Progressive atrophy of cerebellum and brainstem as a function of age and the size of the expanded CAG repeats in the MJD1 gene in Machado-Joseph disease

Machado-Joseph disease (MJD) is an autosomal dominat neurodegenerative disease characterized by cerebellar ataxia associated to varying degrees with pyramidal signs, extrapyramidal signs, or peripheral amyotrophy. It is caused by unstable expansion of the CAG repeat in the MJD1 gene on chromosome 14q32.1. To determine how the neurodegenerative process in the central nervous system of patients with MJD correlates with the size of expanded CAG repeats in the MJD1 gene and other factors, we performed detailed quantitative analyses of findings of magnetic resonance imaging of the central nervous system of 21 patients with MJD of various ages and with various sizes of expanded CAG repeats. We found that atrophy of the brainstem and cerebellar vermis in MJD patients is closely correlated not only with the size of expanded CAG repeat in the MJD1 gene but also with patient age, which suggests that the neurodegenerative process in MJD is regulated by the size of expanded CAG repeats as well as by the patient age.     

MJD1基因单个碱基多态性与CAG重复序列不稳定性的关系

马查多－约瑟夫病患者的ＭＪＤ１基因存在ＣＡＧ三核苷酸不稳定扩展突变，为探讨这种不稳定扩展突变的分子机制。方法对５８名正常人和２０名ＭＪＤ患者的ＭＪＤ１基因内ＣＡＧ／ＣＡＡ、ＣＧＧ／ＧＧＧ两个位点的多态性进行检测。结果正常染色体中，具有ＣＧＧ等位基因的ＣＡＧ重复数目（２７．３２±０．６１，ｎ＝２８）较具有ＧＧＧ等位基因的ＣＡＧ重复数目（１５．９０±０．６９，ｎ＝３０）明显大（Ｐ＜０．０１）。ＣＧＧ等位基因在患者中的分布频率（１００％）明显高于正常人（４８．３％）。结论ＭＪＤ１基因内单个碱基置换影响ＣＡＧ重复序列的稳定性。     

遗传性痉挛性截瘫患者MJD1基因的突变分析

目的探讨中国汉族人群中遗传性痉挛性截瘫(Hereditary Spastic Paraplegia,HSP或SPG)患者的MJD1基因突变特点,进一步探索HSP和遗传性脊髓小脑性共济失调(Spinocerebellar Ataxia,SCA)的遗传和临床异质性。方法应用聚合酶链反应、8%变性聚丙烯酰胺凝胶电泳和DNA T载体连接测序等方法对78例临床诊断为HSP的患者进行MJD1基因突变分析。结果在18个HSP家系中检出SCA3/MJD1家系2个,占11.1%,该2例家系均为常染色体显性遗传,2例家系先证者在临床上符合HSP的诊断标准,突变的MJD1等位基因CAG三核苷酸异常重复次数分别为65和69次,散发的HSP病例未发现MJD1等位基因的异常。结论HSP和SCA都具有明显的临床和遗传异质性,其表型在临床上有相互交叉现象,部分SCA3/MJD1患者临床上可为典型的痉挛性截瘫特征而无任何明显的共济失调表现。对临床表现为HSP的患者,尤其是有明显阳性家族史的患者进行MJD1基因诊断可以弥补HSP临床诊断的不足。     

COMT基因多态性与颅脑创伤患者执行功能障碍相关性的研究

目的探讨儿茶酚胺氧位甲基转移酶(COMT)基因多态性与颅脑创伤患者执行功能障碍的相关性。方法选取河北联合大学神经外科颅脑创伤患者168例为病例组和134例健康体检人群为对照组。采集患者静脉血检测COMT基因多态性,应用钟表绘画测验(CDT)、威斯康星卡片测验系统(WCST)对患者进行执行功能评估。结果正常对照组和病例组COMT基因型及等位基因频率之间分布差异无统计学意义(P>0.05);不同教育程度、损伤部位、损伤类型及有无饮酒的颅脑创伤患者间COMT基因型和等位基因频率差异无统计学意义(P>0.05);不同病情程度颅脑创伤患者间COMT基因型差异有统计学意义(P>0.05),而等位基因频率差异无统计学意义(P>0.05)。WCST评测显示携带G/G基因型颅脑创伤患者的完成分类数(CC)分值低于携带GA+AA基因型患者;而持续性错误数(RPE)、完成第一个分类所需应答数(RF)分值高于携带GA+AA基因型颅脑创伤患者(P<0.05)。结论 COMT G/G基因型与颅脑创伤患者执行功能障碍有一定关系,可能是颅脑创伤患者执行功能损伤的风险。     

Subclinical autonomic dysfunction in patients with beta-thalassemia

We electrophysiologically evaluated the autonomic function (AF) in a consecutive series of patients with beta-thalassemia and in normal individuals. Six quantitative autonomic function tests (AFTs) were used: tilt test, hand grip test and sympathetic skin response for sympathetic function; R-R interval, inspiration-expiration difference and 30/15 ratio for parasympathetic function. The prevalence of impaired AF was higher in beta-thalassemia patients (13%, n = 5) than in control subjects (0%, n = 0; p = 0.026). Subclinical autonomic dysfunction appeared to be more prevalent in beta-thalassemia patients compared to controls in our series. Further independent validation of this finding is required in larger cohorts of beta-thalassemia patients.     

