脊髓小脑共济失调3型的产前诊断方法研究

目的探讨基于羊水细胞培养和毛细管电泳片段分析技术的脊髓小脑共济失调3型(SCA3/MJD)的产前诊断方法。方法对1例孕20周的确诊SCA3/MJD患者及8名孕16~19周的高龄孕妇进行羊膜穿刺术并抽取羊水细胞培养。采用毛细管电泳片段分析技术对MJD1基因内(CAG)n重复序列动态突变进行检测。结果 SCA3/MJD患者胎儿MJD1基因(CAG)n次数为22/78次,胎儿携带其母亲的异常等位基因,诊断为SCA3/MJD。8例高龄孕妇胎儿MJD1基因(CAG)n重复次数13~26次,均在正常范围内。结论羊水细胞培养并毛细管电泳片段分析技术简便,准确,可作为SCA3/MJD产前诊断的可靠方法进一步推广。     

Double-blind crossover trial of trimethoprim-sulfamethoxazole in spinocerebellar ataxia type 3/Machado-Joseph disease

OBJECTIVE: To evaluate the efficiency of a combination of trimethoprim and sulfamethoxazole in patients with spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). DESIGN: Placebo-controlled, double-blind crossover trial in 22 patients with genetically confirmed SCA3/MJD. Study phases of 6 months were separated by a washout period of 4 weeks. Dosages were a combination of trimethoprim, 160 mg, and sulfamethoxazole, 800 mg, twice daily for 2 weeks, followed by a combination of trimethoprim, 80 mg, and sulfamethoxazole, 400 mg, twice daily for 5.5 months. SETTING: Outpatient department of the Neurological Clinic, Ruhr-University, Bochum, Germany. MAIN OUTCOME MEASURES: Ataxia ranking scale, self-assessment score, static posturography, and results of motor performance testing. Effects on the visual system were studied using the achromatic Vision Contrast Test System and the Farnsworth-Munsell 100-hue test for color discrimination. Physical and mental health were documented using the Medical Outcomes Study 36-Item Short-Form Health Survey. Subgroup analyses assessed the influence of age, sex, age at onset, duration of the disease, phenotype, and CAG repeat length on test performance. RESULTS: Twenty of 22 patients completed the study. Dropouts were due to a rash (placebo phase) and an attempted suicide in a family conflict. Trimethoprim-sulfamethoxazole therapy had no significant effect in SCA3/MJD patients in the short-term analysis (2 weeks) or in the long-term interval (6 months). CONCLUSIONS: In contrast to previous reports that studied smaller groups of patients, treatment with trimethoprim-sulfamethoxazole did not improve the diverse and complex movement disorders caused by SCA3/MJD. Trimethoprim-sulfamethoxazole had no effect on the visual system and cannot be recommended as a continuous treatment for SCA3/MJD patients.     

Cambodian founder effect for spinocerebellar ataxia type 3 (Machado-Joseph disease)

Four families from the same region of Cambodia immigrated to the Pacific Northwest of the United States. All four families have been discovered to have spinocerebellar ataxia type 3 (SCA 3; Machado–Joseph disease) with a similar clinical phenotype. CAG repeat expansions in the ATXN3 gene range from 72 to 77. Mean age of onset has varied from 19 to 44 years and mean age at death of 4 individuals has been 60 years. The prevalence of the various subtypes of SCA varies worldwide from country to country. Neurologists should be alert to the possibility of SCA 3 in Cambodian patients with unexplained cerebellar ataxia.     

Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease

The autosomal dominant spinocerebellar ataxias are clinically and genetically a heterogeneous group of neurodegenerative disorders. Genetic studies have classified some of these disorders based on the mapping of their respective genes. The gene for Machado-Joseph disease, one type of spinocerebellar ataxia, has been mapped to the long arm of chromosome 14q24.3-ter. The gene for another spinocerebellar ataxia, which is clinically distinct from Machado-Joseph disease, has been also localized to the same region on 14q and has been named type 3 spinocerebellar ataxia. Recently, expansions of a CAG trinculeotide repeat in a novel gene on chromosome 14q32.1 were shown in 11 patients affected with Machado-Joseph disease. In this study, we analyzed the DNA samples from 103 individuals representing 42 independent families with dominantly inherited ataxia to determine whether any had the Machado-Joseph disease mutation. The Machado-Joseph disease CAG expansion was detected in 5 of these 42 families. Sixteen affected individuals displayed a normal allele containing 14 to 31 CAG repeats and an expanded allele ranging between 66 and 79 CAG repeats. Seven asymptomatic individuals showed an allele ranging between 67 and 80 CAG repeats. Two of these families had a phenotype consistent with Machado-Joseph disease while the other 3 had clinical features of type 3 spinocerebellar ataxia. These data suggest that a single locus at 14q32.1 is responsible for two forms of spinocerebellar ataxia, spinocerebellar ataxia type 3 and Machado-Joseph disease, and that this locus may account for approximately 11% of this group of dominantly inherited ataxias.     

