Study On The Clinical Phenotypes And Spastic Paraplegia Subtype Of Spinocerebellar Ataxia Type 3 In Southeast China

Background Spinocerebellar ataxia type 3(SCA3)is the common subtype of hereditary and neurodegenerative disorders,which is caused by a pathological CAG repeat expansion in ATXN3 gene.It shows significant heterogeneity in clinical phenotype.In addition to characteristic progressive cerebellar ataxia,SCA3 patients may also exhibit several non-ataxia manifestations.There are various initial symptoms in SCA3,including ataxic gait which is the most common initial symptom,dysarthria,diplopia,etc.It was reported that the initial symptoms could affect clinical phenotypes in neurodegenerative diseases.However,the contribution of initial symptoms to the phenotypes of SCA3 in China has yet to be reported.Besides,fatigue is a common non-motor symptom in neurodegenerative diseases and also one of most common non-ataxia symptoms.However,the impact of fatigue on the clinical phenotype of SCA3 was rarely studied.Therefore,this part of the study aims to investigate the impacts of initial symptoms and fatigue on the clinical phenotype of SCA3,based on the data of clinical phenotypes and relationship between phenotypes and genotypes in SCA3.Methods In the present study,241 molecular-confirmed SCA3 patients were recruited from Department of Neurology,the First Affiliated Hospital of Fujian Medical University from 2014 to 2020.The self-designed follow-up registration form was used to collect and record detailed medical history and physical examination of the nervous system.The severity of ataxia was assessed using the Ataxia Rating Scale(SARA)and the International Collaborative Ataxia Assessment Scale(ICARS).According to the reported initial symptoms,each subject was categorized into either the gait-onset group or the non-gait-onset group.Multivariable linear regression was performed to determine the influences of initial symptoms on age at onset(AAO),the severity and progression of ataxia.In addition,91 SCA3 patients and 85 age,gender,and living background matched healthy controls were recruited.The degree of fatigue was measured using the 14-item Fatigue Scale(FS-14).Epworth Sleepiness Scale(ESS),Pittsburgh Sleep Quality Index(PSQI),and Beck Depression Inventory(BDI)were evaluated for daytime sleepiness,sleep quality and severity of depression.The risky factors to fatigue and how fatigue affects clinical phenotypes were studied using multivariable linear regression models.Results: 1.A total of 241 SCA3 patients,mainly from southeastern and eastern of China,were enrolled in this study.Among them,222 were completely explicit SCA3 patients(3 homozygotes),and 19 were SCA3 pre-symptomatic patients.Compared with SCA3 patients,pre-symptomatic SCA3 patients had an earlier age of first visit(p = 0.007),lower SARA scores(p = 0.000)and ICARS scores(p = 0.000).There was no significant difference in CAG repeat numbers of expanded alleles(p > 0.05).2.The age of onset of 219 SCA3 patients(except 3 homozygous patients)was negatively correlated with the number of expanded CAG repeat(R2 = 0.471,p = 0.000).Age of onset(p = 0.000),disease duration(p = 0.000),and the number of expanded CAG repeat(p = 0.000)were positively correlated with the severity of ataxia.3.Among 219 SCA3 patients,we found that the frequency of gait-onset was 91.78%,and the frequency of non-gait-onset was 7.31%(diplopia: 4.57%,dysarthria: 2.28%,dystonia: 0.46%).Compared with the non-gait-onset group,the severity of ataxia was significantly higher in the gait-onset group(p = 0.029).The age of onset(p = 0.791)and the degree of ataxia progression(p = 0.243)were no significant difference between the two groups.4.SCA3 patients could exhibit several non-motor manifestations,of which fatigue is one of the most common,55.22% of SCA3 patients reported the subjective symptom of fatigue.Compared with healthy controls,FS-14 scores of SCA3 patients were significantly higher(p < 0.05).Daytime sleepiness(p = 0.024),the number of expanded CAG repeat(p = 0.046)and the severity of ataxia(p = 0.040)are risk factors that affect the degree of fatigue.And fatigue is positively correlated with the severity of ataxia(p = 0.040),however,there was no significant correlation between fatigue and age of onset (p = 0.086)and disease progression(p = 0.309).Conclusions: 1.The age of onset is inversely related to the number of expanded CAG repeat,and the severity of ataxia is positively related to the age of onset,disease duration,and the number of expanded CAG repeat,in patients with.2.SCA3 patients who presented with gait instability as the initial symptom had more severe ataxia compared to non-gait-onset patients during disease development.3.Compared with healthy controls,SCA3 patients are more prone to have severe fatigue,and fatigue can further increase the severity of SCA3 disease.Background: Spinocerebellar ataxia type 3(SCA3)is the most common subtype of