Machado-Joseph disease/SCA3 and myotonic dystrophy type 1 in a single patient

We report here, for the first time, the case of a 41-year-old man with both Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) and myotonic dystrophy type 1. The patient noted dysarthria at 14 years of age and unsteady gait at 30 years of age. Similar sized expansions of the CAG trinucleotide repeats in one allele of the ataxin-3 (ATXN3) gene were found in both the patient and his father, although in the other allele the length of the CAG repeats was shorter in the father compared with the patient. In the dystrophia myotonica protein kinase (DMPK) gene the CTG repeats were much more expanded in the patient compared with his father. Thus it is possible that, in the farther, the short CAG repeat in the non-expanded ATXN3 allele delayed the onset of cerebellar symptoms, and/or that the expanded CTG repeat in the DMPK gene in the patient accelerated the pathogenesis of MJD/SCA3.     

Multiple sclerosis coinciding with Machado-Joseph disease

Abstract Although inflammatory demyelination is considered to be the key feature in multiple sclerosis (MS) pathogenesis, histopathological investigations and MRI studies recently highlighted the extent of neuronal damage that occurs even in the early stages of the disease. We report the unusual case of a patient with Machado-Joseph disease (MJD; spinocerebellar ataxia (SCA) III) and discuss this coincidence in light current pathogenetic paradigms of CNS autoimmunity.     

中国大陆脊髓小脑型共济失调三型/马查多-约瑟夫病女性患者的产前诊断：个案报告

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 mainland China 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.     

REM behavior disorder and excessive daytime somnolence in Machado-Joseph disease (SCA-3).

We reported previously that behavior suggestive of rapid eye movement sleep behavior disorder (RBD) was markedly increased in a small population of SCA-3 patients. We, therefore, asked patients and nonpatient attendees at an SCA-3 annual clinic to complete a questionnaire soliciting RBD-like behavior. Our results support the previous observation that RBD-like behaviors are significantly increased in SCA-3.     

马查多-约瑟夫病/脊髓小脑型共济失调Ⅲ型患者(CAG)n拷贝数与临床特征

目的探讨马查多约瑟夫病基因１（ＭＪＤ１）ＣＡＧ三核苷酸动态突变及其拷贝数与ＭＪＤ／脊髓小脑型共济失调Ⅲ型（ＳＣＡ３）患者临床特征的相关关系。方法应用聚合酶链式反应、变性聚丙烯酰胺凝胶电泳和银染技术,对９个ＭＪＤ／ＳＣＡ３家系１０９名成员进行ＭＪＤ１基因（ＣＡＧ）ｎ拷贝数分析。结果发现异常扩增的（ＣＡＧ）ｎ拷贝数与发病年龄呈负相关,并在一定程度上影响病情严重程度;主要临床症状、体征与异常扩增的（ＣＡＧ）ｎ拷贝数无关,而是受病程影响。同时发现１７例症状前患者。结论异常扩增的（ＣＡＧ）ｎ拷贝数对疾病表型有影响,但不能完全作为临床特征的预测指标     

Sleep symptoms and their clinical correlates in Machado-Joseph disease

Objective – To evaluate the presence of sleep symptoms in Machado–Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3). Subjects/methods – We used a sleep questionnaire and the Epworth Sleepiness Scale to compare 53 patients with MJD/SCA3 and 106 controls. Results – Patients with MJD/SCA3 reported more symptoms of insomnia, restless leg syndrome and REM sleep behavior disorder as well as nocturnal cramps, snoring and nocturnal apnea. Insomnia was the most frequently reported sleep‐related complaint in the MJD/SCA3 group. Conclusions – Our results indicate that sleep disorders are common in patients with MJD/SCA3 and probably have a multifactorial etiology, with components of a primary sleep disorder in addition to sleep‐disrupting symptoms such as nocturia and cramps.     

Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians.

We describe several families of African origin with SCA3/Machado-Joseph disease gene expansions. In these cases, the phenotype ranges from ataxia with parkinsonian signs to a syndrome clinically almost indistinguishable from idiopathic, L-dopa-responsive Parkinson's disease. In contrast, these parkinsonian phenotypes are rare in those of European descent. Haplotype analysis shows that these African families do not share a common founder, thus a cis-acting element in the promoter is unlikely to be responsible these unusual presentations. We suggest that trans-acting factors are responsible for the variable phenotype and discuss the implications of diseases showing racially different expressivities.     

