Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding...Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.展开更多
BACKGROUND Spinocerebellar ataxia recessive type 7(SCAR7)is a rare clinical manifestation beginning in childhood or adolescence.SCAR7 is caused by tripeptidyl peptidase 1(TPP1)gene mutations,and presents with cerebell...BACKGROUND Spinocerebellar ataxia recessive type 7(SCAR7)is a rare clinical manifestation beginning in childhood or adolescence.SCAR7 is caused by tripeptidyl peptidase 1(TPP1)gene mutations,and presents with cerebellar ataxia,pyramidal signs,neurocognitive impairment,deep paresthesia,and cerebellar atrophy.CASE SUMMARY Here,we describe a 25-year-old female patient in China who presented with increasing difficulty walking,falling easily,shaking limbs,instability holding items,slurred speech,coughing when drinking,palpitations,and frequent hunger and overeating.Magnetic resonance imaging showed cerebellar atrophy.Whole exome sequencing detected two compound heterozygous mutations in the TPP1 gene:c.1468G>A p.Glu490Lys and c.1417G>A p.Gly473Arg.Considering the patient’s clinical presentation and genetic test results,we hypothesized that complex heterozygous mutations cause TPP1 enzyme deficiency,which may lead to SCAR7.CONCLUSION We report the first case of SCAR7 from China.We also identify novel compound heterozygous mutations in the TPP1 gene associated with SCAR7,expanding the range of known disease-causing mutations for SCAR7.展开更多
Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or...Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.展开更多
The human glutamate receptor delta 2 gene （GRID2） shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a s...The human glutamate receptor delta 2 gene （GRID2） shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion （IVS5-121_-118 GAGT） and two single nucleotide polymor-phisms （c.1251G〉T and IVS14-63C〉G） were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.展开更多
BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,...BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,dysphagia,lingual fibrillation,pyramidal tract sign,and extrapyramidal system sign.However,it rarely has clinical manifestations similar to Parkinson-like symptoms,and is even rarer in patients sensitive to dopamine.We report a patient initially diagnosed with dopamine-responsive dystonia who was ultimately diagnosed with SCA3 by genetic testing,which was completely different from the initial diagnosis.CASE SUMMARY A 40-year-old Chinese woman was admitted to hospital due to severe inflexibility.At the beginning of the disease,she presented with anxiety and sleep disorder.At the later stage,she presented with gait disorder,which was similar to Parkinson's disease.Her medical history was unremarkable,but her mother,grandmother,and uncle all had similar illnesses and died due to inability to take care of themselves and related complications.Laboratory and imaging examinations showed no abnormalities,but electromyography and electroencephalography revealed delayed somatosensory evoked potentials and slow background rhythm,respectively.Her symptoms fluctuated during the daytime,and we initially diagnosed her with dopamine-responsive dystonia.After treatment with lowdose levodopa,the patient’s symptoms were significantly improved,but the final genetic diagnosis was SCA3.CONCLUSION SCA3 has various clinical phenotypes and needs to be differentiated from Parkinson's syndrome and dopamine-responsive dystonia.展开更多
BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar at...BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.展开更多
<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodege...<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>展开更多
