Symptom onset of spinocerebellar ataxia type 10 in pregnancy and puerperium

Spinocerebellar ataxia type 10 is an autosomal dominant neurodegenerative disorder. It was initially described in Mexican families presenting with ataxia and epilepsy, with or without polyneuropathy, pyramidal signs and cognitive symptoms. The authors report three patients from the same family who were asymptomatic until gestation and puerperium, when they developed symptoms and signs suggestive of the syndrome. Genetic diagnosis was made in the three patients. The authors hypothesize that hormonal changes are likely to influence the manifestation of the condition.     

The impact of ethnicity on the clinical presentations of spinocerebellar ataxia type 3

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

Analysis of diffusion tensor parameters in spinocerebellar ataxia type 3 and type 10 patients

IntroductionThere is a dearth of studies of spinocerebellar ataxias (SCAs) and diffusion tensor magnetic resonance imaging (DTI).ObjectiveTo analyze changes observed in DTI parameters and correlate these to clinical findings in SCA3 and SCA10 patients.MethodsSCA3 (n = 19) and SCA10 (n = 18) patients were compared with a similar number of controls and assessed clinically and with the scale for the assessment and rating of ataxia (SARA) before undergoing the same MRI protocol. TRACULA (TRActs Constrained by UnderLying Anatomy) software was used to analyze the DTI metrics FA, AD, RD and MD.ResultsMore white matter fiber tracts with changes in diffusivity were found in SCA3 patients than in SCA10 patients. There was a reduction in AD in altered fiber tracts in SCA3 and a greater increase in RD in SCA10. In the SCA3 patients, FA was reduced in the corticospinal tract (CST) and inferior longitudinal fasciculus (ILF), but this was not observed in the SCA10 patients. SARA score was correlated with DTI findings in SCA3 but not in SCA10.ConclusionChanges were observed in DTI for both SCA3 and SCA10 but were more widespread in SCA3. Our finding of myelin-sheath changes in SCA10 and secondary axonal changes in SCA3 may reflect the more rapid, aggressive clinical course of SCA3.     

The molecular diagnosis of spinocerebellar ataxia type 1 in patients with ataxia

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat in the SCA1 gene on chromosome 6. We screened 40 probands with ataxia for the CAG repeat expansion and found five probands with SCA1 representing five different families. The SCA1 gene was analysed in 50 members of these families, and the CAG repeat expansion was found in all 17 affected persons and in 14 unaffected at-risk individuals. The range of expansion was 41–53 repeat units, while the range of normal alleles was 22–36 repeat units. We found pronounced inter- and intrafamilial phenotypical variation. One of the families had a comparatively mild phenotype which correlates with a CAG repeat length in the low end of the range of expansions and a late age at onset. With few exceptions, normal alleles of the SCA1 gene have one to three CAT interruptions in the middle of the CAG repeat, while all expanded alleles are uninterrupted. We report the hitherto longest normal uninterrupted allele of 22 repeat units and stress the importance of analysis for the presence of CAT interruptions in the diagnosis of SCA1.     

脊髓小脑性共济失调3型一家系的临床表现分析

目的 探讨1个脊髓小脑性共济失调3型(SCA3)家系中患者的临床表现,分析影响其特征、异质性及严重程度的原因。方法 采用PCR、琼脂糖凝胶电泳的方法对1个脊髓小脑性共济失调家系进行基因检测明确分型并获得等位基因内CAG三核苷酸重复扩增次数; 对比该家系中5例患者的典型症状、非典型症状,了解其临床异质性并分析产生原因。结果 确定该家系为脊髓小脑性共济失调SCA3型,发现3名表现正常的女性携带者。CAG重复次数与病程长短呈负相关(r=-0.942,P<0.05); 病程与共济失调严重程度呈正相关(r=1.000,0.913,P<0.01)。结论 该家系所有患者以明显共济失调及构音障碍为临床特征,特别是躯干及下肢的共济失调; CAG重复次数、病程及共济失调严重程度之间有明显相关性; 认知功能障碍随着疾病的进展逐渐显现; 眼肌麻痹、括约肌功能障碍或吞咽困难与CAG重复次数之间无明显关系但增加疾病持续时间; 锥体束受损及严重程度可能提示预后不良。     

Estimation of skeletal muscle mass in patients with spinocerebellar ataxia type 3 and 10

Background: Neurodegenerative diseases may progress to a level in which patients present spontaneous weight loss, resulting in increased falls and functional disabilities when the disease is associated with muscle mass depletion.

