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Introduction Due to diverse symptoms of spinocerebellar ataxia type 3 (SCA3) and the high prevalence of SCA3 in China, a more in-depth study of Chinese SCA3 patients in a large cohort is well merited. Methods During the last 10 years, 730 patients and 133 premanifest individuals from 667 SCA3 families genetically confirmed to have SCA3 were enrolled from three leading academic hospitals in China. The clinical profile and genotype-phenotype correlation were analyzed. Results A quadratic equation best explained the relationship between the logarithmically transformed age at onset (AAO) and expanded CAG repeats (expCAGs) (r2 = 0.634, p 10 years. Intriguingly, onset after parturition happened in 10 female patients with the AAO of 26.7 ± 4.3 years and the expCAG of 77.4 ± 1.4 repeats. Five out of 12 patients with subtype V and larger expCAGs (78.8 ± 4.8 repeats) suffered from spastic gait initially, and 10 out of 12 showed no limb ataxia. Nystagmus happened most frequently (10.5%) in premanifest individuals. Conclusion We demonstrated the genotype-phenotype correlation in the largest cohort of SCA3 individuals to date, and interestingly found some new phenomena in Chinese SCA3 individuals.

Objective Spinocerebellar ataxia type 3 (SCA3) is one of the most common hereditary neurodegenerative diseases, with balance instability as main symptom. Balance quantification is crucial for evaluating the efficacy of therapeutic interventions. However, balance evaluation in SCA3 is often subject to bias. Here, we aimed to quantitatively evaluate postural instability and investigate the relationship between postural instability and clinical characteristics in SCA3 patients. Methods Sixty‐two SCA3 patients and 62 normal controls were recruited, and their postural balance was measured using a posturographic platform. Principal component analysis was performed as data reduction to identify postural instability factors. Multivariable linear regression was used to investigate potential risk factors for postural instability and to explore whether postural instability predicts the severity and progression of ataxia in SCA3 patients. Results We found SCA3 patients experience postural instability characterized by significant impairment in static and dynamic stability. The condition without visual feedback was the most sensitive measure in differentiating SCA3 from controls. Regression analyses revealed that ataxia severity predicted both static (P = 0.014) and dynamic stability (P = 0.001). Likewise, along with expanded CAG repeats (P

Spinocerebellar ataxia type 3 (SCA3) is caused by unstable expanded CAG repeats (expCAGs) in ATXN3. Factors associated with intergenerational instability (delta-expCAG) and genetic anticipation in SCA3 have never been reported in Chinese mainland. Here, we demonstrated that unstable transmissions occurred more often in sons than in daughters (91% vs 72%, Fisher’s exact test, p = 0.012). The extended delta-expCAG of father-son transmissions was greater than that of mother-son transmissions (3.8 ± 2.3 repeats vs 1.6 ± 1.0 repeats, Mann-Whitney U, p = 0.001). Genetic anticipation was frequently observed between generations but not affected by the delta-expCAG.

BackgroundPostural instability is one of the most disabling features of spinocerebellar ataxias type 3 (SCA3) and often leads to falls that reduce mobility and functional capacity. This study aimed to quantitatively analyse static and dynamic balance and proprioception function on postural control in patients with SCA3 using the Pro-kin system and optimise rehabilitation programmes for them.MethodsEight-one clinically diagnosed SCA3 patients (38 women, 43 men; aged 39.00 ± 9.66) and 62 healthy controls were studied and evaluated using the Pro-kin system (PK254P, Tecnobody S.r.l, Dalmine, Italy). The measurements included (1) a static balance test in two visual feedback conditions: eyes open (EO) and eyes closed (EC); (2) a dynamic balance test measuring limits of stability (LOS); and (3) a proprioception function test to obtain proprioceptive measurements on a multiaxial balance evaluator for both right and left lower limbs.ResultsCompared to controls, SCA3 patients showed significantly higher values of all static balance outcome variables with eyes open and eyes closed, implying postural instability. SCA3 patients showed significantly higher values in the standard deviation of body sway along the medio-lateral (ML) axis and in the velocity of body sway along the anterior-posterior (AP) axis. The overall scores and the scores for all eight LOS components were significantly lower in the SCA3 patients than in the controls. The mean values of AP index (API), ML index (MLI), Stability index (SI) and average trace error (ATE) were significantly greater in SCA3 patients compared to HC subjects, while API showed a trend toward higher values.ConclusionsSCA3 patients have a significant postural control disorder, and are likely to fall on the AP plane and prefer performing postural adjustments in the ML direction; a decreased proprioception function in the knee and ankle is also evident. Visual cues and proprioception should be emphasized in balance rehabilitation training. Attention should also be paid to improve muscle strength and range of motion.Trial registrationThe Chinese clinical test registration center. ChiCTR1800020133. Registered 15 december 2018 - Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=33950