spinocerebellar ataxias(SCAs)in China.It is an autosomal dominant neurodegenerative disease,which shows significant heterogeneity both clinically and genetically.According to the difference in clinical phenotype,SCA3 can be divided into 5 subtypes,of which the 5th type is also called spastic paraplegia subtype.Since the absence of the diagnostic criteria and the rarity of reports in spastic paraplegia subtype,there is still considerable controversy about this subtype.This part of study aims to analysis the clinical phenotypes of spastic paraplegia subtype,and investigate the possible risky factors of the subtype and its’ impact on clinical phenotypes in SCA3.Using functional magnetic resonance to study the cerebellum volume and gray matter distribution of spastic paraplegia subtype.Method: In the present study,241 molecular-confirmed SCA3 patients were recruited.Patients with the two or more following 4 signs of " lower muscle strength in bilateral lower limbs,increased muscle tone in bilateral lower limbs,hypertensive reflexes in bilateral lower limbs,positive pathological signs in bilateral lower limbs " were classified and included into the group of spastic paraplegia subtype;the remaining patients were classified and included into the group of as non-spastic paraplegia subtype.Multivariable logistic regression models were used to explore the risky factors of spastic paraplegia subtypes,and multivariable linear regression models were used to analyze the effects of spastic paraplegia subtype on the age of onset,severity of ataxia,and degree of ataxia progression.In order to further observe the differences in brain structure,18 age,gender-matched spastic paraplegia subtype patients,non-spastic paraplegia subtype patients,and healthy controls were selected to collect brain magnetic resonance images data.Manually draw the region of interest(cerebellum)and VBM technology were used to evaluate and compare the changes of cerebellar volume and the change of whole brain gray matter volume,respectively.Results: 1.29.1% of the patients presented with spastic paraplegia subtype.Compared with patients with non-spastic paraplegia subtype,patients with spastic paraplegia subtype have an earlier age of first visit(p = 0.000),an earlier age of onset(p = 0.000),severer ataxia(p = 0.046),and a larger numbers of expanded CAG repeat(p = 0.000).2.After adjusting for gender and the number of normal CAG repeat,patients with spastic paraplegia subtype have an earlier age of onset(p = 0.001)than patients with non-spastic paraplegia subtype;similarly,after adjusting for gender,age of onset,disease duration,the number of normal and expanded CAG repeat,the severity of ataxia was significantly increased in the spastic paraplegia subtype group(p = 0.006).The degree of disease progression was not significantly different between the two groups(p = 0.815).3.The earlier the age of onset(p = 0.000)or the larger the number of expanded CAG repeat(p = 0.000),the more chance the patients would be spastic paraplegia subtype.After analyzing the ROC curve,the optimal cut-off value of age at onset was 30.5 years(sensibility: 0.820;specificity: 0.585),and the optimal cut-off value of number of expanded CAG repeat was 76.5(sensibility: 0.725;specificity: 0.600).4.Compared with healthy controls,patients with spastic paraplegia subtype(p = 0.009)and patients with non-spastic paraplegia subtype(p = 0.005)showed a significant cerebellar atrophy,while there was no significant difference in cerebellar volume between patients with spastic paraplegia subtype and patients with non-spastic paraplegia subtype(p = 0.406).5.Compared with normal controls,spastic paraplegia subtype patients have atrophy of gray matter in the cerebellum,pons,hippocampal gyrus,fusiform gyrus,thalamus,putamen,posterior cingulate gyrus,supratemporal gyrus,and mid-temporal gyrus;Non-spastic paraplegia subtype patients have atrophy of gray matter volume in the cerebellum,pons,superior temporal gyrus,middle temporal gyrus,caudate nucleus,putamen nucleus,posterior cingulate gyrus,insular lobe,superior occipital gyrus,frontal Leaves,wedges,and margins.There was no significant difference in the distribution of gray matter between patients with spastic paraplegia subtype and nonspastic paraplegia subtype.Conclusions: 1.The spastic paraplegia subtype did exist in SCA3,and had significant severer clinical phenotypes,compared to the non-spastic paraplegia subtype.2.SCA3 patients with an age of onset < 30.5 years or the number of CAG repeat > 76.5 are more likely to become spastic paraplegia subtype.3.Although compared with healthy controls,patients with spastic paraplegia subtype and non-spastic paraplegia subtype have significant atrophy in cerebellum and gray matter in different part of brain,there was no significant difference in the volume of cerebellum and the gray matter of whole brain between two groups of spastic paraplegia subtype and non-spastic paraplegia subtype.