Familial Spinocerebellar Ataxia Research Articles

Neuronal activity and outcomes from thalamic surgery for spinocerebellar ataxia.

ObjectivesWe investigated the effects of deep brain stimulation (DBS) or lesions of the ventral intermediate nucleus (Vim) of the thalamus for spinocerebellar ataxia (SCA) and examined the pathophysiological role of neuronal activity of the Vim underlying ataxia.MethodsFive patients with SCA with cortical atrophy (ages 60‐69 years; 2 sporadic and three familial SCA) and five patients with essential tremor (ET) (ages 57–71 years) were treated with Vim surgery. Intraoperatively, we recorded neuronal activity from single neurons in the Vim thalamus while patients were at rest and compared the physiological properties of those neurons between patients with SCA and those with ET.ResultsPostsurgery mean scores for the Fahn–Tolosa–Marin Tremor Scale were improved from 78 to 44 in SCA patients and from 54 to 21 in ET patients. Stronger stimulation was necessary to optimize outcomes in SCA as compared to ET patients. We analyzed 68 Vim neurons in SCA and 60 Vim neurons in ET. Mean discharge rates, burst characteristics, and oscillatory activity were similar for both patient groups, however, we observed that the ratio of cells responding to passive manipulation was significantly smaller (P = 0.0001) in SCA (22%) than in ET (71%).InterpretationThalamic surgery led to a significant improvement in tremor in SCA patients. One potential mechanism underlying ataxia in SCA may be disruption of cerebellar sensory feedback, which modulates motor commands in the cerebello‐thalamo‐cortical network.

760 – Cognitive and affective impairments of a novel sca/mnd crossroad mutation asidan

Background A variety of hereditary spinocerebellar ataxia (SCA) develops a broad spectrum of both ataxia and non-ataxia symptoms. Cognitive and affective changes are one such non-ataxia symptoms, but have been described only in hereditary SCAs with exonic CAG gene expansion. Methods We newly found intronic hexanucleotide GGCCTG gene expansion in NOP56 gene as the causative mutation (=SCA36) in nine unrelated Japanese familial SCA originating from Asida river area in the western part of Japan, thus nicknamed Asidan for this mutation. These patients show unique clinical balance of cerebellar ataxia and motor neuron disease (MND), locating on the crossroad of these two diseases. We examined cognitive and affective analyses on 12 Asidan patients who agreed to join the examination. Results The 12 Asidan patients demonstrated a significant decrease in their frontal executive functions measured by frontal assessment battery (FAB) and Montreal cognitive assessment (MoCA) compared with age- and gender-matched controls, whilst mini-mental state examination (MMSE) and Hasegawa dementia score-revised (HDS-R) were within normal range. The decline of frontal executive function was related to their disease duration and scale for the assessment and rating of ataxias (SARA). They also demonstrated mild depression and apathy. Single-photon emission tomography (SPECT) analysis showed that these Asidan patients showed decline of regional cerebral blood flow (rCBF) in a particular areas of cerebral cortices such as Brodmann areas 24 and 44-46. Conclusions These data suggest the patients with Asidan mutation show unique cognitive and affective characteristics different from other hereditary SCAs with exonal CAG expansion or MND.

Cognitive and affective impairments of a novel SCA/MND crossroad mutation Asidan

A variety of hereditary spinocerebellar ataxia (SCA) develops a broad spectrum of both ataxia and non-ataxia symptoms. Cognitive and affective changes are one such non-ataxia symptoms, but have been described only in hereditary SCAs with exonic CAG gene expansion. We newly found intronic hexanucleotide GGCCTG gene expansion in NOP56 gene as the causative mutation (=SCA36) in nine unrelated Japanese familial SCA originating from Asida river area in the western part of Japan, thus nicknamed Asidan for this mutation. These patients show unique clinical balance of cerebellar ataxia and motor neuron disease (MND), locating on the crossroad of these two diseases. In the nine families, 14 patients were clinically examined and genetically confirmed to Asidan. In the present study, we examined cognitive and affective analyses on 12 patients (seven men and five women) who agreed to join the examination with average age at onset of 53.1 ± 3.2 years, average duration of 12.1 ± 5.2 years, and current average age at 65.1 ± 6.2 years. The 12 Asidan patients demonstrated a significant decrease in their frontal executive functions measured by frontal assessment battery (FAB) and Montreal cognitive assessment (MoCA) compared with age- and gender-matched controls, whilst mini-mental state examination (MMSE) and Hasegawa dementia score-revised (HDS-R) were within normal range. The decline of frontal executive function was related to their disease duration and scale for the assessment and rating of ataxias (SARA). They also demonstrated mild depression and apathy. Single-photon emission tomography (SPECT) analysis showed that these Asidan patients showed decline of regional cerebral blood flow (rCBF) in a particular areas of cerebral cortices such as Brodmann areas 24 and 44-46. These data suggest that the patients with Asidan mutation show unique cognitive and affective characteristics different from other hereditary SCAs with exonal CAG expansion or MND.