Background: Spinocerebellar ataxia type 3 (SCA3) is an inherited form of ataxia that leads to progressive neurodegeneration. Fatigue is a common non-motor symptom in SCA3 and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Although risk factors to fatigue in these diseases have been thoroughly studied, whether or not fatigue can affect clinical phenotypes has yet to be investigated. Methods: Ninety-one molecularly confirmed SCA3 patients and 85 age- and sex-matched controls were recruited for this study. The level of fatigue was measured using the 14-item Fatigue Scale (FS-14), and the risk factors to fatigue and how fatigue correlates with clinical phenotypes were studied using multivariable linear regression models. Results: We found that the severity was significantly higher in the SCA3 group than in the control group (9.30 ± 3.04% vs. 3.94 ± 2.66, P = 0.000). Daytime somnolence (β = 0.209, P = 0.002), severity of ataxia (β = 0.081, P = 0.006), and poor sleep quality (β = 0.187, P = 0.037) were found to have a positive relationship with fatigue. Although fatigue had no relationship with age at onset or ataxic progression, we found that it did have a positive relationship with the severity of ataxia (β = 7.009, P = 0.014). Conclusions: The high level of fatigue and the impact of fatigue on the clinical manifestation of SCA3 patients suggest that fatigue plays a large role in the pathogenesis of SCA3, thus demonstrating the need for intervention and treatment options in this patient cohort.

Background For a variety of sporadic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, it is well-established that ethnicity does affect the disease phenotypes. However, how ethnicity contributes to the clinical symptoms and disease progressions in monogenetic disorders, such as spinocerebellar ataxia type 3 (SCA3), remains less studied. Methods We used multivariable linear and logistical regression models in 257 molecularly-confirmed SCA3 patients (66 Caucasians, 43 African Americans, and 148 Asians [composed of 131 Chinese and 17 Asian Americans]) to explore the influence of ethnicity on age at onset (AAO), ataxia severity, and non-ataxia symptoms (i.e. depression, tremor, and dystonia). Results We found that Asians had significantly later AAO, compared to Caucasians (β = 4.75, p = 0.000) and to African Americans (β = 6.64, p = 0.000) after adjusting for the pathological CAG repeat numbers in ATXN3. African Americans exhibited the most severe ataxia as compared to Caucasians (β = 3.81, p = 0.004) and Asians (β = 4.39, p = 0.001) after taking into consideration of the pathological CAG repeat numbers in ATXN3 and disease duration. Caucasians had a higher prevalence of depression than African Americans (β = 1.23, p = 0.040). Ethnicity had no influence on tremor or dystonia. Conclusions Ethnicity plays an important role in clinical presentations of SCA3 patients, which could merit further clinical studies and public health consideration. These results highlight the role of ethnicity in monogenetic, neurodegenerative disorders.

Background Spinocerebellar ataxia type 3 (SCA3) is a rare, inherited form of ataxia that leads to progressive neurodegeneration. The initial symptoms could affect clinical phenotypes in neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis. However, the contribution of initial symptoms to the phenotypes of SCA3 has been scarcely investigated. Methods In the present study, 143 SCA3 patients from China were recruited and divided into two groups of gait‐onset and non‐gait‐onset. For determining the influences of initial symptoms on age at onset (AAO), the severity and progression of ataxia, and the possible factors affecting the initial symptoms, multivariable linear regression, and multivariate logistic regression were performed. Results We found that the frequency of gait‐onset was 87.41%, and the frequency of non‐gait‐onset was 12.59% (diplopia: 7.69%, dysarthria: 4.20%, dystonia: 0.70%). Compared to the non‐gait‐onset group, the gait‐onset group had significantly more severe ataxia (p = 0.046), while the initial symptoms had no effect on AAO (p = 0.109) and progression of ataxia (p = 0.265). We failed to find the existence of any factors affecting initial symptoms. Conclusion These findings collectively suggested that initial symptoms influenced phenotypes in SCA3 and that neurodegeneration in different parts of brain may induce different disease severity in SCA3., To investigate the contribution of initial symptoms to the phenotypes of spinocerebellar ataxia type 3 (SCA3), 143 SCA3 patients from China were recruited and divided into two groups of gait‐onset and non‐gait‐onset. We found that compared to the group of non‐gait‐onset, the group of gait‐onset had significantly more severe ataxia. Our finding suggested that initial symptoms influenced phenotypes in SCA3 and that neurodegeneration in different parts of brain may induce different severity in SCA3.

