3 Cases Of PARK14-linked Parkinsonism With Literature Review Of Clinical Heterogeneity

PurposeTo summarize and analyze the clinical data,pathogenicity of gene mutations and phenotype-genotype correlation of 3 cases of PARK14-linked parkinsonism.To review and discuss the heterogeneity of Parkinson Disease 14,thus to provide supports for clinical diagnosis,selection of treatments and prediction of prognosis.MethodsWe collected and retrospectively analyzed the clinical data of 3 patients with PARK 14-linked parkinsonism from December 2014 to October 2016 in the Department of Neurology,Qilu Hospital of Shandong University.The 2015 MDS Clinical Diagnostic Criteria for Parkinson's Disease was applied to make the diagnosis of parkinsonism or Parkinson's Disease.We used the OMIM,HGMD Pro and other databases to make the annotations of mutations and made predictions of pathogenicity by Polyphen2.0.SIFT and MutationTaster.Combined with Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics(ACMG),we made the pathogenicity analyses of mutations found in our cases.Phenotype-genotype correlation analyses were carried out with aid of OMIM,HGMD pro databases.Additionally,we reviewed articles of case reports and population studies of PARK14-linked parkinsonism recorded by Pubmed database to summarize and discuss the clinical heterogeneity of this disease.Results1.We collected 3 cases of PARK14-linked parkinsonism(?-?)consisting of 1 male(?)and 2 females(?,?).Combined with clinical data and pathogenicity analyses of mutations,the 3 patients were diagnosed as early-onset idiopathic Parkinson's Disease(I),Parkinson Disease 14(?)and early-onset dystonia-parkinsonism(III),respectively.2.In the pathogenicity analyses of PARK 14(PLA2G6)mutations,we classified c.2255C>G as "likely benign",c.991 G>T as "pathogenic",c.967G>A and c.1918G>A as "uncertain significance".We classified c.704G>C of PRKRA gene as "likely benign".3.We reviewed 7 kinds of PARK14(PLA2G6)homozygous mutations as well as compound heterozygous mutations and summarized related clinical features.c.2222G>A and c.991G>T homozygous mutations are most common in these cases.All patients presented as early-onset(dystonia-)parkinsonism with common clinical manifestations as bradykinesia,rigidity,tremor,dystonia,eye disorders,speech and language disorders,gait disorders,cognitive impairments,psychiatric symptoms and autonomic dysfunctions.Patients with strongly pathogenic mutations(such as homozygous mutations and compound heterozygous mutations of c.2222G>A),presented with earlier onset,severe progression with more additional neuropsychiatric symptoms.Patients with less pathogenic mutations(such as homozygous mutations of c.991G>T)presented with later onset,slower progression and better prognosis whose main symptoms were related with parkinsonism.ConclusionPARK14-linked parkinsonism is rare and has significant clinical heterogeneity.The clinical diagnosis should unite with clinical data and gene sequencing analysis.Determination of clinical heterogeneity may contribute to selection of treatments and prediction of prognosis.