Progressive myoclonic ataxia with intrathecal immune activation in six patients

In six patients with slowly progressive sporadic cerebellar ataxia and cortical multifocal action myoclonus, cerebrospinal fluid (CSF) IgG index was persistently very high (1.2–6.7) and numerous oligoclonal bands were detected. Progressive cognitive impairment and MRI cerebellar and cerebral atrophy were observed. No serum antibodies were found. Various degenerative, metabolic, inflammatory and systemic diseases were excluded. The cerebellum may be the main target of a degenerative or immune process and releases antigens that, enhancing a compartmentalised (auto)immune response, as suggested by the persistent intrathecal activation, could lead to further cerebellar damage. As the frequency of CSF oligoclonal banding in myoclonic ataxia is unknown, our patients’ disease might represent a hitherto unreported entity or a subset of progressive myoclonic ataxia.

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Sommario Descriviamo sei pazienti con atassia cerebellare sporadica e mioclono corticale d’azione multifocale, nel cui liquor i valori dell’indice IgG si mantenevano persistentemente elevati ed erano presenti numerose bande oligoclonali. I pazienti manifestavano un progressivo declino cognitivo e la RM mostrava atrofia cerebellare e cerebrale. In assenza di anticorpi identificabili non era possibile formulare una diagnosi di malattia nota. Suggeriamo che il cervelletto possa essere il principale bersaglio di un processo degenerativo o immuno-mediato e che gli antigeni liberati inducano la produzione di anticorpi che ulteriormente provocano danno cerebrale. Poiché non è nota la frequenza delle bande oligoclonali nel liquor di pazienti con atassia mioclonica, non sappiamo se la malattia qui descritta sia una entità nuova o un sottogruppo delle atassie miocloniche.

     

遗传性小脑型共济失调症(附55例报告)

本文分析了55例小脑型遗传性共济失调的临床资料，男女之比为4：1，2/3患者年龄在37～50之间，并发症状多为行走不稳。主要临床表现为兼有躯干和肢体共济失调（78.2％），眼震（56.4），构音障碍（69.l％），约1/4病人有病理征及家族史。讨论了本病与其他疾病所致共济失调的鉴别诊断，以及本病的病理学基础。     

Inter-rater reliability of the International Cooperative Ataxia Rating Scale (ICARS).

We assessed the inter-rater reliability of the 100-point International Cooperative Ataxia Rating Scale (ICARS). Three neurologists independently rated videotaped ICARS examinations of 22 subjects with genetically determined ataxias (spinocerebellar ataxia [SCA] Type 1 in 11; SCA Type 2 in 1; Friedreich's ataxia in 10) and 4 controls. Scores on live ICARS assessment had ranged from 0 to 7 for controls and 11 to 74 for ataxic subjects (clinically very mildly affected to wheelchair-bound). Inter-rater correlation was very high for the total score (Kendall's omega 0.994, 95% confidence interval, 0.988-0.997), and high to very high for each component subscore (0.791 for speech to 0.994 for posture/gait). All correlations were significant at P < 0.00001. The ICARS exhibits very high inter-rater reliability even without prior observer standardisation and is sensitive to a range of ataxia severities from very mild to severe.     

Genetic Analysis of Rapid Tolerance to Ethanol's Incoordinating Effects in Mice: Inbred Strains and Artificial Selection

Ethanol tolerance, a decrease in drug responsiveness with repeated administrations, is an important diagnostic criterion for alcoholism. Rapid tolerance develops within 8-24 hours of an initial ethanol exposure and shares many similarities with chronic tolerance. The genetic contribution to rapid tolerance to ethanol-induced ataxia was estimated using a panel of inbred strains of mice. Strains differed significantly in the degree of rapid tolerance development, which had a broad-sense heritability estimate of 0.11. Artificial selection was carried out to develop lines of mice that would show High (HRT) and Low (LRT) levels of Rapid Tolerance. Starting with HS/Npt mice, derived from a systematic cross of eight inbred strains, a significant response to selection was seen in replicate 1 by the third selection generation. No difference was found in replicate 2. Heritability estimates after the fourth generation were 0.25 for HRT-1 mice and 0.06 for LRT-1 mice. HRT-1 and LRT-1 mice also differed significantly in chronic tolerance development to four doses of ethanol. These studies provide evidence for a genetic contribution to rapid tolerance and support a genetic link between rapid and chronic tolerance to ethanol's ataxic effects.     