Vestibulo-ocular arreflexia in families with spinocerebellar ataxia type 3 (Machado-Joseph disease)

OBJECTIVE: To identify the presence of vestibulo-ocular arreflexia in patients with Machado-Joseph disease (MJD), which can easily be diagnosed at the bedside. METHODS: Seven patients with MJD from five unrelated families and 11 patients with sporadic or hereditary cerebellar ataxia other than MJD underwent a detailed neuro-otological and oculomotor examination. Six MJD and five non-MJD patients also underwent electro-oculographic recordings and caloric tests. RESULTS: Gaze evoked nystagmus, smooth pursuit, and saccade abnormalities were found in both MJD and non-MJD patients. However, in all seven MJD patients but in none of the non-MJD patients, sudden passively induced head thrust to both sides elicited pathological corrective catch-up saccades, indicating bilateral loss of the horizontal vestibulo-ocular reflex. This was further confirmed in six MJD patients who had absent vestibular response to both a standard caloric test and ice water ear irrigation. Nystagmus was induced by standard caloric irrigation in all non-MJD patients examined. There was no correlation between the loss of vestibular function and the severity of cerebellar impairment. CONCLUSIONS: The presence of vestibulo-ocular arreflexia, as measured by the head thrust test in a patient with dominant cerebellar ataxia, strongly suggests the diagnosis of MJD.     

Age related axonal neuropathy in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD)

To identify determinants of peripheral involvement in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) the influence of CAG repeat length, age of onset, disease duration and age on the results of nerve conduction studies was analysed in 58 patients with SCA3/MJD. Patients with SCA3/MJD showed marked reduction of compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes indicating axonal neuropathy of both motor and sensory fibres. In addition, there was moderate slowing of nerve conduction suggestive of mild peripheral demyelination. Multivariate regression showed that CMAP and SNAP amplitudes decreased with age, but were not affected by CAG repeat length, age of onset, or disease duration. The age related decline of CMAP and SNAP amplitudes in SCA3/MJD was greater than in normal subjects. The data suggest that the degree of peripheral damage in SCA3/MJD does not depend on CAG repeat length, age of onset, or disease duration, but is mainly related to the time period over which the SCA3/MJD mutation exerts its effect.     

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.     

New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease)

PURPOSE OF REVIEW: This review summarizes recent neuropathological findings in spinocerebellar ataxia type 3 and discusses their relevance for clinical neurology. RECENT FINDINGS: The extent of the spinocerebellar ataxia type 3 related central nervous neurodegenerative changes has been recently systematically investigated in a series of pathoanatomical studies. These studies showed that the extent of the central nervous degenerative changes of spinocerebellar ataxia type 3 has been underestimated so far. The newly described pattern of central nervous neurodegeneration includes the visual, auditory, vestibular, somatosensory, ingestion-related, dopaminergic and cholinergic systems. These pathological findings were correlated with clinical findings and explain a variety of the spinocerebellar ataxia type 3 symptoms observed in clinical practice. SUMMARY: Systematic pathoanatomical analysis of spinocerebellar ataxia type 3 brains helps to understand the structural basis of this neurodegenerative disease and offers explanations for a variety of disease symptoms. This better understanding of the neuropathology of the condition has implications for the treatment of spinocerebellar ataxia type 3 patients and represents a basis for further biochemical and molecular biological studies aimed at deciphering the pathomechanisms of this progressive ataxic disorder.     

Mouse models of Machado-Joseph disease and other polyglutamine spinocerebellar ataxias

Machado-Joseph disease (MJD), also called spinocerebellar ataxia type 3, is caused by mutant ataxin-3 with a polyglutamine expansion. Although there is no treatment available at present to cure or delay the onset of MJD, mouse models have been generated to facilitate the development of a therapy. In this review, the published reports on mouse models of MJD and other polyglutamine spinocerebellar ataxias are compared. Based on these studies, the following approaches will be discussed as candidate treatments for MJD: 1) interfering with the formation of the mutant ataxin-3 cleavage fragment and possibly aggregate or inclusions, 2) reducing the disease protein nuclear localization, and 3) decreasing mutant ataxin-3 expression in neurons.     

Vergence disorders in patients with spinocerebellar ataxia 3/Machado-Joseph disease: a synoptophore study

Diplopia, a common symptom in spinocerebellar ataxia 3/Machado-Joseph disease (SCA3/MJD) cases, is not always due to asymmetric ophthalmoplegia. We found a Japanese SCA3/MJD family, in which three patients clearly had an impairment of divergence eye movement. We thus quantitatively examined the vergence ranges in eight Japanese SCA3/MJD cases using the synoptophore test. An impairment of the vergence eye movements was found in all patients, and the vergence impairment pattern, but not the ophthalmoplegia pattern, was found to be compatible with the diplopia pattern. The diplopia in SCA3/MJD cases is, therefore, attributed, at least in part, to the impairment of the vergence eye movements.     

