Asako Takei

MSA-C is the predominant clinical phenotype of MSA in Japan: Analysis of 142 patients with probable MSA

We investigated the clinical features and mode of disease progression in 142 patients with probable multiple system atrophy (MSA) according to the Consensus Criteria. The subjects included 84 men and 58 women with a mean age at onset of 58.2+/-7.1 years (range: 38-79 years). Cerebellar signs were detected in 87.3% of these patients at the time of initial examination, and were found in 95.1% of them at latest follow-up. MSA-C was diagnosed in 83.8% of the patients at their first examination. Parkinsonism was initially detected in 28.9% of the patients, increasing to 51.4% at the latest follow-up. Among all of the subjects, only 16.2% were classified as having MSA-P on initial examination. At the latest follow-up, parkinsonian features had become predominant over cerebellar features in 24.6% of the 65 patients with MSA-C who were followed for more than 3 years. Although parkinsonism usually masked the signs of cerebellar involvement in MSA-C patients, none of the patients with MSA-P at an early stage showed predominance of cerebellar features at the latest follow-up. Parkinsonism is the predominant feature of MSA among Western patients, even at an early stage, but this study showed that cerebellar deficits are the main feature in Japanese patients. This difference of disease manifestations between ethnic groups suggests that genetic factors may influence the clinical phenotype of MSA.

Heredity in Multiple System Atrophy

We investigated the family histories of 157 Japanese patients with probable or possible multiple system atrophy (MSA). A family history of neurodegenerative disorders was only detected in three MSA patients (1.9%). We evaluated these patients by careful neurological examination, neuroimaging studies, and genetic studies to exclude hereditary spinocerebellar ataxia with a similar clinical phenotype to MSA. The results indicated that one of them had a family history of MSA. Although the familial presence of neurodegenerative disorders is rare in MSA patients, the existence of such cases suggests that MSA may have a genetic background.

Positional vertigo and macroscopic downbeat positioning nystagmus in spinocerebellar ataxia type 6 (SCA6)

Abstract. To investigate the frequency of positioning nystagmus in degenerative ataxic disorders, we examined downbeat positioning nystagmus (DPN) in 25 patients with spinocerebellar ataxia type 6 (SCA6) and 58 patients with other types of degenerative ataxia. DPN was observed in 21 of the 25 patients with SCA6 (84 %) versus only 3 of the 58 patients (5.2 %) with other types of degenerative ataxia, including multiple system atrophy, SCA1, SCA2, SCA3/Machado-Joseph disease, and non-SCA6 late-onset pure cerebellar ataxia. Our findings indicated that DPN is a distinct part of the clinical presentation of SCA6, showing that vestibular cerebellum is more affected in SCA6 than other types of degenerative ataxia.

Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes.

Multiple system atrophy (MSA) is an adult‐onset sporadic neurodegenerative disease. Although the etiology of MSA remains obscure, recent studies suggest that oxidative stress is associated with the pathogenesis of MSA. The aim of this study was to evaluate genetic associations between the candidate genes involved in oxidative stress and MSA in a case‐control study. We examined 119 Japanese patients with MSA and 123 controls, and genotyped single‐nucleotide polymorphisms (SNPs) of the following eight genes: CCAAT/enhancer‐binding protein homologous protein, activating transcription factor 3, CCAAT/enhancer‐binding protein‐β, sequestosome 1 (SQSTM1), cysteinyl‐tRNA synthetase, solute carrier family 1A4 (SLC1A4), activating transcription factor 4, and eukaryotic translation initiation factor 4E‐binding protein 1 (EIF4EBP1). SLC1A4 SNP +28833 (V398I, rs759458, genotype: Pc = 0.0186, allele: Pc = 0.0303, Pc: P‐value with Bonferroni correction), two major haplotypes of SLC1A4 “T‐C‐C‐G” and “T‐C‐T‐A” (Pc = 0.0261 and 0.000768), two‐SNP haplotypes of SQSTM1 “C‐T” and “A‐T” (Pc = 0.0136 and 0.0369), and the most common haplotype of EIF4EBP1 “C‐T‐G‐C” (Pc = 0.0480) showed significant associations. This study revealed genetic associations of SLC1A4, SQSTM1, and EIF4EBP1 with MSA. These results may lend genetic support to the hypothesis that oxidative stress is associated with the pathogenesis of MSA.

Treatment of cerebellar ataxia with 5-HT1A agonist

Effective, pharmacologic approaches to the treatment of cerebellar ataxia are lacking or inadequate. We recently reported preliminary evidence that tandospirone citrate (tandospirone), a 5-HT1A agonist, improved cerebellar ataxia in patients with Machado-Joseph disease (MJD). In the course of that study, we found that such treatment also alleviated the pain associated with cold sensations in the legs, insomnia, anorexia, and depression, all of which are thought to be mediated through activation of the 5-HT1A receptor. In this paper, we reviewed the few published clinical trials that involved the use of 5-HT 1A receptor agonists for the treatment of cerebellar ataxia, and discussed the current theories regarding their mechanism of action. Cortical cerebellar atrophy (CCA) was reported, in a double-blind study, to be amenable to treatment with tandospirone. Other types of spinocerebellar degeneration (SCD) i.e., olivopontocerebellar atrophy (OPCA) and Machado-Joseph disease (MJD) have also been reported to respond to the drug, but these have been small studies. Responsive patients exhibited only mild ataxia. The doses of 5-HT1A agonists that have been used successfully ranged from 12.5 mg/day to 60 mg/day (or 1mg/kg), and were well tolerated by most patients.