Short half-lives of ataxia-associated aprataxin proteins in neuronal cells

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1) is caused by mutations in the gene encoding aprataxin (APTX). Although several in vitro findings proposed that impaired enzymatic activities of APTX are responsible for EAOH/AOA1, potential instability of mutant proteins has also been suggested as the pathogenesis based on in vivo finding that mutant proteins are almost undetectable in EAOH/AOA1 tissues or cells. The present study aimed to experimentally prove instability of mutant proteins in neuronal cells, the cell type preferentially affected by this disease. Results of pulse-chase experiments demonstrated that all of the disease-associated mutants had extremely shorter half-lives than the WT. We further found that mutants were targeted for rapid proteasome-mediated degradation. These results help establish pathogenic and physiological protein characteristics of APTX in neuronal cells.     

Procedure for the quantitative evaluation of motor disturbances in cerebellar ataxic patients

Cerebellar ataxia is a complex motor disturbance that involves the planning and execution of movements and reduces movement accuracy and co-ordination. The quantification of ataxic signs is commonly realised through visual examination of motor tasks performed by the patient and assignment of scores to specific items composing the international co-operative ataxia rating scale (ICARS). The present work studied an experimental procedure to characterise specific aspects of motor disturbances in ataxia objectively. Four tests belonging to the ICARS were considered: walking, knee-tibia test, finger-to-nose and finger-to-finger test. Through a kinematic analysis performed during the above tests, specific indices were defined to quantify velocity, linearity, asymmetry, tremor, instability and smoothness of movement or posture. The procedure was applied to five patients with cerebellar ataxia and to ten healthy adult subjects. Results demonstrated that the patients moved significantly more slowly than the healthy subjects (0.67 against 0.97 m s⁻¹ and 0.81 against 1.02 m s⁻¹, respectively, for straight walk and finger-to-nose tests) and showed poorer linearity and smoothness behaviour. Velocity, linearity, tremor, smoothness and instability indices showed moderate to good correlation with the corresponding ICARS score. Some of these indices can separately evaluate aspects that are combined in single ICARS subscores. It is concluded that the combination of clinical assessments and instrumental evaluations allows a better insight into ataxic patients' motor disturbances and is a useful tool for the definition and follow-up of rehabilitation programmes.     

ZK 91296, a partial agonist at benzodiazepine receptors

ZK 91296 (ethyl 5-benzyloxy-4-methoxymethyl--carboline-3-carboxylate) is a potent and selective ligand for benzodiazepine (BZ) receptors. Biochemical investigations indicate that ZK 91296 may be a partial agonist at BZ receptors. Such partial agonism may explain to some extent why ZK 91296 needs higher BZ receptor occupancy than diazepam for the same effect against chemical convulsants and for behavioural effects. The lack of sedatiye effects, and the very potent inhibition of reflex epilepsy, spontaneous epilepsy and DMCM-induced seizures suggest, furthermore, that ZK 91296 may possess pharmacological selectivity for a particular type of BZ receptor interaction, perhaps including topographic as well as receptor subtype differentiation.     

Distinctions among sedative,disinhibitory, and ataxic properties of ethanol in inbred and selectively bred mice

Three different domains of behavioral action of ethanol (ETOH) were examined in a battery of seven inbred strains and in the selectively bred Long-Sleep (LS) and Short-Sleep (SS) mice. Sedative effects were examined with the loss of the righting reflex test at 3.8 g/kg. The variation among inbred strains was only half the size of the difference between LS and SS mice which were selectively bred for extremes in this phenotype; such a result is expected for phenotypes controlled polygenically. Blood ETOH levels at waking from the narcosis also showed a range of differences among the inbred strains that was less than the LS/SS difference. Ataxia was measured with the grid test, and the inbred strains fell into two groups, resembling the highly ataxic LS line, and the less ataxic SS line. Biphasic effects of ETOH on locomotor activity were strongly genotype dependent. Variation in degree of activation/disinhibition produced by doses up to 1.5 g/kg (IP) ranged from no activation, in the C57BL/6Abg strain, to a stimulation effect in the MOLD/RkAbg strain which was larger than that seen for SS mice. The patterns of strain differences for both ataxia and activation were highly different from the duration of loss of righting reflex measure, suggesting multiple independent genetically based sensitivities to ETOH.