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 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:Although many causative genes have been uncovered in recent years,genetic diagnosis is still missing for approximately 50%of autosomal recessive cerebellar ataxia(ARCA)patients.Few studies have been perform...Background:Although many causative genes have been uncovered in recent years,genetic diagnosis is still missing for approximately 50%of autosomal recessive cerebellar ataxia(ARCA)patients.Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population.Methods:Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing(WES)and copy number variation(CNV)calling with ExomeDepth.Likely causal CNV predictions were validated by CNVseq.Results:Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients,providing a 46.3%positive molecular diagnostic rate.Ten different genes were involved,of which four most common genes were SACS,SYNE1,ADCK3 and SETX,which accounted for 76.0%(19/25)of the positive cases.The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide.Clinical features of the patients carrying SACS,SYNE1 and ADCK3 mutations were summarized.Conclusions:Our results expand the genetic spectrum and clinical profiles of ARCA patients,demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA,and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.展开更多
Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological d...Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological disorders has increased considerably over the past 30 years because of population aging.Overall,neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow.Autism spectrum disorder,motor neuron disease,encephalopathy,epilepsy,stroke,ataxia,Alzheimer's disease,amyotrophic lateral sclerosis,Huntington's disease,and Parkinson's disease represent a non-exhaustive list of neurological illnesses.These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system.Among the common features of neurological handicaps,we find protein aggregation,oxidative stress,neuroinflammation,and mitochondrial impairment in the target tissues,e.g.,the brain,cerebellum,and spinal cord.The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis,are responsible for their dependence on functional mitochondria for their integrity.Reactive oxygen species,produced along with the respiration process within mitochondria,can lead to oxidative stress,which compromises neuronal survival.Besides having an essential role in energy production and oxidative stress,mitochondria are indispensable for an array of cellular processes,such as amino acid metabolism,iron-sulfur cluster biosynthesis,calcium homeostasis,intrinsic programmed cell death(apoptosis),and intraorganellar signaling.Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases,therapies that are effective to diminish or halt neuronal dysfunction/death are rare.Given the genetic complexity responsible for neurological disorders,the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life.A promising candidate is the neuroglobin,a globin superfamily member of 151 amino acids,which is found at high levels in the brain,the eye,and the cerebellum.The protein,which localizes to mitochondria,is involved in electron transfer,oxygen storage and defence against oxidative stress;hence,possessing neuroprotective properties.This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions,which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.展开更多
BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes...BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.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
Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage se...Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.展开更多
AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by beh...AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.展开更多
Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene pr...Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene product, ataxin-3. The precise mechanism of the MJD/SCA3 pathogenesis remains unclear. A growing body of evidence demonstrates that phosphorylation plays an important role in the pathogenesis of many neurodegenerative diseases. However, few kinases are known to phosphorylate ataxin-3. The present study is to explore whether ataxin-3 is a substrate of casein kinase 2 （CK2）. Methods The interaction between ataxin-3 and CK2 was identified by glutathione S-transferase （GST） pull-down assay and co-immunoprecipition assay. The phosphorylation of ataxin-3 by CK2 was measured by in vitro phosphorylation assays. Results （1） Both wild type and expanded ataxin-3 interacted with CK2α and CK2β in vitro. （2） In 293 cells, both wild type and expanded ataxin-3 interacted with CK2β, but not CK2α. （3） CK2 phosphorylated wild type and expanded ataxin-3. Conclusion Ataxin-3 is a substrate of protein kinase CK2.展开更多