BACKGROUND AND PURPOSE Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder with varied prevalence in different populations, which may be associated with specific haplotypes. This study aimed to explore the haplotypes encompassing the HTT gene in the Chinese population. METHODS A total of 406 individuals with HD and 59 normal relatives from 253 families with HD were enrolled. A total of 29 tag single nucleotide polymorphisms (tSNPs) were selected and genotyped for the haplotype analysis. RESULTS In stage one, we used 18 tSNPs to replicate the distribution of three major haplogroups (A, B, C). We found that risk-associated haplogroup variants A1 and A2, enriched on Caucasian HD chromosomes, were totally absent from both Chinese HD and control chromosomes, and the distributions of haplogroups between HD and control chromosomes were similar. Therefore, in stage two, we used 29 tSNPs (including the18 tSNPs) to define new haplogroups (I, II, III) and found that haplogroup I accounted for 61.4% on HD chromosomes and 34.4% on control chromosomes, indicating that haplogroup I was enriched on Chinese HD chromosomes. CONCLUSIONS This is the first haplotype analysis encompassing HTT in the Chinese population. The results contribute to explaining the low prevalence of HD in China and provide a better understanding of genetic diversity in the HTT region.

Genetic mutations in transglutaminase 6 (TGM6) are recently identified to be associated with spinocerebellar ataxia type 35 (SCA35). We report a Hispanic SCA35 patient, who was confirmed to have a heterozygous, single-nucleotide deletion in TGM6, causing a frameshift mutation with a premature stop codon. An immune-mediated ataxia previously found to be associated with autoantibody reactivity to TG6 may share a similar pathomechanism to SCA35, suggesting a converging role for TG6 in cerebellar function.

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG triplet repeats expansion in exon 1 of the Huntingtin gene (HTT). In China, HD is considered to have a low prevalence. The goal of this study was to describe the clinical characteristic and genetic profiles of HD in a Chinese cohort. A total of 322 individuals with expanded CAG repeats were consecutively recruited from the neurologic clinics of three medical centers in Southeastern China between 2008 and 2018. Among them, 80 were pre-symptomatic mutation carriers and 242 were symptomatic patients. The mean age at onset (AAO), defined here as the age at motor symptom onset, of the 242 manifest HD individuals was 40.3 ± 11.9 years and the mean CAG repeat length was 46.1 ± 7.5 in the group of symptomatic patients. Initial symptoms were abnormal movements in 88.8% of the patients with psychiatric symptoms in 6.2%, cognitive impairment in 3.3% and others in 1.7%. The AAO of motor was negatively correlated with the CAG repeat length in an exponential regression analysis (R 2 = 0.74, P

Spinocerebellar ataxia type 3 (SCA3), the most common subtype of SCA worldwide, is caused by mutation of CAG repeats expansion in ATXN3. Body mass index (BMI) is an important modulatory factor in the progression of neurodegenerative disorders such as Huntington disease and amyotrophic lateral sclerosis. However, its relevance in SCA3 is not well understood. In this study, BMI was investigated in 134 molecularly confirmed SCA3 patients and 136 healthy controls from China. The multivariable linear regression models were performed to establish the putative risk factors for BMI, and whether BMI could affect the severity of ataxia. We found that BMI was significantly lower in the case group than that in the control group. The age at onset (positive correlation) and severity of ataxia (negative correlation) were the risk factors affecting BMI. Conversely, BMI along with the disease duration, the age at onset, and the numbers of CAG repeats could also have influence on the severity of ataxia. In conclusion, SCA3 patients had lower BMI than matched controls and BMI is a predictor of disease progression in SCA3. Nutritional intervention to promote weight gain could be a promising strategy to impede SCA3 progression.