Objective: Evaluate the muscle compartment in patients presenting spinocerebellar ataxia (SCA) type 3 and 10.

Methods: Forty-six patients presenting SCA type 3 and 10 were assessed and 76 volunteers were selected to the control group. In order to evaluate the muscle compartment, muscle mass anthropometric measurements were assessed and total skeletal muscle mass calculated through a predictive equation.

Results: Women with SCA3 presented greater weight loss and muscle mass reduction compared to those with SCA10 and the control group. Among the predictive measurements, calf muscle circumference showed a more significant correlation with total skeletal muscle mass (p = 0.718).

Conclusion: Patients presenting both types of ataxia did not show severe depletion in their nutritional status; however, those with SCA3 displayed greater weight loss and muscle mass reduction compared to the SCA10 group.     

Prefrontal hypoperfusion and cognitive dysfunction correlates in spinocerebellar ataxia type 6

OBJECTIVE: The aim of this study is to evaluate the correlation between brain perfusion and cognitive dysfunction in spinocerebellar ataxia type 6 (SCA6) patients. METHODS: Thirteen genetically confirmed SCA6 patients and 21 age- and education-matched control subjects were subjected to single photon emission computed tomography (SPECT) and neuropsychological tests. Brain perfusion was examined with SPECT analysis, while general cognition, verbal and visual memory, attention, visuospatial ability, language, executive function, depression, and anxiety were examined with the neuropsychological tests. RESULTS: SCA6 patients showed prefrontal hypoperfusion, and impairments of visual memory, verbal fluency, and executive function compared to control subjects. These neuropsychological impairments in SCA6 patients were significantly correlated with a decrease in prefrontal perfusion. This relation was not correlated to other factors, such as age, education and severity of cerebellar ataxia, which are possible relevant factors associated with cognitive performance. CONCLUSIONS: SCA6 patients have mild cognitive impairment, and correlating prefrontal hypoperfusion. These results indicate cognitive impairment in SCA6 patients resulting from prefrontal hypoperfusion.     

Genotype-phenotype correlation in 667 Chinese families with spinocerebellar ataxia type 3

IntroductionDue to diverse symptoms of spinocerebellar ataxia type 3 (SCA3) and the high prevalence of SCA3 in China, a more in-depth study of Chinese SCA3 patients in a large cohort is well merited.MethodsDuring the last 10 years, 730 patients and 133 premanifest individuals from 667 SCA3 families genetically confirmed to have SCA3 were enrolled from three leading academic hospitals in China. The clinical profile and genotype-phenotype correlation were analyzed.ResultsA quadratic equation best explained the relationship between the logarithmically transformed age at onset (AAO) and expanded CAG repeats (expCAGs) (r² = 0.634, p < 0.001). The expCAG and AAO in Asian populations and western populations were compared with the Chinese population. SCA3 individuals had shorter normal CAG repeats (norCAGs) than healthy controls (Mann-Whitney, p < 0.0001). Most (92.1%) SCA3 patients had gait-ataxia onset. Their AAO and expCAGs were not significantly different from SCA3 patients with non-gait-ataxia onset. Limb ataxia and pyramidal impairment occurred less in patients with disease duration >10 years. Intriguingly, onset after parturition happened in 10 female patients with the AAO of 26.7 ± 4.3 years and the expCAG of 77.4 ± 1.4 repeats. Five out of 12 patients with subtype V and larger expCAGs (78.8 ± 4.8 repeats) suffered from spastic gait initially, and 10 out of 12 showed no limb ataxia. Nystagmus happened most frequently (10.5%) in premanifest individuals.ConclusionWe demonstrated the genotype-phenotype correlation in the largest cohort of SCA3 individuals to date, and interestingly found some new phenomena in Chinese SCA3 individuals.     