AIM: To investigate the expression deficiency of key molecular markers in the homologous recombination pathway. METHODS: Expression loss of breast cancer type 1 susceptibility protein (BRCA1), ataxia telangiectasia mu...AIM: To investigate the expression deficiency of key molecular markers in the homologous recombination pathway. METHODS: Expression loss of breast cancer type 1 susceptibility protein (BRCA1), ataxia telangiectasia mutated (ATM), ATM-Rad3-related (ATR), mediator of DNA damage checkpoint protein 1 (MDC1) and meiotic recombination 11 (Mre11) were correlated with their clinicopathological parameters in gastric cancer (GC). One hundred and twenty treatment-naive GC samples were formalin-fixed and paraffin-embedded into tissue blocks. Two representative cores from each block were extracted and constructed into tissue microarrays. Expression levels of BRCA1, ATM, ATR, MDC1 and Mre11 were determined using immunohistochemical analysis, and correlated with clinical parameters, including age, gender, Lauren subtype, tumor grades, clinical stage and overall survival.RESULTS: Expression loss of BRCA1, ATM, ATR, MDC1, and Mre11 was found in 21.4%, 20.2%, 21.0%, 11.1% and 4.6%, respectively, of interpretable cases. BRCA1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 8.2% vs 31.7%, P = 0.001), higher tumor grade (Ⅰ/Ⅱ vs Ⅲ, 10.7% vs 20.5;Ⅰ/Ⅱ vs Ⅳ, 10.7% vs 54.5%, P = 0.047) and advanced clinical stage (Ⅰ/Ⅱ vs Ⅲ, 12.9% vs 16.9%;Ⅰ /Ⅱ vs Ⅳ, 12.9% vs 45.5%, P = 0.006). MDC1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 0% vs 19.7%, P = 0.001) and higher tumor grade (Ⅰ/Ⅱ vs Ⅲ, 0% vs 12%;Ⅰ/Ⅱ vs Ⅳ, 0% vs 30.8%, P = 0.012). In addition, the survival time of the patients with expression loss of BRCA1 was significantly shorter than those with positive expression of BRCA1 (2-year survival rate, 32.4% vs 62.8%, P = 0.015). No correlations were found between clinicopathological parameters and expression loss of ATM, ATR and Mre11. CONCLUSION: Our results support the hypothesis that homologous recombination deficiency plays an important role in the progression of gastric carcinoma. Loss of expression of BRCA1 and MDC1 may serve as predictive factors in tumor development or progression in GC patients.展开更多
Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene produc...Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene product, ataxin-3 （AT3）. This disease is characterized by the formation of intraneuronal inclusions, but the mechanism underlying their formation is still poorly understood. The present study is to explore the relationship between wild type （WT） AT3 and polyQ expanded AT3. Methods Mouse neuroblastoma （N2a） cells or HEK293 cells were co-transfected with WTAT3 and different truncated forms of expanded AT3. The expressions of WT AT3 and the truncated forms of expanded AT3 were detected by Western blotting, and observed by an inverted fluorescent microscope. The interactions between AT3 and different truncated forms of expanded AT3 were detected by immunoprecipitation and GST pull-down assays. Results Using fluorescent microscope, we observed that the truncated forms of expanded AT3 aggregate in transfected cells, and the full-length WT AT3 is recruited onto the aggregates. However, no aggregates were observed in cells transfected with the truncated forms of WT AT3. Immunoprecipitation and GST pull-down analyses indicate that WT AT3 interacts with the truncated AT3 in a polyQ length-dependent manner. Conclusion WT AT3 deposits in the aggregation that was formed by polyQ expanded AT3, which suggests that the formation of AT3 aggregation may affect the normal function of WT AT3 and increase polyQ protein toxicity in MJD.展开更多
Chronic post-hypoxic myoclonus, also known as Lance-Adams syndrome (LAS), is a rare complication of successful cardiopulmanry resuscitation often accompanied by action myoclonus and cerebellar ataxia. It is seen in pa...Chronic post-hypoxic myoclonus, also known as Lance-Adams syndrome (LAS), is a rare complication of successful cardiopulmanry resuscitation often accompanied by action myoclonus and cerebellar ataxia. It is seen in patients who have un-dergone a cardiorespiratory arrest, regained consciousness afterwards, and then developed myoclonus days or weeks after the event. Worldwide, 122 cases have been reported in the literature so far, including 1 case of Chinese. Here we report 2 Chinese LAS patients with detailed neuroimagings. Cranial single photon emission computed tomography (SPECT) of patient 1, a 52-year-old woman, showed a mild hypoperfusion in her left temporal lobe, whereas patient 2, a 54-year-old woman, manifested a mild bilateral decrease of glucose metabolism in the frontal lobes and a mild to moderate decrease of the N-acetyl aspartate (NAA) peak in the bilateral hippocampi by cranial [18F]-fluorodeoxyglucose positron emission tomographic (PET) scan and cranial magnetic resonance spectroscopy (MRS), respectively. We also review the literature on the neuroimaging, pathogenesis, and treatment of LAS.展开更多
