The Clinical Heterogeneity Of PRKN And LRRK2 Gene Mutations In Patients With Early-Onst Parkinson's Disease

BackgroundParkinosn's disease(PD)is the second most common neurodegenerative disorder.Environmental factors,lifestyle and genetic factors are involved in the occurrence and development of the disease.The number of early-onset Parkinson's disease patients whose onset age is less than or equal to 50 years old is increasing year by year.Studies have shown that genetic mutations play an important role in the occurrence and development of EOPD.LRRK2 is the most common autosomal dominant pathogenic gene,which is common in late-onset PD.With the popularity of gene sequencing technology,the role of LRRK2 gene in early-onset PD patients has been emphasized.PRKN is the most common chromosomal recessive inherited pathogenic genes of EOPD.Patients with EOPD have a early onset age,a great differences in genetic background and have a high degree of clinical heterogeneity.The correlation between genotype and clinicalphenotype is a hotspot and difficultpoint.ObjectiveThe purpose of this study is to screen EOPD patients with PRKN mutation,LRRK2 mutation and no PD-related disease-causing gene mutations by high-throughput targeted sequencing technology,collect their clinical data in detail,clarify the correlation between genotype and clinical phenotype of EOPD patients in our center,in order to guide clinical diagnosis,selection of gene screening population and individualized treatment of EOPD patients in the future,and judge prognosis.Subjects and MethodsThis study included 48 patients with early-onset Parkinson's disease who were admitted to the Department of Neurology,Qilu Hospital of Shandong University from March 2017 to December 2018.Among them,15 patients with PRXN mutations and 11 patients with LRRK2 mutations,and 22 patients with negative results of parkinson's disease-related gene chip detection.The basic information of patients,age at onset,primary symptoms,anti-Parkinson's disease medication information,time of use of levodopa,levodopa equivalent daily dose,olfaction condition,sleep benefit and motor complications were collected.Completed the evaluation of corresponding scale assessment:movement disorder society-sponsored revision of the unified parkinson's disease rating scale(MDS-UPDRS),Hoehn and Yahr Staging,the sacles for outcomes in parkinson's disease-autonomic(SCOPA-AUT),Pittsburgh sleep quality index(PSQI),mini-mental state examination(MMSE),montreal cognitive assessment(MOCA),hamilton depression rating scale(HAMD),rapid eye movement sleep behavior disorder screening questionnaire(RBD-SQ).The differences of clinical data between mutation carriers of EOPD and idiopathic EOPD patients were compared to explore the correlation between genotype and phenotype.Results1.There was no statistical difference between the PRKN group and the idiopathic EOPD group in general information including age,gender,family history,and education level.The PRKN group had earlier onset age(P<0.001)and longer course of disease(P=0.011).The proportion of patients with bilateral onset was high in the PRKN group,but there was no statistical difference between the two groups.There was no statistical difference between the two groups in the time of levodopa use and the ratio of dopamine receptor agonist use,but the equivalent dose of levodopa was less in the PRKN group(P=0.003).In terms of motor symptoms,tremor was the main type of motor phenotype in both groups,and there was no statistical difference in the proportion of motor classification.There were no significant differences in MDS-UPDRS part ?,?,?,total score and H&Y staging between the two groups,while the PRKN group scored higher in the MDS-UPDRS part IV(P=0.024).There were more patients with dyskinesia and dystonia in the PRKN group(P=0.038,P=0.015).In terms of non-motor symptoms,the proportion of olfactory dysfunction was lower in the PRKN group(P=0.011).There were no significant differences in the scores of the digestive system,urinary system,and cardiovascular system between the two groups in the SCOPA-AUT score.There were no significant differences in MMSE and MOCA scores between the two groups.The HAMD score was higher in the PRKN group,but there was no statistical difference between the two groups.There was no significant difference in PSQI total score and nighttime sleep length between the two groups,but the sleep efficiency was relatively low in the PRKN group(P=0.011).There was no significant difference in the proportion of patients with REM sleep disorder between the two groups.The proportion of patients with sleep benefit in the PRKN group was high,but there was no statistical difference between the two groups.2.There was no statistical difference between the LRRK2 group and the idiopathic EOPD group in general information including age,gender,family history,and education level.There were no significant differences in the age of onset,duration of disease,time of levodopa use,LED,and the ratio of dopamine receptor agonist use.In terms of motor symptoms,there was no statistical difference between the composition ratio of motor phenotype,scores of MDS-UPDRS,and H&Y staging.There were no statistical differences in the incidence of dyskinesia and dystonia between the two groups.Regarding non-motor symptoms,there was no significant difference in the proportion of patients with olfactory dysfunction,SCOPA-AUT score,MMSE score,MOCA score,and HAMD score between the two groups.There were no significant differences in total PSQI score,nighttime sleep length,sleep efficiency,proportion of RBD patients,and proportion of patients with sleep benefit between the two groups.Conclusion1.Compared with idiopathic early-onset Parkinson's disease,early-onset Parkinson's disease patients with PRKN mutation have earlier onset age,longer course of disease,better olfactory function,better response to fewer doses of dopaminergic drugs,and higher rates of the occurrence of dyskinesia and dystonia.There were no significant differences in motor function,autonomic nerve damage,cognitive impairment,depression and REM sleep disorder.Previous reports of PRKN mutation carriers tend to have bilateral onset and a high rate of sleep benefit were also found in this study,but there was no statistical difference between the two groups.2.There was no significant difference in onset age,motor symptoms and non-motor symptoms between EOPD patients with LRRK2 mutation and idiopathic EOPD patients.3.The dystonia in EOPD patients with PRKN mutation is not all the motor complications caused by drugs.Lower extremity dystonia can appear as the first symptom which can be manifested as exercise-induced dystonia.This may be a clue to the early diagnosis of the disease.Prompt,it deserves our attention.