Clinical Characteristics And Gene Mutations Detection In A Chinese Family With Early-onset Parkinson’s Disease

Background and purpose:Parkinson’s disease(PD)is the second most common progressive degenerative disorder of the central nervous system after Alzheimer’ s disease It is clinically characterized by motor symptoms,such as bradykinesia,resting tremor,rigidity and postural instability,as well as nonmotor symptoms,such as hyposmia,autonomic nervous system,sleep disorders,and psychiatric symptoms.The incidence of PD increases with age,affecting greater than 1%of the population over the age of 60 and greater than 5%of the population over the age of 80.Although most patients with PD exhibit the sporadic form,10-15%of patients inherit the disease in a Mendelian pattern Recent studies have identified approximately 27 genes that are associated with genetic parkinsonism,including autosomal recessive mutations in PARK2,PINK1 and DJ-1 and autosomal dominant mutations in SNCA,LRRK2,VPS35 and GCH1.PARK2 is the most common genetic cause of early-onset Parkinson’s disease(EOPD).Therefore,studying these genes associated with hereditary PD can better reveal the genetic mechanism of EOPD to guide clinical diagnosis and treatment.The aim of our study was to explore the clinical characteristics and gene mutations in a Chinese family with EOPD.Methods:(1)The clinical and genetic characteristics of the EOPD family in three generations were analyzed through family investigation,clinical data collection of 12 members,and blood collection and genetic testing of 6 members;(2)Magnetic Resonance Imaging(MRI)and Positron Emission Computed Tomography imaging(PET/CT)were performed on two EOPD patients to analyze their imaging characteristics;(3)We extracted genomic DNA from all blood samples.After the purified DNA samples were randomly fragmented,PCR amplification was performed.Target region capture and high-throughput sequencing were used to screen these gene mutations associated with parkinsonism and related disorders.The multiplex ligation-dependent probe amplification(MLPA)method was applied to detect rearrangements in PARK2 exons Direct Sanger sequencing of samples from all subjects further verified the detected abnormal PRKRA,SPTBN2,and ATXN2 gene fragmentsResults:(1)There was a three-generation family with 12 members,2 of whom died.Only 6 members participated in peripheral blood collection.Two members were affected,one member was suspected to be affected.They were proband,proband’s older brother and proband’s father(deceased),showing typical clinical characteristics of PD;(2)According to clinical characteristics,inheritance and imaging analysis,two family members(proband and proband’s older brother)were clinically diagnosed with EOPD,and the onset age was less than 40 years of age.(3)Heterozygous deletion of exon 3 and heterozygous duplication of exon 6 in PARK2 were identified in proband and proband’s older brother.A single heterozygous deletion of exon 3 in PARK2 was detected in proband’s younger brother and proband’s son.A single duplication of exon 6 in PARK2 was detected in proband’s uncle.Both the heterozygous mutation c.2834 G>A(p.R945H)in exon 16 and the heterozygous mutation c.1924 C>T(p.R642W)in exon 14 of the SPTBN2 gene were identified in proband,proband’s older brother and proband’s uncle The heterozygous mutation c.2989 C>T(p.R997X)in exon 24 of the ATXN2 gene was detected in proband’s older brother and proband’s younger brother,and the heterozygous mutation c.170 C>A(p.S57Y)in exon 2 of the PRKRA gene was detected in proband,proband’s older brother and proband’s uncle.Other gene mutations associated with parkinsonism and related disorders were not detectedConclusions:(1)PARK2 gene was considered to be the causative gene of the EOPD family;(2)In this study,the compound heterozygous mutations(heterozygous deletion of exon 3 and heterozygous duplication of exon 6)in PARK2 were the first to be identified in a Han Chinese family with EOPD;(3)According to ACMG guide,the pathogenicity of SPTBN2,A TXN2 and PRKRA gene mutations that were found in this study is uncertain The clinical symptoms of spinocerebellar ataxia type 5(SCA5),spinocerebellar ataxia type 14(SCA14),spinocerebellar ataxia type 2(SCA2)and dystonia-parkinsonism(DTY16)were not observed in all members.This requires further follow-up to confirm;(4)18F-dihydroxyphenylalanine(18F-DOPA)PET/CT showed disease progression in EOPD patients with PARK2 mutations was more slowly than idiopathic Parkinson’s disease(IPD)patients.