Background Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCAs worldwide. SCA3 homozygote is defined as expanded CAG repeats in both alleles that might exhibit severe phenotype due to gene dosage effect. However, a study on the systematic comparison of clinical phenotypes between homozygotes and heterozygotes to indicate these verity of phenotypes of homozygotes is still lacking. Methods A total of 14 SCA3 homozygotes (3 Chinese participants and 11 participants from various ethnicity in different published studies) and 143 Chinese heterozygotes of SCA3 were recruited for this study. The 95% confidence intervals (CIs) of age at onset and disease severity expected from heterozygous patients were analyzed to detect the phenotypic differences between homozygotes and heterozygotes. Results Almost all the homozygotes (13 of 14) were found to present a significant earlier age at onset compared with heterozygotes, because age at onset of most homozygotes was lower than the 95% CIs of age at onset of heterozygotes. Also, the clinical severity in most of the homozygotes (3 of 4) with identified clinical phenotypes was higher than the 95% CIs of severity in heterozygotes, indicating more severe clinical phenotypes in SCA3 homozygotes. Conclusions The homozygosity for SCA3 could lead to an earlier age of onset and putative severe clinical features. The findings of the present study suggested an influence of gene dosage on SCA3 phenotypes.

Background In traditional models of essential tremor, the inferior olivary nucleus was posited to play a central role as the pacemaker for the tremor. However, recent data call this disease model into question. Case presentation Our patient had progressive, long-standing, familial essential tremor. Upper limb tremor began at age 10 and worsened over time. It continued to worsen during the nine-year period he was enrolled in our brain donation program (age 85 – 94 years), during which time the tremor moved from the moderate to severe range on examination. On postmortem examination at age 94, there were degenerative changes in the cerebellar cortex, as have been described in the essential tremor literature. Additionally, there was marked degeneration of the inferior olivary nucleus, which was presumed to be of more recent onset. Such degeneration has not been previously described in essential tremor postmortems. Despite the presence of this degeneration, the patient’s tremor not only persisted but it continued to worsen during the final decade of his life. Conclusions Although the pathophysiology of essential tremor is not completely understood, evidence such as this suggests that the inferior olivary nucleus does not play a critical role in the generation of tremor in these patients.

Background Essential tremor (ET) is heterogeneous in nature and cases may be subdivided based on clinical features. ET patients may thus be subdivided by age of onset, family history of tremor, and presence of head tremor. We recently described climbing fiber-Purkinje cell (CF-PC) synaptic abnormalities in ET; however, these CF pathological features have not been studied across different ET subtypes. Objectives To explore whether these CF-PC synaptic abnormalities differ across ET subtypes. Methods We studied two climbing fiber (CF-PC) synaptic pathologies (CF synaptic density and percentage of CFs in the parallel fiber [PF] territory) in the cerebella of 60 ET cases with a range of clinical presentations and 30 age-matched controls. Results Compared to controls, ET cases had lower CF synaptic density and a higher percentage of CFs in the PF territory. ET cases with tremor onset ≥ 50 years did not differ significantly with respect to CF synaptic density and percentage of CFs in the PF territory. Similar results were found when comparing familial vs. sporadic ET cases, and ET cases with head tremor vs. those without head tremor. Among all ET cases, lower CF synaptic density was associated with lower PC counts and higher torpedo counts. In addition, higher percentage of CFs in the PF territory was associated with lower PC counts and higher torpedo counts. Conclusions These findings support the notion that changes in the distribution of CF-PC synapses are broadly part of the neurodegenerative process in the ET cerebellum.

Background Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known. Objectives To study clinical characteristics and ataxia progression in SCAs with and without dystonia. Methods We studied 334 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and compared the clinical characteristics of SCAs with and without dystonia. We repeatedly measured ataxia progression by the Scale for Assessment and Rating of Ataxia every 6 months for 2 years. Regression models were employed to study the association between dystonia and ataxia progression after adjusting for age, sex and pathological CAG repeats. We used logistic regression to analyze the impact of different repeat expansion genes on dystonia in SCAs. Results Dystonia was most commonly observed in SCA3, followed by SCA2, SCA1, and SCA6. Dystonia was associated with longer CAG repeats in SCA3. The CAG repeat number in TBP normal alleles appeared to modify the presence of dystonia in SCA1. The presence of dystonia was associated with higher SARA scores in SCA1, 2, and 3. Although relatively rare in SCA6, the presence of dystonia was associated with slower progression of ataxia. Conclusions The presence of dystonia is associated with greater severity of ataxia in SCA1, 2, and 3, but predictive of a slower progression in SCA6. Complex genetic interactions among repeat expansion genes can lead to diverse clinical symptoms and progression in SCAs.