BACKGROUND Type 1 sialidosis,also known as cherry-red spot-myoclonus syndrome,is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life.The most common symptoms are myoclonus,ata...BACKGROUND Type 1 sialidosis,also known as cherry-red spot-myoclonus syndrome,is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life.The most common symptoms are myoclonus,ataxia and seizure.It is rarely encountered in the Chinese mainland.CASE SUMMARY A 22-year-old male presented with complaints of progressive myoclonus,ataxia and slurred speech,without visual symptoms;the presenting symptoms began at the age of 15-year-old.Whole exome sequencing revealed two pathogenic heterozygous missense variants[c.239C>T(p.P80L)and c.544A>G(p.S182G)in the neuraminidase 1(NEU1)gene],both of which have been identified previously in Asian patients with type 1 sialidosis.All three patients identified in China's Mainland come from three unrelated families,but all three show the NEU1 mutations p.S182G and p.P80L pathogenic variants.Increasing sialidase activity through chaperones is a promising therapeutic target in sialidosis.CONCLUSION Through retrospective analysis and summarizing the clinical and genetic characteristics of type 1 sialidosis,we hope to raise awareness of lysosomal storage disorders among clinicians and minimize the delay in diagnosis.展开更多
The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases.While conventional magnetic resonance imaging(MRI) is widely used for ...The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases.While conventional magnetic resonance imaging(MRI) is widely used for brain and cerebellar morphologic evaluation,advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics.Volumetry,voxel-based morphometry,diffusion MRI based fiber tractography,resting state and task related functional MRI,perfusion,and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum.In the present review,after providing a brief description of each technique's advantages and limitations,we focus on their application to the study of cerebellar injury in major neurodegenerative diseases,such as multiple sclerosis,Parkinson's and Alzheimer's disease and hereditary ataxia.A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease,followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance.展开更多
BACKGROUND Familial cases of autosomal recessive spastic ataxia of charlevoix-saguenay have not been reported in the Arabian Peninsula,although the consanguineous marriage rate is very high.We report the first family ...BACKGROUND Familial cases of autosomal recessive spastic ataxia of charlevoix-saguenay have not been reported in the Arabian Peninsula,although the consanguineous marriage rate is very high.We report the first family from the Arabian Peninsula harboring a novel frameshift mutation in the SACS gene.CASE SUMMARY A 33-year-old man presented to our neurology clinic with balance problems and weakness of distal upper and lower limbs.He was previously clinically diagnosed with Friedreich's ataxia.However,the severity of polyneuropathy and the electrodiagnostic studies(EDX)findings are atypical features of Friedreich’s ataxia,and the deterioration was attributed to diabetic neuropathy.Close examination of other family members identified cerebellar ataxia,lower-limb pyramidal signs,peripheral neuropathy,and magnetic resonance imaging findings characterized by pontine linear hypointensities.Genetic testing for Friedreich’s ataxia did not yield a diagnosis.Whole exome sequencing identified a novel frameshift germline mutation in the SACS gene termed c.5824_5827delTACT using the transcript NM_014363.5,which is predicted to cause premature termination of the sacsin protein at amino acid position 1942(p.Tyr1942Metfs*9)and disrupts the sacsin SRR3 and domains downstream from it.The mutation segregated with the disease in the family.CONCLUSION Our data add to the spectrum of mutations in the SACS gene and argues for a need to implement suitably integrated clinical and diagnostic services,including next generation sequencing technology,to better classify ataxia in this area of the world.展开更多
