Investigation And Genetic Study On A Pedigree With Early-onset Parkinson’s Disease Appearing Incompatible With MDS Clinical Diagnostic Criteria

Background:Globally,around 1%of persons over the age of 65 are diagnosed with Parkinson’s disease（PD）,the second most common neurodegenerative disorder after Alzheimer’s disease.PD is a type of alpha synucleinopathy with aggregation of abnormally foldedα-synuclein proteins,which form intracellular inclusions in substantia nigra pars compacta,causing the damage of dopaminergic neurons.The loss of dopamine finally generates symptoms like resting tremor,bradykinesia,and rigidity.The cause of PD is currently unclear but is influenced by aging,environment factors,and genetic factors according to previous studies.Mostly,PD was categorized as an idiopathic disorder.Around 15%of patients with PD have a family history,and 5–10%have confirmed genetic causes.PRKN is responsible for autosomal recessive Parkinson’s disease（ARPD）and is the most common gene responsible for early-onset Parkinson’s disease,while rare variants of PLA2G6,another gene responsible for ARPD,likely raise PD susceptibility in the Chinese population.To diagnose PD,not only are the mandatory criteria needed but also diagnostic supportive criteria,diagnostic exclusion criteria and red flags for PD diagnosis should be considered according to the MDS clinical diagnostic criteria for PD.We encountered a family with known PD appearing incompatible with MDS clinical diagnostic criteria.Objective:To investigate possible pathogenic gene in a pedigree with known EOPD appearing incompatible with MDS clinical diagnostic criteria.Methods:Clinical history,physical examination,blood laboratory test,and brain imaging data of the patients were collected.Genetic information of 13 members of the family,including the proband and other affected members,was investigated by whole-exome sequencing and Sanger sequencing.Family pedigree map was established for cosegregation analysis,and SIFT,Polyphen-2 and Mutation Taster were used to predict impact of an amino acid substitution caused by mutation on the protein’s structure and function.Results:Of the23 members from 4 generation in the family,two including the proband were considered PD patients.Two members were dead（including the proband’s father）,and8 members were not able to be analyzed（including the other patient’s father）.The proband exhibited a rare symmetrical resting tremor limited to her lower limbs and neither exhibited signs of rigidity nor presented obvious bradykinesia.Treatment of Levodpa was effective.The other patient exhibited typical parkinsonian characteristic including resting tremor,rigidity,and bradykinesia.No obvious abnormalities were observed from the blood examination and brain MRI scan of the proband.¹⁸F-DOPA PET/CT scan indicated a reduced signaling in the striatum.A novel homozygous frameshift mutation,c.856del T,and a compound heterozygous mutation,c.1321T>C/c.856del T of PRKN,were identified.The proband carried the compound heterozygous mutation of PRKN and her affected cousin carried the homozygous frameshift mutation.Of all candidates,six were found to be heterozygous for the mutation,c.856del T and one was found to be heterozygous for the mutation,c.1321T>C.Two single nucleotide variants of PLA2G6 and TENM4 were also detected.Conclusion:The novel frameshift mutation and compound heterozygous mutation of PRKN are likely to be the genetic causes of PD in this family.The symmetrical resting tremor limited to the proband’s lower limbs,which is different from her affected cousin,is incompatible with MDS clinical diagnostic criteria of PD.The difference of the phenotypes between the two patients of the family might be related to the difference between their genotypes.The relation between the special phenotype and genotype is still necessary for further study.And weather it is necessary to improve and draw up a targeted clinical diagnostic criterion for PD needs to be discussed.