Purpose: To disclose the association between spinocerebellar ataxia with oculomotor apraxia and high grade (7 diopters) congenital astigmatism. Methods: Single observational case report. A 39-year-old patient affected...Purpose: To disclose the association between spinocerebellar ataxia with oculomotor apraxia and high grade (7 diopters) congenital astigmatism. Methods: Single observational case report. A 39-year-old patient affected by spinocerebellar ataxia from the age of 20 was submitted to genetic and ophthalmic investigations to reach a diagnosis. Results: Genetic testing did not lead to a sure diagnosis, while clinical and instrumental ophthalmic examinations pointed out an oculomotor apraxia and a congenital severe astigmatism. Conclusion: To conclude the eye movement recording permitted to identify an oculomotor apraxia in this case of spinocerebellar ataxia. This is the first report of severe astigmatism in cases of ataxia with oculomotor apraxia.展开更多
Background： Spinocerebellar ata^ias （SCAs） are a group ofneurodegenerative disorders that primarily cause the degeneration in the cerebellum, spinal cord, and brainstem. We study the clinical characteristics, radio...Background： Spinocerebellar ata^ias （SCAs） are a group ofneurodegenerative disorders that primarily cause the degeneration in the cerebellum, spinal cord, and brainstem. We study the clinical characteristics, radiological features and gene mutation in Chinese families with SCAs. Methods： In this study, we investigated 10 SCAs Chinese families with SCAI, SCA3/Machado-Joseph disease （MJD}, SCA7, SCAB. There were 27 people who were genetically diagnosed as SCA, of which 21 people showed clinical symptoms, and 6 people had no clinical phenotype that we called them presymptomatic patients. In addition, 3 people with cerebellar ataxia and cataracts were diagnosed according to the Harding diagnostic criteria but tailed to be recognized as SCAs on genetic testing. Clinical characteristic analyses of each type of SCAs and radiological examinations were perlbrmed. Results： We found that SCA3/MJD was the most common subtype in Hart population in China, and the ratio of the pontine tegmentum and the posterior fossa area was negatively con＇elated with the number of cytosine-adenine-guanine （CAG） repeats： the disease duration was positively correlated with the International Cooperative Ataxia Rating Scale score; and the CAG repeats number of abnormal alleles was negatively correlated with the age of onset. Conchlsions： Collectively our study is a systematic research on SCAs in China, which may help for the clinical diagnosis and prenatal screening of this disease, and it may also aid toward better understanding of this disease.展开更多
Background Dominantly inherited spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous group of neurodegenerative disorders. This study was to further assess the frequency of SCA1 (spinocerebellar ...Background Dominantly inherited spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous group of neurodegenerative disorders. This study was to further assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, SCA8, SCA10, SCA12, SCA14, SCA17 and DRPLA (dentatorubro-pallidoluysian atrophy) in mainland Chinese, and to specifically characterize mainland Chinese patients with SCA6 in terms of clinical and molecular features.Methods Using a molecular approach, we investigated SCA 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. Results 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(0%), SCA14(0%), SCA17(0%) and DRPLA(0%). The genes responsible for 41 (34.2%) of dominantly inherited SCA families remain to be determined. Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) was found to harbor SCA3 mutations while none was found to harbor SCA6 mutations. In the 4 families with SCA6, significant anticipation was found in the absence of genetic instability on transmission.Conclusion A geographic cluster of families with SCA6 subtype was initially identified in a mainland Chinese population.展开更多