The peripheral neuropathy in Machado-Joseph disease

Summary Peripheral nerve biopsies were taken from 11 patients with Machado-Joseph disease (MJD), a heredodegenerative disease within the group of autosomal dominant ataxias. On the basis of the clinical symptoms, 2 patients were found to suffer from type I, 4 from type II and 5 from type III. All cases shared the same pathological features, which consisted of a reduction in density of myelinated and unmyelinated fibres and an increase in endoneurial collagen. It was also observed that some Schwann cells were not related to axons, whilst others showed numerous budding processes. The intensity of the changes varied considerably: it was mild in type I and II and severe in type III. Peripheral nerve changes in MJD are compared with those previously described in other forms of heredo-ataxias. It is concluded that involvement of peripheral nerves is a significant feature in this group of diseases and that peripheral nerve biopsy could be useful in the identification of the subtypes of MJD.     

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3

IntroductionAccumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients.MethodsWe analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay.ResultsPolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset.ConclusionAs clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.     

脑梗死伴阻塞性睡眠呼吸暂停低通气综合征患者睡眠结构及认知功能分析

目的 探讨脑梗死伴阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者睡眠结构的特点及与认知功能的相关性.方法 选择2009年12月至2011年3月在天津医科大学总医院神经内科及呼吸睡眠监测室就诊的打鼾患者,行多导睡眠监测,筛选出60例患者,分为合并组(脑梗死合并OSAHS)20例,OSAHS组(单纯OSAHS)20例及对照组(无脑梗死及OSAHS)20例,均完善相关检查及进行认知功能的评分[ MMSE和蒙特利尔认知评估量表(MoCA)].结果 睡眠结构比较:合并组及OSAHS组与对照组比较,患者醒觉时间、非快速眼球运动(NREM)期、NREM 1+2期延长,NREM3+4期及快速眼球运动(REM)期缩短.合并组与OSAHS组比较,NREM期及NREM 1期延长,NREM 3+4及REM期缩短.认知功能与呼吸紊乱及低氧相关指数相关性分析:OSAHS组患者MMSE和MoCA评分与呼吸暂停低通气指数(AHI)、氧减指数(ODI)呈线性负相关(MMSE r=-0.450、-0.671,MoCA r=-0.486、-0.494,均P＜0.05),与夜间平均血氧及夜间最低血氧呈线性正相关(MMSE r=0.477、0.485,MoCA r=0.507、0.482,均P＜0.05).合并组患者MoCA评分与ODI、微觉醒指数呈线性负相关(r=-0.463、-0.480,均P＜0.05),MMSE评分与呼吸紊乱及低氧相关指数相关无统计学意义.认知功能与睡眠分期相关性分析:OSAHS组患者MMSE及MoCA评分均与NREM 3 +4期呈线性正相关(r=0.521、0.474,均P＜0.05),MMSE评分与NREM 1+2期呈线性负相关(r=-0.458,P＜0.05).合并组患者MoCA评分与REM期呈线性正相关(r=0.472,P＜0.05),MMSE评分与睡眠分期相关无统计学意义.结论 OSAHS患者睡眠结构紊乱,特点为觉醒时间与浅睡眠延长,深睡眠与REM期缩短,脑梗死伴OSAHS睡眠结构紊乱更严重,合并脑梗死使OSAHS浅睡眠1期延长更明显.OSAHS患者夜间血氧越低,呼吸紊乱指数越高,微觉醒次数越多,浅睡眠时间越长,深睡眠及REM期睡眠越短,认知功能受损越严重,但认知功能损害与低氧的相关性比睡眠结构紊乱的相关性明显.脑梗死伴OSAHS患者MoCA评分与缺氧程度及睡眠结构的一些指标相关性明显,MoCA在轻中度血管性认知功能障碍筛选中的敏感性高于MMSE.     