BACKGROUND Gerstmann-Str?ussler-Scheinker(GSS) disease is an inherited prion disease that is clinically characterized by the early onset of progressive cerebellar ataxia. The incidence of GSS is extremely low and it i...BACKGROUND Gerstmann-Str?ussler-Scheinker(GSS) disease is an inherited prion disease that is clinically characterized by the early onset of progressive cerebellar ataxia. The incidence of GSS is extremely low and it is particularly rare in China. Therefore,clinicians may easily confuse this disease with other diseases that also cause ataxia, resulting in its under-diagnosis or misdiagnosis.CASE SUMMARY Here, we report the first case of genetically diagnosed GSS disease in Northeast China. The patient exhibited typical ataxia and dysarthria 2.5 years after symptom onset. However, magnetic resonance imaging of the brain and spinal cord revealed a normal anatomy. Screening results for the spinocerebellar ataxia gene were also negative. We thus proposed to expand the scope of genetic screening to include over 200 mutations that can cause ataxia. A final diagnosis of GSS was presented and the patient was followed for more than 3.5 years, during which we noted imaging abnormalities. The patient gradually exhibited decorticate posturing and convulsions. We recommended administration of oral sodium valproate, which resolved the convulsions.CONCLUSION Patients with inherited ataxia should be considered for a diagnosis of GSS via genetic testing at an early disease stage.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.
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.
基金supported by grants from the National Natural Science Foundation of China(82071260 to Z.-Y.W.)the Research Foundation for Distinguished Scholar of Zhejiang University(188020-193810101/089 to Z.-Y.W.).
文摘Background:Although many causative genes have been uncovered in recent years,genetic diagnosis is still missing for approximately 50%of autosomal recessive cerebellar ataxia(ARCA)patients.Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population.Methods:Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing(WES)and copy number variation(CNV)calling with ExomeDepth.Likely causal CNV predictions were validated by CNVseq.Results:Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients,providing a 46.3%positive molecular diagnostic rate.Ten different genes were involved,of which four most common genes were SACS,SYNE1,ADCK3 and SETX,which accounted for 76.0%(19/25)of the positive cases.The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide.Clinical features of the patients carrying SACS,SYNE1 and ADCK3 mutations were summarized.Conclusions:Our results expand the genetic spectrum and clinical profiles of ARCA patients,demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA,and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.
基金supported by AFM-Telethon grants N°21704 and 23264,Universite Paris Cite(Paris)the National Institute of Health and Medical Research(INSERM)+3 种基金the National Center for Scientific Research(CNRS)the French Association Connaître les Syndromes Cerebelleux(CSC)(to MCD)GV/2021/188 granted from Conselleria of Innovation,Universities,28 Science and Society digital of the Community of Valencia(Spain)(to ITC)Subprograma Atraccion de Talento-Contratos Postdoctorales de la Universitat de Valencia(to IMY).
文摘Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological disorders has increased considerably over the past 30 years because of population aging.Overall,neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow.Autism spectrum disorder,motor neuron disease,encephalopathy,epilepsy,stroke,ataxia,Alzheimer's disease,amyotrophic lateral sclerosis,Huntington's disease,and Parkinson's disease represent a non-exhaustive list of neurological illnesses.These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system.Among the common features of neurological handicaps,we find protein aggregation,oxidative stress,neuroinflammation,and mitochondrial impairment in the target tissues,e.g.,the brain,cerebellum,and spinal cord.The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis,are responsible for their dependence on functional mitochondria for their integrity.Reactive oxygen species,produced along with the respiration process within mitochondria,can lead to oxidative stress,which compromises neuronal survival.Besides having an essential role in energy production and oxidative stress,mitochondria are indispensable for an array of cellular processes,such as amino acid metabolism,iron-sulfur cluster biosynthesis,calcium homeostasis,intrinsic programmed cell death(apoptosis),and intraorganellar signaling.Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases,therapies that are effective to diminish or halt neuronal dysfunction/death are rare.Given the genetic complexity responsible for neurological disorders,the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life.A promising candidate is the neuroglobin,a globin superfamily member of 151 amino acids,which is found at high levels in the brain,the eye,and the cerebellum.The protein,which localizes to mitochondria,is involved in electron transfer,oxygen storage and defence against oxidative stress;hence,possessing neuroprotective properties.This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions,which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.