Effects of tandospirone on "5-HT1A receptor-associated symptoms" in patients with Machado-Josephe disease: an open-label study.

BackgroundWe investigated the frequencies of the symptoms such as “ataxia, depression, insomnia, anorexia, and pain,” that have been reported to be associated with 5-HT1A receptor, and the effect of tandospirone citrate (tandospirone: 5-HT1A agonist) in patients with Machado-Joseph disease (MJD). MethodsTen MJD patients received tandospirone (15-30mg/d) for seven weeks. During that time, they were evaluated weekly using the Ataxia Rating Scale (ARS) and Total Length Traveled (TLT) by Stabilimetry tests, the Self-rating Depression Scale (SDS), which in addition to evaluating their level of depression, also evaluated their degree of insomnia and anorexia, and a pain questionnaire. ResultsBefore tandospirone therapy, all patients displayed cerebellar ataxia, while insomnia, and leg pain was observed in 7 patients, depression in 6 patients, and anorexia was observed in 2 patients. In response to treatment, 7 of the 10 patients who were ataxic showed a reduction in their ARS, while 3 of 6 patients showed a reduction in their SDS, and 5 of 7 patients showed an alleviation of their insomnia and leg pain. Both of the affected patients showed a marked improvement in their anorexia. A stabilimetry test could be performed in 7 patients, 5 of whom showed a reduction in TLT. ConclusionsOur data indicate that the patients with MJD are prone to manifest 5-HT1A receptor-associated symptoms, and tandospirone is a useful drug for these symptoms in patients with MJD, though a double-blind study is needed.

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

Abstract 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.

Four mutations of the spastin gene in Japanese families with spastic paraplegia

AbstractHereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. HSP is caused by failure of development or selective degeneration of the corticospinal tracts, which contain the longest axons in humans. The most common form of HSP is caused by mutations of the spastin gene (SPAST), located on chromosome 2p21-p22, which encodes spastin, one of the ATPases associated with diverse cellular activities (AAA). In this study, we detected four causative mutations of SPAST among 14 unrelated patients with spastic paraplegia. Two missense mutations (1447A→G, 1207C→G) and two deletion mutations (1465delT, 1475-1476delAA) were located in the AAA cassette region. Three of these four mutations were novel. Previous reports and our results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant HSP, although SPAST mutations are also observed in patients with sporadic spastic paraplegia.

Cognitive dysfunction in patients with spinocerebellar ataxia type 6

The aim of this study was to assess the cognitive functions of patients with spinocerebellar ataxia type 6 (SCA6). We examined 13 patients with genetically confirmed SCA6 and 13 healthy control subjects matched for age, years of education, global cognitive status, and intellectual ability. We administered verbal memory (word recall and word recognition), executive function (digit span, category and letter fluency, Frontal Assessment Battery, and Trail Making Test-A and B), and visuospatial construction (figure copying) tests. We found that the patients with SCA6 had significantly lower scores on the demanding word recall and letter fluency tests compared to the control subjects, while word recognition was well preserved in the patients with SCA6. The other executive functions tested, as well as visuospatial construction, were preserved in the SCA6 group. However, although memory encoding and storage processes were preserved, the retrieval of memorized information concerning frontal function might be selectively affected in patients with SCA6 compared to in control subjects. The impaired word recall and letter fluency noted in patients with SCA6 were interpreted as being related to a word-retrieval disability. Such dysfunctions may be attributed to damage in the frontal-cerebellum circuit owing to SCA6.

Estimation of skeletal muscle energy metabolism in Machado‐Joseph disease using 31P‐MR spectroscopy

The aim of this study was to determine if muscle energy metabolism, as measured by 31P‐magnetic resonance spectroscopy (MRS), is a metabolic marker for the efficacy of treatment of Machado‐Joseph disease (MJD). We obtained 31P‐MRS in the calf muscle of 8 male patients with MJD and 11 healthy men before, during, and after a 4 minute plantar flexion exercise in a supine position. The data showed that there was a significant difference between the groups in terms of the PCr/(Pi + PCr) ratio at rest (P = 0.03) and the maximum rate of mitochondrial ATP production (Vmax) (P < 0.01). In addition, Vmax was inversely correlated with the scale for the assessment and rating of ataxia score (r = −0.34, P = 0.04). The MJD group also showed a reduction in Vmax over the course of 2 years (P < 0.05). These data suggest that this noninvasive measurement of muscle energy metabolism may represent a surrogate marker for MJD.