Axonal Dysfunction in the Deep White Matter in Machado-Joseph Disease

We evaluated spectroscopy findings at the deep white matter in Machado-Joseph disease (MJD). We obtained brain MRI and single-voxel proton MR spectroscopy (MRS) over the superior-posterior region of the left hemisphere at the level of the corpus callosum in 40 patients (44.6 ± 2.3 years-old) and 27 controls (31.4 ± 3.6 years). Four patients were excluded due to poor quality spectra. We observed a decrease in signal intensity of N-acetylaspartate relative to creatine-phosphocreatine signal (NAA/Cr) in MJD compared to control [1.63 ± 0.41 (1.15-2.76) versus 1.97 ± .51 (1.50-2.92); U test = 219.0; P < .001]. No statistical difference was observed in choline-containing compounds relative to creatine (Cho/Cr). There was no significant correlation between NAA/Cr and clinical and genetic variables. Due to the younger age of the control group, we performed a secondary analysis in a subgroup of 15 MJD patients matched by age to 15 controls. Matching was performed blindly to MRS results and subject identification, except for age and sex. A statistically significant difference was observed in NAA/Cr ratios (U test = 44.0; P = .004), as well as Cho/Cr levels (U test = 53.0; P = .014). We conclude that the metabolic abnormalities observed in the deep white matter in MJD suggest extensive neuronal and axonal dysfunction in these patients.     

Sleep apnea syndrome and subthalamic stimulation in Parkinson's disease

ObjectivesΤhe association between Parkinson's disease (PD) and sleep apnea syndrome (SAS) is not fully elucidated and very few studies reported on SAS outcome after deep brain stimulation (DBS). Here, we compare the clinical profile of PD patients with and without SAS and assess, for the first time, the value of pre-DBS SAS as predictor of post-DBS outcome in PD.MethodsFifty patients were grouped into PD with SAS (PD-SAS+,n = 22) and without (PD-SAS-,n = 28), based on the Apnea-Hypopnea-Index (AHI≥5) in polysomnography. We used novel multivariate statistical models to compare pre-DBS profiles and assess post-DBS motor, non-motor and quality of life (QoL) changes in both groups.ResultsIn the entire cohort, 44% of patients had at least mild SAS (AHI≥5), while 22% had at least moderate (AHI≥15). Mean AHI was 11/h (NREM-AHI = 10.2/h and REM-AHI = 13.5/h). The two groups had equal demographics and PD characteristics, and did not differ in respect to unified Parkinson's disease rating scale (UPDRS)-II_OFF, Body-Mass-Index, polysomnographic features, RBD, depression, sleepiness and QoL scores. The PD-SAS+ group had significantly higher scores in UPDRS-III_OFF (41.1 ± 17.7 vs. 30.9 ± 11.7,p < 0.05) compared to PD-SAS- group.The groups did not differ in respect to post-DBS change in UPDRS-II, UPDRS-III, Epworth sleepiness scale, Hamilton depression rating scale and PDQ39 scores. Positive airway pressure therapy had no impact on post-DBS outcome.ConclusionsIn patients with PD and candidates for DBS, the presence of SAS is associated with increased motor signs, but not with a specific non-motor, QoL or sleep-wake profile. The presence of SAS prior to STN-DBS is not associated with worse outcome after surgery.     

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.     

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。     

Beneficial effects of tandospirone on ataxia of a patient with Machado-Joseph disease

Tandospirone citrate (tandospirone) is an anti-anxiety drug that acts by combining with serotonin receptor (5-hydroxytryptamine-1 A [5-HT1A]). Recently, there have been a few reports of its potential role in the treatment of cerebellar ataxia. We report the first case of a patient with Machado-Joseph disease in which we successfully treated cerebellar ataxia. In addition, his leg pain, insomnia, anorexia, and depression, which are thought to be related to 5-HT1A receptors, were also remarkably alleviated by treatment with tandospirone.     

A large Japanese family with Machado-Joseph disease: clinical and genetic studies

A large Japanese family with probable Machado-Joseph disease (MJD) is described. Detailed neurological examination in 12 patients from 3 generations revealed variable combinations of cerebellar ataxia, ocular paresis, difficulty in eye-lid opening, bulging eyes, facial "myokymia", facial dystonia, pyramidal signs, extrapyramidal signs, and peripheral neuropathy. Mode of inheritance was in all likelihood autosomal dominant. Blood components were typed for 19 conventional chromosome markers. Although association of the affected members with the PGM1 system was high, linkage analysis failed to reveal any markers studied with a lod score higher than 3. The unique constellation of symptoms appeared sufficient to rule out other types of spinocerebellar degeneration. When there is a typical case in a given family, MJD appears to be a clinically recognizable entity.