Comorbid genetic diseases, von Hippel-Lindau disease and spinocerebellar ataxia type 2, confounding the diagnosis of cerebellar dysfunction in an adolescent

The authors report a 15-year-old female who presented with difficulties in ambulation as well as difficulties with balance and penmanship. She had a known genetic risk of von Hippel-Lindau (VHL; MIM 193300) disease, with a unique VHL mutation, but had no tumors of the brain or spine to explain her symptoms. Laboratory analysis of peripheral blood lymphocytes was targeted at genetic loci associated with ataxic disorders. Allelic expansion of the ataxin-2 gene was identified. Spinocerebellar ataxia type 2 (SCA2) was diagnosed as a comorbid genetic condition in this patient.     

Spinocerebellar ataxia type 10 - A review

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant inherited ataxia caused by an expanded ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene, on chromosome 22q13.3. SCA10 represents a rare form of SCA, until now only described in Latin America, particularly in Mexico, Brazil, Argentina and Venezuela. In Mexico and Brazil SCA10 represents the second most common type of autosomal dominant cerebellar ataxia. The phenotype described in Mexico, is characterized by the association of cerebellar ataxia with epilepsy, while in Brazil the SCA10 phenotype is that of a pure cerebellar ataxia. As yet unidentified genotypic variables may account for this phenotypic difference.     

Ataxin-7 expression analysis in controls and spinocerebellar ataxia type 7 patients

Expansion of polymorphic CAG repeats encoding polyglutamine cause at least eight inherited neurodegenerative diseases, including Huntington disease and the spinocerebellar ataxias. However, the pathways by which proteins containing expanded polyglutamine tracts cause disease remain unclear. To gain insight into the function of the SCA7 gene product, ataxin-7, as well as its contribution to cell death in spinocerebellar ataxia type 7 (SCA7), polyclonal antibodies were generated and ataxin-7 expression was examined within neuronal tissues from controls and three SCA7 patients. Immunoblotting demonstrates that ataxin-7 is widely expressed but that expression levels vary between tissues. Immunohistochemical analyses indicate that ataxin-7 is expressed within neurons both affected and unaffected in SCA7 pathology and that subcellular localization varies depending upon the neuronal subtype. Additionally, ataxin-7 staining was detected throughout control retina, including intense staining within the cell bodies and photosensitive outer segments of cone photoreceptors. Anti-ataxin-7 antibodies revealed intranuclear inclusions within surviving inferior olivary and cortical pyramidal neurons, as well as within surviving photoreceptor and ganglion cells of SCA7 patients harboring either 42 or 66 CAG repeats at the SCA7 locus. In contrast, inclusion formation was not detected within neurons of a patient with 41 repeats. This study broadens the current understanding of ataxin-7 localization and incorporates for the first time analysis of late-onset SCA7 patients where polyglutamine tract lengths are relatively shorter and disease course less severe than in previously described infantile-onset cases. Electronic Publication     

脊髓小脑共济失调2型、3型患者10例基因突变与临床表型分析

目的探讨脊髓小脑共济失调（SCA）2型、3型患者的基因突变特点及临床表型。方法总结4个SCAs家系的9例患者和1例散发患者的临床表现，对全部患者、43名家系成员及60名健康对照，采用PCR、荧光PCR、毛细管电泳等技术检测分析SCA2、3基因内CAG三核苷酸重复序列的长度及拷贝数。结果3个家系中的6例患者、1例散发患者存在SCA3／MJD（CAG）n扩展突变，CAG重复数为68—75次；1个家系的3例患者存在SCA2（CAG）n扩展突变，CAG重复数为39—41次。两型患者的临床表现有重叠之处，但在发病年龄、病程进展、神经系统受累部位等方面有明显差异。结论SCA3／MJD型与SCA2型在临床表现上存在一定差异性，有助于鉴别和分型，但基因检测是明确诊断的惟一方法。     