Background Spinocerebellar ataxia type 7 （SCA7） is known as an autosomal dominant cerebellar ataxia; patients with genetically confirmed diagnoses of SCA7 have increased rapidly in recent years.However, SCA7 is a ra...Background Spinocerebellar ataxia type 7 （SCA7） is known as an autosomal dominant cerebellar ataxia; patients with genetically confirmed diagnoses of SCA7 have increased rapidly in recent years.However, SCA7 is a rare subtype of SCA, and most data available about SCA7 are those of white people.The aim of the present study was to systematically review the prevalence and clinical and genetic aspects of SCA7 patients in East Asian population.Methods A search for publications on SCA7 was performed by using the ＂PubMed＂ database with the published language limited in English.Publications mainly focusing on the prevalence of SCA7 in patients with SCA and the clinical and genetic features of SCA7 patients were fully reviewed and analyzed.Results The prevalence of SCA7 in SCA patients ranged from 0 to 7.7%, which was similar to those reported previously.The clinical manifestations were typically present at the 30＇s of its victims （median, 29 years; interquartile range （IQR）,19.5-36.5 years）, and the symptoms appeared 15 years （（15.17±4.22） years） earlier on average in the offspring than in the parents.Gait ataxia and visual impairment were both found in all patients of whom the clinical features were described.Mutant SCA7 alleles contained 40-100 CAG repeats, with a median of 47 repeats （IQR, 44.5-50.0）; and the offspring had 13 more repeats on average compared with their parents （12.62±19.03）.A strong negative correlation was found between CAG repeat size and the onset age of patients （r=-0.739, P=0.000）.In addition, no significant difference was found in CAG repeat sizes between patients with visual impairment as the initial symptom and those with gait disturbance as their initial symptom （P=0.476）.Conclusions The prevalence of SCA7 in SCA patients, the age at onset and CAG repeats of SCA7 patients in East Asia are consistent with those of white people.However, larger population study is needed to assess the correlation between the CAG repeat size and initial symptoms of SCA7 patients in East Asia.展开更多
报道1例表现为多系统萎缩小脑型的脊髓小脑性共济失调8型(spinocerebellar ataxia type 8,SCA8)患者。该患者为57岁男性,病程4年,以头晕、共济失调为首发症状,后出现自主神经功能障碍、快速眼动睡眠障碍等表现。神经系统查体提示自主神...报道1例表现为多系统萎缩小脑型的脊髓小脑性共济失调8型(spinocerebellar ataxia type 8,SCA8)患者。该患者为57岁男性,病程4年,以头晕、共济失调为首发症状,后出现自主神经功能障碍、快速眼动睡眠障碍等表现。神经系统查体提示自主神经功能障碍、眼球震颤、构音障碍、共济失调,颅脑核磁共振见脑干、小脑对称性萎缩及脑桥“十字征”。基因检测结果显示ATXN8OS的两个等位基因CTA/CTG重复次数异常增多,确诊为SCA8。治疗上予以改善共济失调、自主神经功能障碍等对症治疗后患者反应良好。SCA8为罕见的运动障碍性疾病,临床异质性高。本报道旨在提示临床医师,SCA8也可表现为自主神经功能障碍、共济失调、脑桥“十字征”等类似多系统萎缩小脑型的特点,临床工作中要避免误诊、漏诊。展开更多
Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or ...Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.展开更多
基金funded by national fundsthrough the Foundation for Science and Technology (FCT)-project UIDB/50026/2020 and UIDP/50026/2020by the National Ataxia Foundation (NAF)
文摘Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.
基金Supported by Postdoctoral program of the Affiliated Hospital of Jining Medical University,No.JYFY303573Health Commission of Shandong Province,No.202006010928+1 种基金Academician Lin He New Medicine in Jining Medical University,No.JYHL2018FMS05Affiliated Hospital of Jining Medical University,No.2018-BS-004.
文摘BACKGROUND Spinocerebellar ataxia recessive type 7(SCAR7)is a rare clinical manifestation beginning in childhood or adolescence.SCAR7 is caused by tripeptidyl peptidase 1(TPP1)gene mutations,and presents with cerebellar ataxia,pyramidal signs,neurocognitive impairment,deep paresthesia,and cerebellar atrophy.CASE SUMMARY Here,we describe a 25-year-old female patient in China who presented with increasing difficulty walking,falling easily,shaking limbs,instability holding items,slurred speech,coughing when drinking,palpitations,and frequent hunger and overeating.Magnetic resonance imaging showed cerebellar atrophy.Whole exome sequencing detected two compound heterozygous mutations in the TPP1 gene:c.1468G>A p.Glu490Lys and c.1417G>A p.Gly473Arg.Considering the patient’s clinical presentation and genetic test results,we hypothesized that complex heterozygous mutations cause TPP1 enzyme deficiency,which may lead to SCAR7.CONCLUSION We report the first case of SCAR7 from China.We also identify novel compound heterozygous mutations in the TPP1 gene associated with SCAR7,expanding the range of known disease-causing mutations for SCAR7.