文摘BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.
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.
基金supported by the National Natural Science Foundation of China, No.61932008Natural Science Foundation of Shanghai, No.21ZR1403200 (both to JC)。
文摘Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.
基金Supported by the Natural Science Foundation of Chongqing Municipality,China(No.CSTB2022NSCQ-BHX0725)the National Natural Science Foundation of China(No.82401728).
文摘AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.
基金the National Natural Sciences Foundation of China (No. 30770664)a grant from Educational Committee of Anhui Province, China (No. ZD2008008-2).
文摘Objective Machado-Joseph disease （MJD）/Spinocerebellar ataxia type 3 （SCA3） is an autosomal dominant neurodegenerative disorder caused by an expansion of polyglutamine tract near the C-terminus of the MJD1 gene product, ataxin-3. The precise mechanism of the MJD/SCA3 pathogenesis remains unclear. A growing body of evidence demonstrates that phosphorylation plays an important role in the pathogenesis of many neurodegenerative diseases. However, few kinases are known to phosphorylate ataxin-3. The present study is to explore whether ataxin-3 is a substrate of casein kinase 2 （CK2）. Methods The interaction between ataxin-3 and CK2 was identified by glutathione S-transferase （GST） pull-down assay and co-immunoprecipition assay. The phosphorylation of ataxin-3 by CK2 was measured by in vitro phosphorylation assays. Results （1） Both wild type and expanded ataxin-3 interacted with CK2α and CK2β in vitro. （2） In 293 cells, both wild type and expanded ataxin-3 interacted with CK2β, but not CK2α. （3） CK2 phosphorylated wild type and expanded ataxin-3. Conclusion Ataxin-3 is a substrate of protein kinase CK2.
文摘AIM: To investigate the expression deficiency of key molecular markers in the homologous recombination pathway. METHODS: Expression loss of breast cancer type 1 susceptibility protein (BRCA1), ataxia telangiectasia mutated (ATM), ATM-Rad3-related (ATR), mediator of DNA damage checkpoint protein 1 (MDC1) and meiotic recombination 11 (Mre11) were correlated with their clinicopathological parameters in gastric cancer (GC). One hundred and twenty treatment-naive GC samples were formalin-fixed and paraffin-embedded into tissue blocks. Two representative cores from each block were extracted and constructed into tissue microarrays. Expression levels of BRCA1, ATM, ATR, MDC1 and Mre11 were determined using immunohistochemical analysis, and correlated with clinical parameters, including age, gender, Lauren subtype, tumor grades, clinical stage and overall survival.RESULTS: Expression loss of BRCA1, ATM, ATR, MDC1, and Mre11 was found in 21.4%, 20.2%, 21.0%, 11.1% and 4.6%, respectively, of interpretable cases. BRCA1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 8.2% vs 31.7%, P = 0.001), higher tumor grade (Ⅰ/Ⅱ vs Ⅲ, 10.7% vs 20.5;Ⅰ/Ⅱ vs Ⅳ, 10.7% vs 54.5%, P = 0.047) and advanced clinical stage (Ⅰ/Ⅱ vs Ⅲ, 12.9% vs 16.9%;Ⅰ /Ⅱ vs Ⅳ, 12.9% vs 45.5%, P = 0.006). MDC1 loss was significantly associated with patients of diffused subtype (intestinal vs diffused, 0% vs 19.7%, P = 0.001) and higher tumor grade (Ⅰ/Ⅱ vs Ⅲ, 0% vs 12%;Ⅰ/Ⅱ vs Ⅳ, 0% vs 30.8%, P = 0.012). In addition, the survival time of the patients with expression loss of BRCA1 was significantly shorter than those with positive expression of BRCA1 (2-year survival rate, 32.4% vs 62.8%, P = 0.015). No correlations were found between clinicopathological parameters and expression loss of ATM, ATR and Mre11. CONCLUSION: Our results support the hypothesis that homologous recombination deficiency plays an important role in the progression of gastric carcinoma. Loss of expression of BRCA1 and MDC1 may serve as predictive factors in tumor development or progression in GC patients.
