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Background: Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA without effective treatment. This study aimed to evaluate the comparative efficacy of low-frequency repetitive transcranial magnetic stimulation (rTMS) and intermittent Theta Burst Stimulation (iTBS) in a larger cohort of SCA3 patients. Methods: One hundred and twenty patients with SCA3 were randomly assigned to the 3 groups: 40 patients in the 1 Hz rTMS, 40 in the iTBS and 40 in the sham group. Patients underwent 10 sessions of rTMS targeting the cerebellum delivering for 5 consecutive days per week for 2 weeks (a total of 1200 pulses per session). Primary outcomes included the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Secondary outcomes included 10-m walking test (10MWT), nine-hole peg test (9-HPT), and PATA Rate Test (PRT). Outcome assessments were performed at baseline and on the last day of rTMS intervention. Results: This study revealed that active rTMS outperformed sham in reducing the SARA and ICARS scores in SCA3 patients, but with no difference between the 1 Hz rTMS and iTBS protocol. Moreover, no significant differences were observed in SARA and ICARS scores between the mild and moderate to severe groups after the 1 Hz rTMS/iTBS therapy. Additionally, no severe adverse events were recorded in this study. Conclusions: The study concluded that both 1 Hz rTMS and iTBS interventions targeting the cerebellum are effective to improve the symptoms of ataxia in patients with SCA3. [ABSTRACT FROM AUTHOR]

With complicated conditions and a large number of potentially causative genes, the diagnosis of a patient with complex inherited peripheral neuropathies (IPNs) is challenging. To provide an overview of the genetic and clinical features of 39 families with complex IPNs from central south China and to optimize the molecular diagnosis approach to this group of heterogeneous diseases, a total of 39 index patients from unrelated families were enrolled, and detailed clinical data were collected. TTR Sanger sequencing, hereditary spastic paraplegia (HSP) gene panel, and dynamic mutation detection in spinocerebellar ataxia (SCAs) were performed according to the respective additional clinical features. Whole-exome sequencing (WES) was used in patients with negative or unclear results. Dynamic mutation detection in NOTCH2NLC and RCF1 was applied as a supplement to WES. As a result, an overall molecular diagnosis rate of 89.7% was achieved. All 21 patients with predominant autonomic dysfunction and multiple organ system involvement carried pathogenic variants in TTR, among which nine had c.349G > T (p.A97S) hotspot variants. Five out of 7 patients (71.4%) with muscle involvement harbored biallelic pathogenic variants in GNE. Five out of 6 patients (83.3%) with spasticity reached definite genetic causes in SACS, KIF5A, BSCL2, and KIAA0196, respectively. NOTCH2NLC GGC repeat expansions were identified in all three cases accompanied by chronic coughing and in one patient accompanied by cognitive impairment. The pathogenic variants, p.F284S and p.G111R in GNE, and p.K4326E in SACS, were first reported. In conclusion, transthyretin amyloidosis with polyneuropathy (ATTR-PN), GNE myopathy, and neuronal intranuclear inclusion disease (NIID) were the most common genotypes in this cohort of complex IPNs. NOTCH2NLC dynamic mutation testing should be added to the molecular diagnostic workflow. We expanded the genetic and related clinical spectrum of GNE myopathy and ARSACS by reporting novel variants. [ABSTRACT FROM AUTHOR]