Background: Spinocerebellar ataxia type 3 (SCA3), which is the most common subtype of SCA worldwide, exhibits common neuropsychological symptoms such as depression. However, the contribution of depression to the severity of SCA3 has not yet been thoroughly investigated. Methods: The present study investigated the prevalence of depression using Beck depression inventory in 104 molecularly confirmed SCA3 patients from China. The putative risk factors for depression and whether the depression could affect the severity of ataxia were established by multivariable linear regression models. Results: The frequency of depression in the study subjects was 57.69% (60/104), which was higher than that in SCA3 patients from a subset of other populations. The gender (p = 0.03) and severity (p < 0.01) of ataxia were those risk factors that could affect depression. Conversely, depression (p < 0.01) together with the duration (p < 0.01) of SCA3 could also play a positive role in the severity of ataxia. Conclusions: The extremely common depression results from motor disability caused by ataxia; it also affects the disease severity of SCA3. These findings suggested that depression was a part of neurodegeneration in SCA3 and necessitated intensive focus and interventions while caring for SCA3 patients.

Background and purpose: The clinical overlap between Machado-Joseph disease (MJD) and autosomal dominant complicated hereditary spastic paraplegia (AD-HSP) is extensive and the differentiation between them can be difficult on clinical ground. However, patients are seeking the right diagnosis and it is important for neurologists to distinguish them in the early stage. Methods: In recent 10 years, we have recruited and followed-up three families which were initially diagnosed as complicated AD-HSP based on the clinical criteria. Mutation analyses of SPG4, SPG3A and ATXN3 were performed in the index cases. Results: No mutations on SPG4 and SPG3A were found. Mutation analysis of ATXN3 showed that these cases have one expanded allele and one normal allele. The copy numbers of CAG repeats were 80/28, 86/28 and 83/33, respectively. Conclusions: The molecular diagnosis confirmed that they were MJD patients though they had been misdiagnosed as complicated AD-HSP for many years. The copy numbers of expanded allele were more than 80 and the copy numbers of normal allele were more than 27, which could somewhat explain the earlier onset age of these cases and the anticipation of the pedigrees. Our data emphasize the necessity to perform the mutation analysis of ATXN3 in clinically diagnosed complicated AD-HSP patients.

Spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease (MJD), is one of the most common SCAs worldwide and caused by a CAG repeat expansion located in ATXN3 gene. Based on the CAG repeat numbers, alleles of ATXN3 can be divided into normal alleles (ANs), intermediate alleles (AIs) and expanded alleles (AEs). It was controversial whether the frequency of large normal alleles (large ANs) is related to the prevalence of SCA3 or not. And there were huge chaos in the comprehension of the specific numbers of the range of CAG repeats which is fundamental for genetic analysis of SCA3. To illustrate these issues, we made a novel CAG repeat ladder to detect CAG repeats of ATXN3 in 1003 unrelated Chinese normal individuals and studied haplotypes defined by three single nucleotide polymorphisms (SNPs) closed to ATXN3. We found that the number of CAG repeats ranged from 13 to 49, among them, 14 was the most common number. Positive skew, the highest frequency of large ANs and 4 AIs which had never been reported before were found. Also, AEs and large ANs shared the same haplotypes defined by the SNPs. Based on these data and other related studies, we presumed that de novo mutations of ATXN3 emerging from large ANs are at least one survival mechanisms of mutational ATXN3 and we can redefine the range of CAG repeats as: ANs≤44, 45 ≤AIs ≤49 and AEs≥50.

Summary Aims To investigate the potential effect of six previously reported candidate single nucleotide polymorphisms on age at onset (AAO) among Chinese patients with Machado–Joseph disease (MJD). Methods Three hundred and twenty-four unrelated molecular-confirmed MJD patients were recruited between January 2006 and December 2014. The screening of candidate polymorphisms was first performed in 173 subjects using the SNaPshot® Multiplex System. The mitochondrial NADH dehydrogenase subunit 3 (MT-ND3) polymorphism 10398A>G (rs2853826) was further verified with Sanger sequencing in additional 151 patients. Results An inverse correlation was found between expanded CAG repeat length and AAO. The expanded CAG repeat length can explain 63% of AAO variance. The 10398A polymorphism was significantly associated with a 3-year earlier AAO in male patients with MJD (P = 0.001). Stepwise multiple regressions revealed that the 10398A polymorphism could account for nearly 2% of AAO variance in male patients. Conclusion Six candidate SNPs have been screened in Chinese patients with MJD. A remarkable earlier AAO was noted in male Chinese MJD patients with MT-ND3 gene 10398A polymorphism.