基金grants from the National Science and Technology Pillar Program in the Eleventh Five-year Plan Period, No. 2006BAI05A07the Major State Basic Research Development Program of China (973 Program), No. 2006cb500700+5 种基金the National Key Technologies Research and Development Program of China, No. 2004BA720A03the National Natural Science Foundation of China, No. 30871354, 30710303061 and 30470619the Key Project in the Natural Science Foundation of Hunan Province, No. 08JJ3048the Natural Science Foundation of Hunan Province, No. 11JJ5071the Science and Technology Planning Project of Hunan Province, No. 2009SK3172the Graduate Degree Thesis Innovation Foundation of Central South University, No. 2008yb030
文摘Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.
基金supported by grants from the National Natural Science Foundation of China,No.81371320the Project for Young and Middle-Aged Talents of Fujian Health Care System,No.2013-ZQN-JC-29
文摘The human glutamate receptor delta 2 gene （GRID2） shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion （IVS5-121_-118 GAGT） and two single nucleotide polymor-phisms （c.1251G〉T and IVS14-63C〉G） were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.
基金the National Natural Science Foundation of China,No.81874448 and No.81973789.
文摘BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,dysphagia,lingual fibrillation,pyramidal tract sign,and extrapyramidal system sign.However,it rarely has clinical manifestations similar to Parkinson-like symptoms,and is even rarer in patients sensitive to dopamine.We report a patient initially diagnosed with dopamine-responsive dystonia who was ultimately diagnosed with SCA3 by genetic testing,which was completely different from the initial diagnosis.CASE SUMMARY A 40-year-old Chinese woman was admitted to hospital due to severe inflexibility.At the beginning of the disease,she presented with anxiety and sleep disorder.At the later stage,she presented with gait disorder,which was similar to Parkinson's disease.Her medical history was unremarkable,but her mother,grandmother,and uncle all had similar illnesses and died due to inability to take care of themselves and related complications.Laboratory and imaging examinations showed no abnormalities,but electromyography and electroencephalography revealed delayed somatosensory evoked potentials and slow background rhythm,respectively.Her symptoms fluctuated during the daytime,and we initially diagnosed her with dopamine-responsive dystonia.After treatment with lowdose levodopa,the patient’s symptoms were significantly improved,but the final genetic diagnosis was SCA3.CONCLUSION SCA3 has various clinical phenotypes and needs to be differentiated from Parkinson's syndrome and dopamine-responsive dystonia.
文摘BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.
文摘<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>
文摘Purpose: To disclose the association between spinocerebellar ataxia with oculomotor apraxia and high grade (7 diopters) congenital astigmatism. Methods: Single observational case report. A 39-year-old patient affected by spinocerebellar ataxia from the age of 20 was submitted to genetic and ophthalmic investigations to reach a diagnosis. Results: Genetic testing did not lead to a sure diagnosis, while clinical and instrumental ophthalmic examinations pointed out an oculomotor apraxia and a congenital severe astigmatism. Conclusion: To conclude the eye movement recording permitted to identify an oculomotor apraxia in this case of spinocerebellar ataxia. This is the first report of severe astigmatism in cases of ataxia with oculomotor apraxia.
文摘Background： Spinocerebellar ata^ias （SCAs） are a group ofneurodegenerative disorders that primarily cause the degeneration in the cerebellum, spinal cord, and brainstem. We study the clinical characteristics, radiological features and gene mutation in Chinese families with SCAs. Methods： In this study, we investigated 10 SCAs Chinese families with SCAI, SCA3/Machado-Joseph disease （MJD}, SCA7, SCAB. There were 27 people who were genetically diagnosed as SCA, of which 21 people showed clinical symptoms, and 6 people had no clinical phenotype that we called them presymptomatic patients. In addition, 3 people with cerebellar ataxia and cataracts were diagnosed according to the Harding diagnostic criteria but tailed to be recognized as SCAs on genetic testing. Clinical characteristic analyses of each type of SCAs and radiological examinations were perlbrmed. Results： We found that SCA3/MJD was the most common subtype in Hart population in China, and the ratio of the pontine tegmentum and the posterior fossa area was negatively con＇elated with the number of cytosine-adenine-guanine （CAG） repeats： the disease duration was positively correlated with the International Cooperative Ataxia Rating Scale score; and the CAG repeats number of abnormal alleles was negatively correlated with the age of onset. Conchlsions： Collectively our study is a systematic research on SCAs in China, which may help for the clinical diagnosis and prenatal screening of this disease, and it may also aid toward better understanding of this disease.
