family":"Xue","sequence":"additional","affiliation":[{"name":"Research Center of Neurology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Department of Neurology, Second Affiliated Hospital of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Ying","family":"Wu","sequence":"additional","affiliation":[{"name":"Research Center of Neurology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Department of Neurology, Second Affiliated Hospital of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2203-0046","authenticated-orcid":false,"given":"Hong-Fu","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center of Neurology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Department of Neurology, Second Affiliated Hospital of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9655-9735","authenticated-orcid":false,"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.3389\/fneur.2018.01100","article-title":"PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes","volume":"9","author":"Guo","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/ng1826","article-title":"PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron","volume":"38","author":"Morgan","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.1007\/s12035-016-9991-2","article-title":"Identification of Novel Compound Mutations in PLA2G6-Associated Neurodegeneration Patient with Characteristic MRI Imaging","volume":"54","author":"Guo","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1212\/01.wnl.0000310986.48286.8e","article-title":"Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN)","volume":"70","author":"Kurian","year":"2008","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/ana.21415","article-title":"Characterization of PLA2G6 as a locus for dystonia-parkinsonism","volume":"65","author":"Bhatia","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.parkreldis.2018.02.010","article-title":"Novel PLA2G6 mutations and clinical heterogeneity in Chinese cases with phospholipase A2-associated neurodegeneration","volume":"49","author":"Chen","year":"2018","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.parkreldis.2019.04.002","article-title":"Identification of a novel mutation in PLA2G6 gene and phenotypic heterogeneity analysis of PLA2G6-related neurodegeneration","volume":"65","author":"Ji","year":"2019","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/mds.28807","article-title":"Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism","volume":"37","author":"Magrinelli","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s13023-020-01355-2","article-title":"The natural history of infantile neuroaxonal dystrophy","volume":"15","author":"Altuame","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1086\/508572","article-title":"PLA2G6 Mutation Underlies Infantile Neuroaxonal Dystrophy","volume":"79","author":"Khateeb","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1111\/ene.12552","article-title":"Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort","volume":"22","author":"Romani","year":"2015","journal-title":"Eur. J. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chu, Y.T., Lin, H.Y., Chen, P.L., and Lin, C.H. (2020). Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: Case series and literature review. BMC Neurol., 20.","DOI":"10.1186\/s12883-020-01684-6"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/jns.12377","article-title":"Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease","volume":"25","author":"Dong","year":"2020","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: Clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines","volume":"100","author":"Li","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/bioinformatics\/bth457","article-title":"Haploview: Analysis and visualization of LD and haplotype maps","volume":"21","author":"Barrett","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/gim.2015.148","article-title":"Clinical application of whole-exome sequencing across clinical indications","volume":"18","author":"Retterer","year":"2016","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Elsayed, L.E.O., Mohammed, I.N., Hamed, A.A.A., Elseed, M.A., Salih, M.A.M., Yahia, A., Siddig, R.A., Amin, M., Koko, M., and Elbashir, M.I. (2018). Case report of a novel homozygous splice site mutation in PLA2G6 gene causing infantile neuroaxonal dystrophy in a Sudanese family. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0592-y"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.parkreldis.2015.01.010","article-title":"Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity","volume":"21","author":"Kim","year":"2015","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1007\/s11064-014-1342-y","article-title":"iPLA2\u03b2 Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology","volume":"39","author":"Blanchard","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhao, Z., Wang, J., Zhao, C., Bi, W., Yue, Z., and Ma, Z.A. (2011). Genetic ablation of PLA2G6 in mice leads to cerebellar atrophy characterized by Purkinje cell loss and glial cell activation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026991"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"135","DOI":"10.23838\/pfm.2019.00086","article-title":"Intrafamilial variability and clinical heterogeneity in a family with PLA2G6-associated neurodegeneration","volume":"3","author":"Park","year":"2019","journal-title":"Precis. Future Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.bbalip.2018.10.010","article-title":"iPLA2\u03b2 and its role in male fertility, neurological disorders, metabolic disorders, and inflammation","volume":"1864","author":"Turk","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Engel, L.A., Jing, Z., O\u2019Brien, D.E., Sun, M., and Kotzbauer, P.T. (2010). Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012897"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/cge.13008","article-title":"PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia","volume":"92","author":"Ozes","year":"2017","journal-title":"Clin. Genet."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/12\/5\/517\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:56:41Z","timestamp":1760137001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/12\/5\/517"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,19]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["brainsci12050517"],"URL":"https:\/\/doi.org\/10.3390\/brainsci12050517","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,19]]}}}