Background and purpose: NOTCH2NLC GGC repeat expansions have been identified to be associated with essential tremor (ET). Our aim was to characterize ET patients with NOTCH2NLC repeat expansions versus non‐expansions and describe distinctive clinical features of repeat expanded patients with long‐term follow‐up according to the new tremor classification. Methods: Participants included 597 ET pedigrees, 412 sporadic cases and 1085 healthy controls. Repeat expansions of GGC in NOTCH2NLC were screened, and comprehensive clinical features were investigated. A longitudinal clinical assessment and reclassification were performed in NOTCH2NLC expanded patients. Results: In total, 27 ET pedigrees (27/597) and three sporadic patients (3/412) were identified with pathogenic NOTCH2NLC GGC repeat expansions (≥60 repeats). Intermediate‐length GGC repeats (41–59 repeats) were found in four sporadic ET cases and one control subject, and the frequency was higher than that in control participants (4/412 vs. 1/1085, p = 0.022). About 46 ET patients (43 familial cases from 27 pedigrees and three sporadic cases) with NOTCH2NLC GGC repeat expansions had higher Essential Tremor Rating Assessment Scale I, Essential Tremor Rating Assessment Scale II and Non‐Motor Symptoms Scale scores and lower Mini‐Mental State Examination scores than the patients without expansions. Patients with pathogenic GGC repeats were reclassified as pure ET (25/46), ET‐plus (11/46) and ET‐neuronal intranuclear inclusion disease (10/46) subgroups at 2–8 years of follow‐up. Conclusion: Our results further supported that NOTCH2NLC GGC repeat expansions were associated with ET. Patients with pathogenic GGC repeats presented with more severe motor and non‐motor symptoms. Further long‐term follow‐up and subtype studies will help to define the role of NOTCH2NLC in ET. [ABSTRACT FROM AUTHOR]

Background: Repeat expansions, including those in C9orf72 and ATXN2 , have been implicated in amyotrophic lateral sclerosis (ALS). However, there have been few studies on the association of AR and NOP56 repeat expansion with ALS, especially in China. Accordingly, we aimed to evaluate the frequency of C9orf72 and ATXN2 repeat mutations and investigate whether NOP56 and AR repeat expansion are risk factors for ALS. Methods: In this study, 736 ALS patients and several hundred healthy controls were recruited. Polymerase chain reaction (PCR) and repeat-primed PCR (RP-PCR) were performed to determine the repeat lengths in C9orf72, ATXN2, AR , and NOP56. Results: GGGGCC repeats in C9orf72 were observed in six ALS patients (0.8%, 6/736) but not in any of the controls (0/365). The patients with pathogenic GGGGCC repeats showed shorter median survival times than those with a normal genotype (p = 0.006). Regarding ATXN2 CAG repeats, we identified that intermediate repeat lengths (29–34 copies) were associated with ALS (p = 0.033), and there was no difference in clinical characteristics between the groups with and without intermediate repeats (p > 0.05). Meanwhile, we observed that there was no association between the repeat size in AR and NOP56 and ALS (p > 0.05). Conclusions: Our results demonstrated that pathogenetic repeats in C9orf72 are rare in China, while intermediate CAG repeats in ATXN2 are more frequent but have no effect on disease phenotypes; the repeat size in AR and NOP56 may not be a risk factor for ALS. [ABSTRACT FROM AUTHOR]