Degeneration of the external cuneate nucleus in spinocerebellar ataxia type 3 (Machado-Joseph disease)

Owing to its anatomical connections, the external cuneate nucleus (ECU) plays a crucial role in processing proprioceptive input from the upper trunk and upper limbs. Here, we studied this dorsal column nucleus post-mortem in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, who had manifested upper trunk and upper limb ataxia. Polyethylene glycol-embedded 100-microm sections stained for lipofuscin pigment and Nissl material, as well as paraffin-embedded Nissl-stained thin sections, revealed serious neuronal loss in the ECU of all five SCA3 patients. As observed in other affected central nervous system structures, the ECU of these individuals displayed an astrogliosis, and some of the few surviving neurons harbored one or even two ataxin-3-immunopositive intranuclear inclusion bodies. The findings of the present study suggest that (1) the ECU is among the consistent targets of the degenerative process underlying SCA3 and (2) interruption of the proprioceptive pathway at the level of the ECU contributes significantly to upper limb and trunk ataxia in SCA3 patients.     

Spinocerebellar ataxia type 3/Machado-Joseph disease starting before adolescence

Onset of Machado-Joseph disease (SCA3/MJD) before adolescence has been rarely reported. This study aims to describe a cohort of SCA3/MJD with onset before 12 years of age, comparing their disease progression with the progression observed in patients with usual disease onset. We identified all cases from our cohort whose onset was before adolescence. After consent, patients were examined with clinical scales Scale for the Assessment and Rating of Ataxia (SARA) and Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). Gender, age, age at onset, disease duration, CAG expanded repeats, transmitting parent, and anticipation of cases with infantile and adult onset were studied. Progression of NESSCA and SARA scores was estimated through a mixed model, and was compared with a historical group with onset after adolescence. Between 2000 and 2014, 461 symptomatic individuals from our region were diagnosed as SCA3/MJD. Onset of eight cases (2.2 %), all heterozygotes, was before adolescence: seven were females (p?=?0.054). CAG expanded repeats—75?±?3 versus 84?±?4—and anticipations—7?±?9.7 versus 14.4?±?7.2 years—were different between early childhood and adult onset groups (p?<?0.03). The median survival of early childhood onset group was 23 years of age. The annual progression of SARA—2.3 and 0.6 points/year (p?=?0.001)—and NESSCA—2.04 and 0.88 points/year (p?=?0.043)—was faster in childhood than in adult onset group. Onset of SCA3/MJD before adolescence was related to larger expanded CAG repeats in heterozygosis; females seemed to be at higher risk. Disease progression was faster than in SCA3/MJD starting after 12 years.     

Presumed rapid eye movement behavior disorder in Machado-Joseph disease (spinocerebellar ataxia type 3).

Rapid eye movement behavior disorder (RBD) is a recently recognized sleep disorder in which patients are occasionally not paralyzed during the dream portions of sleep. When not idiopathic, this state has been associated primarily with parkinsonian conditions but also with a small number of medications and other neurodegenerative disorders. Dopamine deficiency may play a role in some patients. This report describes the occurrence of a syndrome that appears to be RBD in 6 of 7 patients followed with Spinocerebellar ataxia type 3 (Machado-Joseph disease). Polysomnography was normal in 1 patient. Two of these patients had had single photon emission computed tomographic imaging of the dopamine transporter 1 year previously.     

Tremor-spectrum in spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) can be present with a combination of cerebellar, neuropathic, pyramidal, or extrapyramidal symptoms. Tremor is a classical but not frequent manifestation of SCA3 and there is a lack of detailed knowledge regarding its origin. To study the clinical and electrophysiological characteristics of tremor in SCA3 patients, the authors conducted a case series of 72 SCA3 patients. Clinical characteristics of tremor and associated signs, response to treatments, follow-up, and genetic results were collected. Electrophysiological study including polymyographic recording was possible in 4/6 patients and DaTSCAN in 2/6. The authors also performed a systematic review of SCA3 cases with tremor (n?=?36) reported previously in the literature. We identified two different tremor-types in 6/72 patients with SCA3 mutations, a “fast” (6.5–8?Hz) action, postural or tremor in orthostatism (initial symptom), which became slower over time with associated parkinsonism with a follow-up of 10?years and a “slow” rest, action and intention tremor (3–4?Hz) with distal and proximal component (including axial tremor in orthostatism). Total improvement of limbs and tremor in orthostatism was obtained with levodopa with occurrence of fluctuations/dyskinesia. Partial benefit was observed when additional signs were present (myoclunus/dystonia). The differences in tremor subtypes in SCA3 may be related to various combinations of mild to severe dysfunctions of the cerebello-thalamo-cortical loop and the nigro-striatal dopaminergic pathway.     

Machado-Joseph disease in Brazil: from the first descriptions to the emergence as the most common spinocerebellar ataxia

Machado-Joseph disease is an autosomal dominant inherited disorder of Azorean ancestry firstly described in 1972. Since then, several Brazilian researchers have studied clinical and genetic issues related to the disease. Nowadays, Machado-Joseph disease is considered the most common spinocerebellar ataxia worldwide. Machado-Joseph disease still has no specific therapy to arrest progression, but the unclear pathophysiological mechanism, features related to genetic characteristics, phenotype variability, apparently global involvement of the nervous system in the disease and the therapeutic challenges continue to attract investigators in the field of spinocerebellar ataxias. Brazilian researchers have distinguished themselves in the ongoing investigation seeking new knowledge about Machado-Joseph disease.