脊髓小脑共济失调2型临床和神经影像学特征分析

研究背景脊髓小脑共济失调2型(SCA2)为常染色体显性遗传性疾病,是由致病基因ATXN2编码区胞嘧啶-腺嘌呤-鸟嘌呤(CAG)三核苷酸重复序列扩展突变引起,目前较公认的正常重复范围为13~31次,异常重复范围>34次。主要表现包括小脑共济失调、眼肌麻痹、慢眼动、腱反射减弱,可伴有动作性震颤、智力减退和周围性感觉神经病等;头部MRI显示脑干、小脑明显萎缩(典型的橄榄脑桥小脑萎缩改变)。本研究针对5例经基因检测明确诊断的SCA2家系先证者进行临床和影像学特点,以及表型与基因型相关性分析。方法对708例常染色体显性遗传性SCA家系的先证者和119例临床拟诊SCA的散发患者进行常规基因学检测,分析SCA1~3、6、7、17型和齿状核红核苍白球路易体萎缩致病基因CAG序列重复动态突变。采用聚合酶链反应扩增重复序列、琼脂糖凝胶电泳检测扩增产物,对于出现2个电泳条带的样品通过荧光标记毛细管电泳片段分析方法进行重复序列计数。结合基因学检测结果,对患者临床表型和神经影像学特征进行分析。结果其中45例患者携带SCA2基因CAG重复扩展突变,临床表现为小脑共济失调、眼肌麻痹、慢眼动、腱反射减弱或消失,部分患者可伴有动作性震颤,MRI均显示脑干、小脑明显萎缩。其中5例典型病例的临床表型均与其基因型相符。结论基因学检测可为SCA2的明确诊断提供依据,临床和神经影像学特征有助于诊断与鉴别诊断。对于携带中间重复等位基因个体的诊断,需结合临床和影像学特点以及家系上下代动态突变进行分析。     

脊髓小脑共济失调17型临床特征和基因突变分析

目的 探讨脊髓小脑共济失调17型(spinocerebellar ataxia 17,SCA17)患者的临床特征和基因突变的特点.方法 对708个常染色体显性遗传SCA家系的先证者和另外119例临床拟诊SCA的散发患者进行常规基因检测,按照患病率不同依次筛选:SCA3、SCA1、SCA2、SCA6、SCA7、SCA8、SCA12、SCA17、齿状核-红核-苍白球-路易体萎缩致病基因三核苷酸重复动态突变分析.其中SCA17致病基因检测采用聚合酶链反应扩增TATA结合蛋白(TBP)基因CAG重复序列,琼脂糖凝胶电泳检测扩增产物;对出现2个电泳条带的样品应用毛细管电泳片段分析方法进行TBP基因CAG重复次数检测,并对其临床表型、神经影像学特征以及表型与基因型相关性进行细致分析.结果 通过上述检测及分析,发现5例患者具有TBP基因CAG重复扩展突变.片段分析显示CAG重复次数分别为37/50、36/45、38/52、38/53、36/54次,长片段重复次数已达到异常范围.5例患者的临床表型各异,以共济失调、记忆力减退为主要症状.结论 在827例共济失调病例中仅发现5例SCA17,说明该病在中国人群中较为罕见;通过对5例患者的临床表型进行分析,初步认为国人SCA17存在临床变异.     

HSP27 and cell death in spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant spinocerebellar degeneration characterized by a wide range of clinical manifestations. In this review, we discuss the role(s) that heat shock protein 27 (HSP27) may play in the cell death process of spinocerebellar ataxia type 3.     

Cognitive impairment and its neuroimaging correlates in spinocerebellar ataxia 2

IntroductionCognitive impairment (CI) is reported but is poorly explored in spinocerebellar ataxia 2 (SCA2). This study was undertaken to evaluate and classify cognitive impairment in patients with SCA2 and to identify their grey matter (GM) correlates.MethodsWe evaluated the neurocognitive profile of 35 SCA2 and 30 age-, gender- and education-matched healthy controls using tests for attention, executive functions, learning and memory, language and fluency, and visuomotor constructive ability. Patients were classified into SCA2 with and without CI based on normative data from population and healthy controls. Furthermore, patients with CI were sub-classified based on the number of impaired domains into multi-domain CI (≥3 domains; MDCI) and limited domain CI (≤2 domains; LDCI). The underlying GM changes were identified using voxel based morphometry.ResultsThe mean age at onset, duration of disease, and ataxia score was 28.7 ± 8.51 years, 66.7 ± 44.1 months, and 16.1 ± 4.9 points, respectively. CI was present in 71.4% of SCA2 subjects (MDCI: 42.7%; LDCI: 28.5%). Patients with CI had significant atrophy of the posterior cerebellum, sensorimotor cortex, and superior frontal gyrus (FWE p-value <0.05). Patients with MDCI had significant GM atrophy of the angular gyrus compared to LDCI (FWE p-value <0.05).ConclusionPatients with CI had significant GM involvement of the posterior cerebellum and frontal lobe, suggestive of impairment in the cerebello-fronto-cortical circuitry.