The symptoms of autonomic dysfunction in HIV-positive Africans

Background

Human immunodeficiency virus (HIV) infection is associated with autonomic neuropathy. The resultant autonomic dysfunction impairs quality of life and can have fatal consequences. Our aim was to clearly define the symptoms of autonomic dysfunction in African HIV-positive patients and determine whether these symptoms were related with (a) autonomic reflex responses (b) the degree of immunosupression.

Methods

Thirty-one HIV-positive treatment-naïve African patients (mean CD4 cell count 269.5 ± 253.4/mm³) and 12 healthy controls completed a detailed questionnaire (Autonomic System Profile, Mayo Clinic, Rochester, MN) relating to specific symptoms of autonomic dysfunction. After completion of the questionnaire, subjects underwent a standard battery of autonomic reflex tests.

Results

The autonomic symptom score was higher in the male HIV-positive patients (26.7 ± 14.7 points) and female patients with CD4 <200/mm³ (24.7 ± 18.0) than sex-matched controls (male controls, 9.9 ± 6.8, P < 0.05; female controls, 8.8 ± 10.1; P < 0.05). Six patients had scores indicative of severe autonomic dysfunction (>43.8 points). The most common autonomic symptoms were: orthostatic intolerance, secretomotor and gastrointestinal dysfunction. There was no relationship between CD4 cell counts and autonomic symptom scores. The blood pressure response to sustained handgrip was blunted, but all other cardiovascular reflex tests were within the normal range or borderline.

Conclusion

African HIV-positive patients report symptoms of autonomic dysfunction, despite normal or borderline autonomic reflex responses.

     

The nature of the autonomic dysfunction in multiple system atrophy

The concept that multiple system atrophy (MSA, Shy-Drager syndrome) is a disorder of the autonomic nervous system is several decades old. While there has been renewed interest in the movement disorder associated with MSA, two recent consensus statements confirm the centrality of the autonomic disorder to the diagnosis. Here, we reexamine the autonomic pathophysiology in MSA. Whereas MSA is often thought of as “autonomic failure”, new evidence indicates substantial persistence of functioning sympathetic and parasympathetic nerves even in clinically advanced disease. These findings help explain some of the previously poorly understood features of MSA. Recognition that MSA entails persistent, constitutive autonomic tone requires a significant revision of our concepts of its diagnosis and therapy. We will review recent evidence bearing on autonomic tone in MSA and discuss their therapeutic implications, particularly in terms of the possible development of a bionic baroreflex for better control of blood pressure.     

Pupillary autonomic dysfunction in patients with ANCA-associated vasculitis

Objective

To assess autonomic function by infrared dynamic pupillometry in patients with ANCA-vasculitis (AAV) in correlation to autonomic symptoms, disease specific clinical parameters and cardiovascular reflex tests.

Methods

Patients with AAV and healthy controls underwent pupillometry at rest and after sympathetic stimulation (cold pressor test). Three parasympathetic parameters (amplitude, relative amplitude, maximum constriction velocity) and one sympathetic parameter (late dilatation velocity) were assessed. Results were correlated with clinical parameters, symptoms of autonomic dysfunction (COMPASS31 questionnaire), heart rate variability during deep breathing test and blood pressure response to pain.

Results

23 patients and 18 age-matched controls were enrolled. Patients had a smaller amplitude (1.44 vs. 1.70 mm; p = 0.009) and a slower constriction velocity (4.15 vs. 4.71 mm/s; p = 0.028) at baseline and after sympathetic stimulation (1.47 vs. 1.81 mm, p = 0.001; 4.38 vs. 5.19 mm/s, p = 0.006, respectively). Relative amplitude was significantly smaller in patients after sympathetic stimulation (28.6 vs. 32.5%; p = 0.043), but not at baseline. There was no difference in sympathetic pupillary response between the groups. In patients, parasympathetic pupil response was correlated negatively with age and positively with parasympathetic cardiac response. After adjusting for age, no significant correlation was observed with clinical parameters. However, there was a trend towards a negative correlation with disease duration, vasculitis damage index and CRP.

Conclusion

Patients with AAV exhibit parasympathetic pupillary autonomic dysfunction. Although correlations were weak and not significant, pupillary autonomic dysfunction is rather linked to chronic damage than to active inflammation or symptoms of autonomic dysfunction.