• We investigated the psychological effect of COVID-19 pandemic on 307 SCA patients. • More than half of SCA patients had anxiety and depression during COVID-19 pandemic. • Depression (56.7%) was more common than anxiety (34.9%) in SCA patients. • Exposure to COVID-19, educational level, and disease course affect mental health. • The more severe the ataxia was, the higher the risk of anxiety and depression. Coronavirus disease 2019 (COVID-19) is currently a global concern, and the psychological impact cannot be overlooked. Our purpose was to evaluate the anxiety and depression in spinocerebellar ataxia (SCA) patients during the pandemic and to analyse the influencing factors. We conducted an online questionnaire survey among 307 SCA patients from China and selected 319 healthy people matched by sex and age as the control group. The questionnaire included general information, the self-rating anxiety scale (SAS), and the self-rating depression scale (SDS). The relevant factors included COVID-19 risk factors, age, sex, body mass index (BMI), educational background, disease course, score on the scale for the assessment and rating of ataxia (SARA), Mini-mental State Examination (MMSE) and International Cooperative Ataxia Rating Scale (ICARS). The proportion of SCA patients with anxiety was 34.9%, and the proportion with depression was 56.7%. The SAS and SDS scores of the SCA patients were significantly higher than those of the control group (SAS: 45.8 ± 10.1 vs. 40.6 ± 8.9, P < 0.01; SDS: 55.1 ± 12.2 vs. 43.6 ± 11.9, P < 0.01). In SCA3, the risk of exposure to COVID-19, educational level, disease course and the severity of ataxia may be factors affecting patients' mental health. More attention should be paid to the mental health of SCA patients during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology. It is not yet clear how ubiquitously-expressed proteins can cause the selective degeneration of particular populations of neurons, such as in spinocerebellar ataxia type 17, SCA17, which results from a CAG trinucleotide repeat expansion in the ubiquitously expressed transcription factor TBP. Here, the authors show that mutant TBP suppresses the cerebellum-enriched transcription of Inpp5a and link altered levels of INPP5A to the selective degeneration of cerebellar neurons. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by CTA/CTG repeat expansion in the ATXN8/ATXN8OS gene. Methods: To analyze the frequency and clinical characteristics of SCA8 patients in mainland China, we combined polymerase chain reaction (PCR) and triplet repeat-primed PCR (TRP-PCR) to detect the CTA/CTG expansion. We studied a cohort of 362 ataxia patients in which the other known causative genes had been previously excluded, from among 1294 index patients. Positive samples were validated by southern blotting. Results: The CTA/CTG expansion was observed in six probands, accounting for approximately 0.46% (6/1294) in all patients, and 1.66% (6/362) in patients without definite molecular diagnosis. Clinically, aside from the typical SCA8 phenotype, some patients carrying the CTA/CTG expansion exhibited the cerebellar form of multisystem atrophy (MSA-C) and ataxia with paroxysmal kinesigenic dyskinesia (PKD). Conclusion: For the first time, we described the PKD phenotype in association with CTA/CTG expansion, suggesting that CTA/CTG expansion might play a role in the pathogenesis of paroxysmal dyskinesia symptoms. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is one of the nine polyglutamine (polyQ) diseases and is caused by a CAG repeat expansion within the coding sequence of the ATXN3 gene. Few multimodal imaging analyses of the macro- and micro-structural changes have been performed. Methods: In the present study, we recruited 31 genetically-confirmed symptomatic SCA3/MJD patients and 31 healthy subjects as controls for a multimodal neuroimaging study using structural magnetic resonance imaging (sMRI), proton magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI). Results: The SCA3/MJD patients displayed a significantly reduced of gray matter volume in the cerebellum, pons, midbrain and medulla, as well as inferior frontal gyrus and insula, and left superior frontal gyrus. The total International Cooperative Ataxia Rating Scale (ICARS) score was inversely correlated with the gray matter volume in the cerebellar culmen, pons and midbrain. The numbers of CAG repeats in the expanded alleles were inversely correlated with the gray matter in the cerebellar culmen. NAA/Cr and NAA/Cho ratio in the middle cerebellar peduncles, dentate nucleus, cerebellar vermis, and thalamus in the SCA3/MJD patients were significantly reduced when compared to that in the normal controls, suggesting neurochemical alterations in cerebellum in the SCA3/MJD patients. Tract-Based Spatial Statistics (TBSS) analysis revealed significant lower volume and mean FA values of the cerebellar peduncles, which inversely correlated with the total scores of ICARS in our patients. Conclusions: In this study, we demonstrated cerebellar degeneration in SCA3/MJD based on tissue volume, neurochemistry, and tissue microstructure. Moreover, the associations between the clinical measures, cerebellar degeneration and genetic variation support a distinct genotype-phenotype relationship in SCA3/MJD. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) play an important role in growth, development, and reproduction and undoubtedly contribute to the pathogenesis and progression of diseases. Emerging evidence suggests the involvement of lncRNAs as regulatory factors in pathological conditions, including some neurodegenerative diseases. Spinocerebellar Ataxia Type 3/Machado–Joseph Disease (SCA3/MJD) has a prominent prevalence in China. Because the role of lncRNAs in SCA3/MJD pathogenesis has not yet been investigated, we conducted a pilot study to investigate the expression profile of lncRNAs by high-throughput sequencing in 12 patients and 12 healthy individuals. The sequencing analysis detected 5,540 known and 2,759 novel lncRNAs. Six lncRNAs were confirmed to be differentially expressed in peripheral blood mononuclear cells between SCA3/MJD patients and healthy individuals and were further validated in cerebellar tissue. Based on these results, NONHSAT022144.2 and NONHSAT165686.1 may be involved in the pathogenesis of SCA3/MJD and may be potential biomarkers for SCA3/MJD. Together with NONHSAT022144.2 and NONHSAT165686.1, the other four novel lncRNAs increase our understanding of lncRNA expression profile. [ABSTRACT FROM AUTHOR]