基金the National Natural Sciences Foundation of China (No.30770664)a grant from Anhui Educational Committee(No. ZD2008008-2)
文摘Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene product, ataxin-3 （AT3）. This disease is characterized by the formation of intraneuronal inclusions, but the mechanism underlying their formation is still poorly understood. The present study is to explore the relationship between wild type （WT） AT3 and polyQ expanded AT3. Methods Mouse neuroblastoma （N2a） cells or HEK293 cells were co-transfected with WTAT3 and different truncated forms of expanded AT3. The expressions of WT AT3 and the truncated forms of expanded AT3 were detected by Western blotting, and observed by an inverted fluorescent microscope. The interactions between AT3 and different truncated forms of expanded AT3 were detected by immunoprecipitation and GST pull-down assays. Results Using fluorescent microscope, we observed that the truncated forms of expanded AT3 aggregate in transfected cells, and the full-length WT AT3 is recruited onto the aggregates. However, no aggregates were observed in cells transfected with the truncated forms of WT AT3. Immunoprecipitation and GST pull-down analyses indicate that WT AT3 interacts with the truncated AT3 in a polyQ length-dependent manner. Conclusion WT AT3 deposits in the aggregation that was formed by polyQ expanded AT3, which suggests that the formation of AT3 aggregation may affect the normal function of WT AT3 and increase polyQ protein toxicity in MJD.
基金the National Natural Science Foundation of China (No. 30600193)the Youth Talent Special Fund of the Health Bureau of Zhejiang Province, China (No. 2004QN012)the Health Bureau of Zhejiang Province, China (Nos. 2000A114 and 2007A100)
文摘Chronic post-hypoxic myoclonus, also known as Lance-Adams syndrome (LAS), is a rare complication of successful cardiopulmanry resuscitation often accompanied by action myoclonus and cerebellar ataxia. It is seen in patients who have un-dergone a cardiorespiratory arrest, regained consciousness afterwards, and then developed myoclonus days or weeks after the event. Worldwide, 122 cases have been reported in the literature so far, including 1 case of Chinese. Here we report 2 Chinese LAS patients with detailed neuroimagings. Cranial single photon emission computed tomography (SPECT) of patient 1, a 52-year-old woman, showed a mild hypoperfusion in her left temporal lobe, whereas patient 2, a 54-year-old woman, manifested a mild bilateral decrease of glucose metabolism in the frontal lobes and a mild to moderate decrease of the N-acetyl aspartate (NAA) peak in the bilateral hippocampi by cranial [18F]-fluorodeoxyglucose positron emission tomographic (PET) scan and cranial magnetic resonance spectroscopy (MRS), respectively. We also review the literature on the neuroimaging, pathogenesis, and treatment of LAS.