     

Mechanism of anemia associated with autonomic dysfunction in rats

The aim of this study was to elucidate the mechanism of anemia associated with autonomic dysfunction in rats. Using 6-hydroxydopamine (6-OHDA)-treated sympathectomized rats, changes in systolic blood pressure, plasma catecholamine levels, hemograms, erythropoietin (EPO) secretion, and beta-adrenergic receptors on erythrocytes were monitored, and compared with desipramine- and 6-OHDA-treated, and control rats. In 6-OHDA-treated rats, systolic blood pressure and plasma catecholamine levels significantly decreased from 7 days after 6-OHDA administration, returning to the control values on day 28. Hemoglobin (Hb), hematocrit (Hct) and red blood cell (RBC) levels significantly decreased from day 14 to day 28, and reached normal values after day 35, but neither corpuscular constants nor white blood cell (WBC) levels changed after anemia occurred. Administration of desipramine 1 day before 6-OHDA injection prevented anemia. EPO levels did not elevate, even after bloodletting to load anemia, and the EPO circadian rhythm was irregular in 6-OHDA-treated rats. beta-adrenergic receptors measured using 125I-cyanopindolol (CYP) significantly decreased from day 7 to day 28, and reached normal values after day 35. These results suggest that irregular EPO secretion via disordered autonomic nerves may induce anemia in patients with autonomic disorders.     

Tests of autonomic dysfunction in patients with multiple sclerosis

Autonomic dysfunction is frequent in patients with multiple sclerosis (MS). The sympathetic skin response (SSR) and the R-R interval variation (RRIV) are simple electrophysiologic tests for the assessment of central and peripheral autonomic disturbances. Both tests were performed in 60 patients with clinically definite MS and 30 controls. The SSR was recorded simultaneously from both upper and both lower limbs. In all volunteers normal responses were recorded from the four limbs, but 39 patients (65%) showed abnormal responses in at least one limb. The reduction in amplitude of the response was correlated with patients' EDSS. In individual limbs, the SSR amplitude correlated with weakness, spasticity and cerebellar dysfunction, but was not sufficiently related to the deep sensory loss. The RRIV was abnormal in 48 MS patients (80%), as compared to the controls, but showed no significant relationship either to the EDSS or to the SSR. The sensitivity of SSR and RRIV is high and comparable with that of visual and somatosensory evoked potentials.     

先天性肌强直一家系的临床特点及CLCN1基因突变筛查

目的 探讨先天性肌强直一家系的临床特点及CLCN1基因突变情况。方法 对一先天性肌强直家系中的22例患者的临床资料进行分析。结果 该家系5代68名成员,连续4代共24例发病,男女均有累及;多于婴幼儿期起病,肌强直见于所有患者,16例伴有肌肥大。全部患者肌酶学检查及血电解质正常;2例肌电图检查见自发性肌强直电位;先证者肌活检见肌纤维排列疏松,大小不一,横纹不清,部分肌纤维增生与肥大,肌细胞轻度变性,周围有少量炎性细胞浸润;3例基因检测未发现CLCN1基因的23对外显子突变。结论 该家系为常染色体显性遗传的Thomsen病,患者均有典型的临床表现。CLCN1基因23对外显子筛查未发现突变,表明可能存在遗传异质性。     

Adult onset autonomic dysfunction coexistent with familial dysautonomia in a consanguineous family

A consanguineous family is described in which autonomic dysfunction developed in the father during adult life while the son had familial dysautonomia at birth. The father's condition is felt to be secondary to olivopontocerebellar atrophy. The concurrence in this family of an adult and a childhood form of dysautonomia may be an expression of the same genetic defect at different stages of development.     

TNFalpha: a trigger of autonomic dysfunction.

During disease, infection, or trauma, the cytokine tumor necrosis factor alpha (TNF alpha) causes fever, fatigue, malaise, allodynia, anorexia, gastric stasis associated with nausea, and emesis via interactions with the central nervous system. Our studies have focused on how TNF alpha produces a profound gastric stasis by acting on vago-vagal reflex circuits in the brainstem. Sensory elements of this circuit (i.e., nucleus of the solitary tract [NST] and area postrema) are activated by TNF alpha. In response, the efferent elements (i.e., dorsal motor neurons of the vagus) cause gastroinhibition via their action on the gastric enteric plexus. We find that TNF alpha presynaptically modulates the release of glutamate from primary vagal afferents to the NST and can amplify vagal afferent responsiveness by sensitizing presynaptic intracellular calcium-release mechanisms. The constitutive presence of TNF alpha receptors on these afferents and their ability to amplify afferent signals may explain how TNF alpha can completely disrupt autonomic control of the gut.     

R-R variations, a test of autonomic dysfunction

ABSTRACT- Beat-to-beat variation of the heart rate was studied as a test of autonomic function. Recordings were made during quiet breathing, deep breathing and tilting from supine to upright position. The heart rate variations were expressed as a % of mean R-R interval. In order to establish normal criteria, the influence of age, wakefulness and intra-individual variations was studied in healthy volunteers. A negative correlation with age was found for all measured parameters. Patients with diabetic polyneuropathy differed from age-matched controls. Patients with symptoms of autonomic failure showed smaller variations than those without such symptoms.     

Neuropathology of autonomic dysfunction in synucleinopathies

The synucleinopathies—Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure—result from distinct patterns of abnormal α‐synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinson's disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy‐related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction. © 2018 International Parkinson and Movement Disorder Society