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia 3 or SCA3) is the most common dominant ataxia worldwide, with an overall average prevalence of 1–5/100,000. To this date, two major ancestral lineages have been found throughout the world. In China, the relative frequency of MJD among the SCAs reaches as high as 63%, however, little is known about its mutational origin in this country. We analyzed 50 families with MJD patients in two or more generations to study the hypothesis that new mutational events have occurred in this population. Haplotypes based on 20 SNPs have shown new genetic backgrounds segregating with MJD mutations in our cohort from China. We found the "Joseph-derived" lineage (Joseph lineage with a G variant in rs56268847) to be very common among Chinese MJD patients. Moreover, we estimated the time for the origin of this MJD SNP background based on STR diversity flanking the (CAG)n of ATXN3. It was surprising to find that the Chinese MJD population originated from 8,000 to 17,000 years ago, far earlier than the previous literature reports, which will be an important evidence to explain the origin, spread and founder effects of MJD. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) is the most common autosomal dominant spinocerebellar ataxia in China with highly clinical heterogeneity, such as progressive cerebellar ataxia, dysarthria, pyramidal signs, external ophthalmoplegia, dysphagia, and distal muscle atrophy. It is caused by the abnormal expansion of CAG repeats in a coding region of ATXN3. However, by focusing on the ATXN3 itself cannot fully explain the heterogeneous clinical features of SCA3/MJD. With the discovery of the increasing number of long noncoding RNAs (lncRNAs) that are believed to be involved in spinocerebellar ataxia type 8 (SCA8) and Huntington disease (HD), we wonder whether the lncRNAs are differentially expressed in the SCA3/MJD patients compared to the nonpatients. As the first step, we used lncRNA-Seq to investigate differential expression of the lncRNAs in the SCA3/MJD mice. Two known lncRNAs, n297609 and n297477, and a novel lncRNA TCONS_00072962 have been identified in SCA3/MJD mice with abnormal expression. The first discovery of the novel lncRNA TCONS_00072962 enriched the lncRNA expression profile in the SCA3/MJD mouse model. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3(SCA3), also known as Machado-Joseph disease (MJD), is the most frequent subtype of autosomal dominant inherited spinocerebellar ataxias, which caused by the expansion of CAG repeats in the ATXN3 gene. The number of CAG repeats of the abnormal allele determines the rate of disease progression in patients with SCA3/MJD. Markers to assess the clinical severity, to predict the course of illness and to monitor the efficacy of therapeutic measures, can be clinical, biological, and radiological. Here, we aimed to explore whether the serum glial fibrillary acidic protein (GFAP) may act as a biomarker in SCA3/MJD patients and to evaluate the correlation between some markers with the number of CAG repeats in SCA3/MJD patients. We showed that the serum levels of GFAP were significantly higher in SCA3/MJD patients than in controls. There was a strong positive correlation between the age-adjusted GFAP levels with the number of CAG repeats. Age-adjusted International Cooperative Ataxia Rating Scale (ICARS) scores and Scale for the Assessment and Rating of Ataxia (SARA) scores correlated with the number of CAG repeats. Raw scores and disease duration-adjusted GFAP levels, ICARS scores, and SARA scores were not correlated with the number of CAG repeats. Our results reveal novel evidence for the role of the triplet expansion in SCA3/MJD-associated neuronal damage. [ABSTRACT FROM AUTHOR]