基金the Research Foundation of Zhejiang Health,No.2020RC061。
文摘BACKGROUND Type 1 sialidosis,also known as cherry-red spot-myoclonus syndrome,is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life.The most common symptoms are myoclonus,ataxia and seizure.It is rarely encountered in the Chinese mainland.CASE SUMMARY A 22-year-old male presented with complaints of progressive myoclonus,ataxia and slurred speech,without visual symptoms;the presenting symptoms began at the age of 15-year-old.Whole exome sequencing revealed two pathogenic heterozygous missense variants[c.239C>T(p.P80L)and c.544A>G(p.S182G)in the neuraminidase 1(NEU1)gene],both of which have been identified previously in Asian patients with type 1 sialidosis.All three patients identified in China's Mainland come from three unrelated families,but all three show the NEU1 mutations p.S182G and p.P80L pathogenic variants.Increasing sialidase activity through chaperones is a promising therapeutic target in sialidosis.CONCLUSION Through retrospective analysis and summarizing the clinical and genetic characteristics of type 1 sialidosis,we hope to raise awareness of lysosomal storage disorders among clinicians and minimize the delay in diagnosis.
文摘The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases.While conventional magnetic resonance imaging(MRI) is widely used for brain and cerebellar morphologic evaluation,advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics.Volumetry,voxel-based morphometry,diffusion MRI based fiber tractography,resting state and task related functional MRI,perfusion,and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum.In the present review,after providing a brief description of each technique's advantages and limitations,we focus on their application to the study of cerebellar injury in major neurodegenerative diseases,such as multiple sclerosis,Parkinson's and Alzheimer's disease and hereditary ataxia.A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease,followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance.
文摘BACKGROUND Familial cases of autosomal recessive spastic ataxia of charlevoix-saguenay have not been reported in the Arabian Peninsula,although the consanguineous marriage rate is very high.We report the first family from the Arabian Peninsula harboring a novel frameshift mutation in the SACS gene.CASE SUMMARY A 33-year-old man presented to our neurology clinic with balance problems and weakness of distal upper and lower limbs.He was previously clinically diagnosed with Friedreich's ataxia.However,the severity of polyneuropathy and the electrodiagnostic studies(EDX)findings are atypical features of Friedreich’s ataxia,and the deterioration was attributed to diabetic neuropathy.Close examination of other family members identified cerebellar ataxia,lower-limb pyramidal signs,peripheral neuropathy,and magnetic resonance imaging findings characterized by pontine linear hypointensities.Genetic testing for Friedreich’s ataxia did not yield a diagnosis.Whole exome sequencing identified a novel frameshift germline mutation in the SACS gene termed c.5824_5827delTACT using the transcript NM_014363.5,which is predicted to cause premature termination of the sacsin protein at amino acid position 1942(p.Tyr1942Metfs*9)and disrupts the sacsin SRR3 and domains downstream from it.The mutation segregated with the disease in the family.CONCLUSION Our data add to the spectrum of mutations in the SACS gene and argues for a need to implement suitably integrated clinical and diagnostic services,including next generation sequencing technology,to better classify ataxia in this area of the world.
基金Supported by Hungarian-Chinese Scientific Foundation,No.HCSCF-2016-4
文摘BACKGROUND Gerstmann-Str?ussler-Scheinker(GSS) disease is an inherited prion disease that is clinically characterized by the early onset of progressive cerebellar ataxia. The incidence of GSS is extremely low and it is particularly rare in China. Therefore,clinicians may easily confuse this disease with other diseases that also cause ataxia, resulting in its under-diagnosis or misdiagnosis.CASE SUMMARY Here, we report the first case of genetically diagnosed GSS disease in Northeast China. The patient exhibited typical ataxia and dysarthria 2.5 years after symptom onset. However, magnetic resonance imaging of the brain and spinal cord revealed a normal anatomy. Screening results for the spinocerebellar ataxia gene were also negative. We thus proposed to expand the scope of genetic screening to include over 200 mutations that can cause ataxia. A final diagnosis of GSS was presented and the patient was followed for more than 3.5 years, during which we noted imaging abnormalities. The patient gradually exhibited decorticate posturing and convulsions. We recommended administration of oral sodium valproate, which resolved the convulsions.CONCLUSION Patients with inherited ataxia should be considered for a diagnosis of GSS via genetic testing at an early disease stage.