文摘Background Dominantly inherited spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous group of neurodegenerative disorders. This study was to further assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, SCA8, SCA10, SCA12, SCA14, SCA17 and DRPLA (dentatorubro-pallidoluysian atrophy) in mainland Chinese, and to specifically characterize mainland Chinese patients with SCA6 in terms of clinical and molecular features.Methods Using a molecular approach, we investigated SCA 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. Results 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(0%), SCA14(0%), SCA17(0%) and DRPLA(0%). The genes responsible for 41 (34.2%) of dominantly inherited SCA families remain to be determined. Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) was found to harbor SCA3 mutations while none was found to harbor SCA6 mutations. In the 4 families with SCA6, significant anticipation was found in the absence of genetic instability on transmission.Conclusion A geographic cluster of families with SCA6 subtype was initially identified in a mainland Chinese population.
文摘Background Spinocerebellar ataxia type 7 （SCA7） is known as an autosomal dominant cerebellar ataxia; patients with genetically confirmed diagnoses of SCA7 have increased rapidly in recent years.However, SCA7 is a rare subtype of SCA, and most data available about SCA7 are those of white people.The aim of the present study was to systematically review the prevalence and clinical and genetic aspects of SCA7 patients in East Asian population.Methods A search for publications on SCA7 was performed by using the ＂PubMed＂ database with the published language limited in English.Publications mainly focusing on the prevalence of SCA7 in patients with SCA and the clinical and genetic features of SCA7 patients were fully reviewed and analyzed.Results The prevalence of SCA7 in SCA patients ranged from 0 to 7.7%, which was similar to those reported previously.The clinical manifestations were typically present at the 30＇s of its victims （median, 29 years; interquartile range （IQR）,19.5-36.5 years）, and the symptoms appeared 15 years （（15.17±4.22） years） earlier on average in the offspring than in the parents.Gait ataxia and visual impairment were both found in all patients of whom the clinical features were described.Mutant SCA7 alleles contained 40-100 CAG repeats, with a median of 47 repeats （IQR, 44.5-50.0）; and the offspring had 13 more repeats on average compared with their parents （12.62±19.03）.A strong negative correlation was found between CAG repeat size and the onset age of patients （r=-0.739, P=0.000）.In addition, no significant difference was found in CAG repeat sizes between patients with visual impairment as the initial symptom and those with gait disturbance as their initial symptom （P=0.476）.Conclusions The prevalence of SCA7 in SCA patients, the age at onset and CAG repeats of SCA7 patients in East Asia are consistent with those of white people.However, larger population study is needed to assess the correlation between the CAG repeat size and initial symptoms of SCA7 patients in East Asia.
文摘报道1例表现为多系统萎缩小脑型的脊髓小脑性共济失调8型(spinocerebellar ataxia type 8,SCA8)患者。该患者为57岁男性,病程4年,以头晕、共济失调为首发症状,后出现自主神经功能障碍、快速眼动睡眠障碍等表现。神经系统查体提示自主神经功能障碍、眼球震颤、构音障碍、共济失调,颅脑核磁共振见脑干、小脑对称性萎缩及脑桥“十字征”。基因检测结果显示ATXN8OS的两个等位基因CTA/CTG重复次数异常增多,确诊为SCA8。治疗上予以改善共济失调、自主神经功能障碍等对症治疗后患者反应良好。SCA8为罕见的运动障碍性疾病,临床异质性高。本报道旨在提示临床医师,SCA8也可表现为自主神经功能障碍、共济失调、脑桥“十字征”等类似多系统萎缩小脑型的特点,临床工作中要避免误诊、漏诊。
基金supported by Dana Impak Perdana Grant(DIP-2019-007)received by NMI from Universiti Kebangsaan Malaysia.
文摘Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.