A young Chinese male patient was identified as homozygous for Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3. This patient had a 4-year medical history mainly presenting severe ataxia, abnormal eye movement and pyramidal signs. Magnetic resonance imaging of the brain and cervical spinal cord revealed no obvious abnormality despite the severe symptoms and the findings of an electromyogram. However, brainstem auditory evoked potential indicated peripheral impairment and visual evoked potential indicated central impairment of his visual pathways. Molecular diagnosis revealed the pattern of CAG repeat units of this patient was 71/71. This case demonstrates that homozygosity for MJD enhances the clinical severity of the disease, which suggests that genetic education is of great importance. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3 (SCA3), or Machado—Joseph disease (MJD), is an autosomal dominantly-inherited disease that produces progressive problems with movement. It is caused by the expansion of an area of CAG repeats in a coding region of ATXN3. The number of repeats is inversely associated with age at disease onset (AO) and is significantly associated with disease severity; however, the degree of CAG expansion only explains 50 to 70% of variance in AO. We tested two SNPs, rs709930 and rs910369, in the 3’ UTR of ATXN3 gene for association with SCA3/MJD risk and with SCA3/MJD AO in an independent cohort of 170 patients with SCA3/MJD and 200 healthy controls from mainland China. rs709930 genotype frequencies were statistically significantly different between patients and controls (p = 0.001, α = 0.05). SCA3/MJD patients carrying the rs709930 A allele and rs910369 T allele experienced an earlier onset, with a decrease in AO of approximately 2 to 4 years. The two novel SNPs found in this study might be genetic modifiers for AO in SCA3/MJD. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is the most common type of spinocerebellar ataxia in China. However, the pathogenesis of SCA3/MJD is still unknown. MicroRNAs (miRNAs) have been repeatedly demonstrated to exist in human peripheral serum in a bio-stable form and have been shown to be useful biomarkers for other neurodegenerative disorders. However, no study of SCA3/MJD patients has assessed specific changes in regulatory miRNAs. Therefore, we systematically used the miRCURYTM LNA Array, followed by quantitative real-time polymerase chain reaction validation, to access miRNA expression levels in the serums from SCA3/MJD patients. Our results show that miR-25, miR-125b, miR-29a, and miR-34b could be potential biomarkers for SCA3/MJD and could be used to further investigate the pathogenesis of SCA3/MJD and drug development. [ABSTRACT FROM AUTHOR]

Abstract: Spinocerebellar ataxia type 6 (SCA6) is a late-onset, autosomal dominantly inherited ataxic disorder, and most previous clinical studies consider SCA6 to be a “pure” cerebellar ataxia. We carried out a detailed pathoanatomical study at autopsy of two patients, brother and sister, with genetically confirmed SCA6. The disease in both patients was early onset and short, which is atypical for SCA6. We observed severe neurodegeneration in the cerebellum, dentate nucleus and olivary nuclei. Both patients showed evidence of synaptic modification in the cerebellar cortex, which morphologically confirmed the existence of retrograde and anterograde trans-synaptic degeneration secondary to the cerebellar cortical lesion. Furthermore, our study shows for the first time that neurodegeneration in SCA6 occurs in the spinal cord. Finally, our postmortem study confirms that SCA6 is not a simple “pure” cerebellar disease, but a complex neurodegenerative condition in which many extracerebellar structures are involved. [Copyright &y& Elsevier]