Prevalence of Autosomal Dominant Cerebellar Ataxia in Aomori, the Northernmost Prefecture of Honshu, Japan

The frequency of autosomal dominant cerebellar ataxia (ADCA) varies between different regions of Japan. This is the first report on the prevalence of ADCA subtypes in Aomori, Japan. Sixty-five familial spinocerebellar ataxia (SCA) patients and 15 sporadic SCA patients were genetically examined. For only the SCA2 patients (n = 8), the magnetic resonance imaging (MRI) data were analyzed in detail. Spinocerebellar ataxia (SCA) type 6 was often observed (77.7% of cases), with SCA2 (10.6% of cases) being the next most common form. In contrast, only one of the eighty patients had SCA1. Among the 15 sporadic SCA patients, genetic mutations for SCA2, SCA6, SCA17, and SCA31 were identified, indicating that ADCAs should be considered in sporadic cases of ataxia. Furthermore, in SCA2 cases, brainstem atrophy, pontine midline linear hyperintensity, and atrophy of the frontal lobes were frequently observed using MRI. The present data indicate that the prevalence of ADCA in Aomori differs from other prefectures in the Tohoku District. MRI findings are very similar between SCA2 and multiple system atrophy (MSA), and thus care must be taken to prevent the misdiagnosis of sporadic SCA2 as MSA.

Successful treatment of spinocerebellar ataxia 6 with medicinal herbs

A case of familial spinocerebellar ataxia 6 with typical symptoms is presented. A 60‐year‐old Japanese female suffered from gait disturbance, ataxia and dizziness. Head magnetic resonance imaging revealed a typical atrophic image in cerebellum. Genetic tests revealed an expanded allele of 22 CAG repeats at the spinocerebellar ataxia type 6 locus. She was diagnosed with spinocerebellar ataxia 6. Her mother was also diagnosed with the same disease. A mixture of 18 medicinal herbs (modified Zhengan Xifeng Tang) was given according to the differential diagnosis based on the guidelines of traditional Chinese medicine. All of the symptoms were remarkably improved after 60 days of the herbal treatment. One year after discontinuation of the treatment, she complained of gait ataxia. She was treated with the modified Zhengan Xifeng Tang for 60 days. Gait ataxia was markedly improved by the second treatment. Fifteen months after discontinuation of the second treatment, she complained of gait ataxia again. The same remedy was given for 60 days. Gait ataxia was remarkably reduced again. The results may imply therapeutic potential of the medicinal herbs for spinocerebellar ataxia 6.

Unique Cerebellar-Cerebral Form of Autosomal Recessive Ataxia

We describe a unique condition affecting two siblings with a form of progressive spinocerebellar ataxia. After a period of very slowly progressive ataxia, the patients developed an extremely accelerated progression of the condition which consisted of cerebellar ataxia, seizure, progressive dementia and spastic tetraparesis. Age of onset was variable at 7 to 18 years. Brain magnetic resonance image (MRI) showed marked atrophy of the cerebellum and cerebrum with strikingly preserved brainstem dimensions. Biochemical or molecular genetic analysis was performed in an elder sister and her parents to exclude known forms of familial spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), progressive myoclonic epilepsy, and some metabolic disorders which could have a similar phenotype. The mode of inheritance appears to be autosomal recessive. We think that the affected siblings may have a new type of autosomal recessive cerebellar ataxia.

Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients.

Expansions of trinucleotide repeats have been discovered in spinocerebellar ataxia (SCA) types 1, 2, 6, 7, 12, and 17, Machado-Joseph disease (MJD/SCA3), and dentatorubropallidoluysian atrophy (DRPLA). However, the frequency of familial SCA in Japan remains unclear. The number of trinucleotide repeats was determined for 1,286 patients. Three hundred and thirty families (523 cases) were autosomal dominant group (A), and 165 families were positive for family history but not autosomal dominant group (B), while the remaining 598 cases were the sporadic group (C). The frequency of SCA subtypes in autosomal dominant group was: 1) 5.5% for SCA1; 2) 2.4% for SCA2; 3) 27.6% for MJD/SCA3; 4) 25.5% for SCA6; 5) 0.3% for SCA17; and 6) 7.3% for DRPLA. Abnormal expansion of SCA12 was not detected. Another 31.5% of the patients in the autosomal dominant group had unknown genetic abnormalities. Within group B, SCA6 was the most prominent and within the sporadic group MJD/SCA3 and SCA6 were the most common subtypes observed. The disease-free survival curve of SCA6 was different from that of other SCAs and the mean age at onset for SCA6 was found to be later than that of the other types. Regional differences were observed in the relative rate of SCA subtypes. MJD/SCA3 appears more common in the Kanto and Kyushu districts of Japan, whereas SCA6 is most common in the Chugoku district. In order to establish an effective social welfare system for SCA patients, clinical course and regional differences in the prevalence of SCA subtypes must be taken into consideration.

Analysis of spinocerebellar ataxia type 2 gene and haplotype analysis: (CCG)1- 2 polymorphism and contribution to founder effect

Spinocerebellar ataxia type 2 is a familial spinocerebellar ataxia with autosomal dominant inheritance. The gene responsible was recently cloned and this disorder was found to be the result of a...