An effective treatment for amyotrophic lateral sclerosis (ALS) has not yet been found because the pathogenesis of this fatal disease is not well understood. A number of previous studies demonstrated that intermediate-length polyglutamine repeats within the ataxin-2 gene (ATXN2) might be a risk factor among patients with ALS in Western countries. Here, we aim to determine whether this sequence is a risk factor in Eastern Chinese ALS patients. Therefore, 379 unrelated sporadic ALS patients, 15 unrelated familial ALS patients, and 900 neurologically normal controls were studied. The ATXN2 CAG repeats were amplified using polymerase chain reaction. The products were separated on an 8% polyacrylamide gel and confirmed using Sanger sequencing. The results were evaluated using SPSS 17.0. We found that ATXN2 intermediate-length polyglutamine expansions greater than 24 and 27 repeats were associated with sporadic ALS. Our finding supports the hypothesis that ATXN2 plays an important role in the pathogenesis of ALS.

The genetic variants in glucocerebrosidase (GBA) gene have been previously examined as potential susceptibility factors for Parkinson's disease (PD). Although of great interest, possible role of GBA gene in PD has not been well investigated in eastern Chinese population. To explore this association, we conducted a genetic screen of three common GBA variants (p.L444P, p.N370S, and p.R120W) in a casecontrol cohort comprised of 638 subjects of Chinese ethnicity. In order to provide a more precise estimate of this association, a meta-analysis was performed. We found that the GBA p.L444P allele was significantly more frequent (P = 0.001) in the PD patients (6/195 = 3.08%) than in the controls (0/443). The p.L444P mutation, but not p.N370S and p.R120W, was found to be associated with PD. Combined analysis including all previously published ancestral Chinese data yielded a highly significant association between the GBA gene and an increased risk for PD (OR = 8.13, 95% CI, 4.43-14.92, P0.00001). Our study suggests that the GBA gene may be a susceptibility gene for PD in the Chinese population. Efforts to elucidate in detail this interesting and biologically plausible genetic association are warranted.

Clinical heterogeneity is the prominent feature of spinocerebellar ataxia type 3 (SCA3) which is sometimes neglected and often impedes the timely diagnosis of patients. In this study, the clinical data of 201 unrelated Chinese SCA3 patients were retrospectively studied. The rare clinical features were summarized and the underlying genetic mutations were screened by direct DNA sequencing. Three patients were found primarily presenting with the rare clinical features, including dystonic phenotype without response to levodopa, chorea and memory decline, and hearing impairment, respectively. We firstly reported three diverse heterogeneities of SCA3 patients, which are quite uncommon in the Chinese SCA3 patients. Our results expanded the variable phenotypes of SCA3 and provided the explicit information for the rare and special SCA3 manifestations. Based on this new knowledge, we suggested that when the presentation was consistent with HD or DRD while negative in the corresponding genetic testing, SCA3 should be considered, and clinicians should divert partial attention to the examinations on the auditory system of SCA3 patients.

Machado-Joseph disease (MJD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene. Although the principal genetic determinant of the age at onset (AAO) is the length of the expanded CAG repeat, the additional genetic contribution of MJD toward the AAO has mostly not yet been clarified. It was recently suggested in two independent studies that apolipoprotein E (APOE) might be associated with AAO variability in MJD patients. To identify the potential modifier effect of APOE polymorphisms on the AAO of MJD patients, 403 patients with MJD (confirmed by molecular tests) from eastern and southeastern China were enrolled in the present study. CAG repeats in the ATXN3 and APOE polymorphisms were genotyped. Data were analyzed using a statistical package. No contribution of APOE polymorphisms to the variance in disease onset was observed using ANCOVA (F = 0.183, P = 0.947). However, significant effects on the AAO of MJD were found for the normal ATXN3 allele and for the interaction of mutant and normal ATXN3 alleles in a multiple linear regression model (P = 0.043 and P = 0.035, respectively). Our study does not support a role for APOE as a genetic modifier of the AAO of MJD. Additionally, our study presents evidence that the normal ATXN3 allele and its interaction with mutant alleles contribute toward AAO variance in MJD patients.