Abstract: The hereditary spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. The genes causing 11 of these diseases have been identified. To date, there is no report of SCA type 6 (SCA6) in Mainland Chinese. Using a molecular approach, we investigated SCA6 as well as other SCA subtype in 120 Mainland Chinese families with dominantly inherited ataxias and in 60 Mainland Chinese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 13 patients from 4 families. We found that SCA3/MJD was the most common type of autosomal dominant SCA in Mainland Chinese, accounting for 83 patients from 59 families (49.2%), followed by SCA2 (8 [6.7%]), SCA1 (7 [5.8%]), SCA6 (4 [3.3%]), SCA7 (1 [0.8%]), SCA8 (0%), SCA10 (0%), SCA12 (1 [0.8%]), SCA14 (0%), SCA17 (0%) and DRPLA (0%). The genes responsible for 40 (33.3%) of dominantly inherited SCA families remain to be determined. Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) were found to harbor SCA3 mutations, whereas none were found to harbor SCA6 mutations. In the 4 families with SCA6, we found significant anticipation in the absence of genetic instability on transmission. This is the first report of geographic cluster of families with SCA6 subtype in Mainland China. [Copyright &y& Elsevier]

Keywords: spinocerebellar ataxia 3; gray matter; white matter; 1HMRS; imaging genetics study The correct number for the National Natural Science Foundation of China is No. 81771231 to HJ and No. 81600995 to YS. Spinocerebellar ataxia 3, gray matter, white matter, 1HMRS, imaging genetics study. [Extracted from the article]

Abstract: Autosomal dominant cerebellar ataxias (ADCAs), genetically classified into spinocerebellar ataxias (SCAs), are a highly heterogeneous group of neurodegenerative disorders. Recently, mutations in the fibroblast growth factor 14 gene (FGF14) have been reported to cause SCA27 subtype. To evaluate the frequency of FGF14 mutations in mainland of China, we performed molecular genetic analysis in 67 unrelated familial ataxia cases and 500 normal controls by denaturing high-performance liquid chromatography (DHPLC) and DNA direct sequencing. Interestingly, we found a pair of siblings carried the same heterozygous variation (c.-10delC) characterized by different clinical features, which is probably a novel insertion/deletion (I/D) polymorphism in the 5′UTR region of the exon 1b. It suggests that SCA27 is a rare subtype in China. [Copyright &y& Elsevier]

Introduction: Hereditary ataxias demonstrate a high degree of clinical and genetic heterogeneity. Understanding the genetic etiology of hereditary ataxias is crucial for genetic counseling and clinical management.Methods: The clinical and genetic data of patients with familial or sporadic ataxias who referred to our tertiary medical center were retrospectively analyzed. Probands in this study underwent SCA repeat expansion panel firstly to screen for repeat expansion SCAs; those with negative results had NGS-targeted panels or WES testing to detect conventional mutations.Results: A total of 223 patients were enrolled from 206 families. 5 kinds of coexisting SCA repeat expansions were observed (SCA3/SCA17, SCA3/SCA8, SCA2/SCA8, SCA3/SCA12 and SCA8/SCA12) in 12 patients from 8 families, among which SCA2/SCA8, SCA8/SCA12 and SCA3/SCA12 were reported for the first time. The coexistence of expanded SCA3 with SCA17 alleles was the most common in our study. NGS identified pathogenic/likely pathogenic variants in 12 ataxia causative genes in 13 probands. Spastic paraplegia ataxia was the most common diagnosis. Six novel mutations were detected in five ataxia-related genes.Conclusion: Coexistence may not specific to a certain SCA subtype and the frequency might have been underestimated before. SCA repeat expansion panel should be considered in patients with overlapping SCA features. In addition, our study broadened the conventional mutation spectrum in ataxia-related genes. These results facilitate a better understanding of the genetic basis for hereditary ataxias. [ABSTRACT FROM AUTHOR]

Polyglutamine (polyQ) diseases are a group of neurodegenerative disorders involving expanded CAG repeats in pathogenic genes that are translated into extended polyQ tracts and lead to progressive neuronal degeneration in the affected brain. To date, there is no effective therapy for these diseases. Due to the complex pathologic mechanisms of these diseases, intensive research on the pathogenesis of their progression and potential treatment strategies is being conducted. However, animal models cannot recapitulate all aspects of neuronal degeneration. Pluripotent stem cells (PSCs), such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), can be used to study the pathological mechanisms of polyQ diseases, and the ability of autologous stem cell transplantation to treat these diseases. Differentiated PSCs, neuronal precursor cells/neural progenitor cells (NPCs) and mesenchymal stem cells (MSCs) are valuable resources for preclinical and clinical cell transplantation therapies. Here, we discuss diverse stem cell models and their ability to generate neurons involved in polyQ diseases, such as medium spiny neurons (MSNs), cortical neurons, cerebellar Purkinje cells (PCs) and motor neurons. In addition, we discuss potential therapeutic approaches, including stem cell replacement therapy and gene therapy. [ABSTRACT FROM AUTHOR]

• Age is the most important independent variable influencing the phenotype of SCA3. • There is an interaction between CAG repeats and developmental or aging factors. • SCA3 phenotype severity might depend on the combined effects of this interaction. • A phenotype-genotype association exists between age and severity of SCA3 phenotype. This study aimed to investigate factors modulating spinocerebellar ataxia type 3 (SCA3) phenotype severity besides the expanded CAG repeats (ExpCAG) of ATXN3. Data regarding CAG trinucleotide repeats, age at onset (AO), duration, age, sex, transmitting parent, and scale scores of SCA3 patients were collected. Multiple linear regression analysis was performed to identify influential independent variables. Age, AO, ExpCAG, and duration were considered control variables to analyze the correlation between independent variables and scale scores. Duration, age, and ExpCAG were screened as influential independent variables (P = 0.000). Age had the greatest impact on multiple linear regression models (P <5E-8). ExpCAG and SARA/ICARS/INAS/Barthel index were not correlated (P > 0.05); considering only age as the control, ExpCAG was slightly-to-moderately correlated with all aforementioned scores except INAS (P < 0.05). Age and all scores, except INAS, were positively correlated (P < 0.05); considering duration, AO, or ExpCAG as controls, their correlations did not change significantly. On controlling age, AO was negatively correlated with all scores (P < 0.05), except for the Barthel index (P > 0.05). Furthermore, the interaction model revealed that the interaction between age, duration, and ExpCAG was significantly associated with SCA3 disease severity (P < 0.05). Age is a potentially important modifier of SCA3 phenotype severity, through the interaction between ExpCAG and aging factors. [ABSTRACT FROM AUTHOR]

• Next-generation sequencing technology was first applied for mtDNA variant analyses in SCA3/MJD patients from mainland China. • The tRNA-transcribed genes were potentially associated with the pathogenesis of SCA3/MJD. • The mitochondrial variations of SCA3/MJD patients were dominantly with high variant loads. Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), is the most common type of autosomal dominant cerebellar ataxias. Few studies focused on the changes of the whole mitochondrial genomes of SCA3/MJD patients and its relationship with the pathogenesis of SCA3/MJD. We adapted one-step long-range PCR to amplify the entire mitochondrial DNA (mtDNA) followed by next-generation sequencing technology to investigate the information of whole mitochondrial genomes in 38 SCA3/MJD patients and 31 healthy controls from mainland China. Compared to the healthy control group, the mitochondrial variations in SCA3/MJD patients were more concentrated in the tRNA-transcribed genes which were further found to be potentially associated with the pathogenesis of SCA3/MJD by SKAT-O analysis. However, owning variations in tRNA-transcribed genes could not affect the age of onset (AO) of SCA3/MJD patients. We also noticed that the variant loads greater than 90% took up more in SCA3/MJD patients than in controls. Moreover, from our preliminary study, compared to the patients whose ages of onset were elder than 20, the mitochondrial genomes showed no difference in those AO less than 20. This is the first study to demonstrate the feasibility of using the next-generation sequencing technology for mtDNA variant analysis of SCA3/MJD patients from mainland China. And this research enriches the genetic information of SCA3/MJD and provides a direction for further investigations about the mitochondrial genomes in SCA3/MJD. [ABSTRACT FROM AUTHOR]

Abstract DNA methylation has been reported as an important regulator of genomic structure stability, including large tandem repeats. To test the modulation effect of variants in DNA methylation–related genes on distribution of expanded (CAG) n alleles and age at onset (AO) of patients with Machado-Joseph disease (MJD), we conducted an association analysis on 23 selected SNPs in these genes in 613 patients with MJD and 581 controls. There were significant differences in the distribution of rs12957023 between patients and controls (OR = 1.296, p = 0.007 and OR = 1.206, p = 0.008, for genotype and alleles, respectively). The distribution of (CAG) n size was also different between patients carrying a CC and the other genotypes (TT and TC, p = 0.011 for expanded (CAG) n and p = 0.012 for normal size alleles), indicating that DNA methylation might modulate the (CAG) n instability. We found also that rs13420827 in DNMT3A and rs7354779 in DNMT3L contribute to AO of MJD (p = 0.019 and p = 0.008, respectively). In conclusion, our data provide the first evidence that SNPs in DNA methylation–related genes may contribute to (CAG) n instability and modulate the AO of this disease. Highlights • The first systemic analysis of DNA methylation on MJD in a large Chinese cohort. • rs12957023 distribution was different in MJD patients and controls. • (CAG) n size was different in patients carrying different genotype of 12957023. • rs13420827 and rs7354779 might modulate age at onset of MJD. [ABSTRACT FROM AUTHOR]

Abstract It has been reported that DNA repair pathways could modify age at onset (AO) in Huntington disease (HD) and spinocerebellar ataxias. We genotyped 22 SNPs from DNA repair pathways in a large cohort of 798 Chinese Machado-Joseph disease patients to investigate the association with AO, and no significant finding was observed. Our findings did not provide a strong evidence for the modulatory effect of DNA repair pathways on the AO of Chinese Machado-Joseph disease patients. Further analyses with more representative DNA repair–related SNPs in different populations are needed to identify new potential genetic modifiers. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative disorders distributed worldwide. Nearly 35 SCAs have been localized and 28 genes have been identified. Recently, mutations in the elongation of a very long chain fatty acids-5 gene ( ELOVL5 ) were reported to cause a SCA38 subtype. To describe the epidemiology of SCA38 in Mainland China, we analyzed the coding sequence of ELOVL5 in 346 patients diagnosed as SCAs. Finally, we did not observe any disease-related gene mutations in ELOVL5 . This suggests that the SCA38 subtype is very rare in Mainland China. [ABSTRACT FROM AUTHOR]

Abstract: Polymorphism of the apolipoprotein E (APOE) gene has been defined as a modifying factor for age at onset (AO) in neurodegenerative disorders. The AO of spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3 or MJD) is inversely correlated with expanded CAG repeat lengths in the ATXN3 gene; however, AO is only partially explained by the expanded CAG repeats. We performed a case-control study to explore whether APOE genotypes play a role in AO of SCA3 or MJD from the Chinese Han population. The APOE genotypes were analyzed in an independent cohort of 155 patients with SCA3 or MJD and 191 controls both from Mainland China. Our study demonstrated that SCA3 or MJD patients experienced an earlier onset if they were carriers of APOE ε2 allele, which decreased the AO by nearly 4 years. This study may also reconfirm the effect of the APOE gene on SCA3 or MJD patients from different races and indicated that certain APOE alleles might be genetic modifiers for AO in SCA3 or MJD. [Copyright &y& Elsevier]