Unravelling the etiology of sporadic late-onset cerebellar ataxia in a cohort of 205 patients: a prospective study.

BACKGROUND: Despite recent progress in the field of genetics, sporadic late-onset (> 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations. METHODS: We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations. RESULTS: We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt-Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p < 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p < 0.01). CONCLUSION: Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA.

Brain MRI of multiple system atrophy of cerebellar type: a prospective study with implications for diagnosis criteria.

AIM: The second consensus statement for the diagnosis of multiple system atrophy type cerebellar (MSA-C) includes pons and middle cerebellar peduncle (MCP) atrophy as MRI features. However, other MRI abnormalities such as MCP hyperintensity, hot cross bun sign (HCB), putaminal hypointensity and hyperintense putaminal rim have been described. OBJECTIVES: To evaluate, in patients with sporadic late-onset cerebellar ataxia (SLOCA), the discriminative value of several MRI features for the diagnosis of MSA-C, to follow their evolution during the course of MSA-C, and to search for correlations between these MRI features and clinical signs. METHODS: Consecutive patients referred for SLOCA underwent comprehensive clinical evaluation and laboratory investigations, brain MRI, DaTscan and a 1-year follow-up. RESULTS: Among 80 patients, 26 had MSA-C, 22 another diagnosis, and 32 no diagnosis at the end of the follow-up. At baseline, MCP hyperintensity and HCB were more frequent in patients finally diagnosed with MSA-C than in other patients with SLOCA (p < 0.0001), and had the highest specificity (98.5%) and positive predictive value (91.7%) for the diagnosis of MSA-C, compared to all other MRI signs. The most relevant MRI sequence regarding HCB sign was the T2-proton density (DP) weighted. All MRI features were more frequent with disease duration. No correlation was found between any MRI feature and neither clinical data, nor dopaminergic neuronal loss (p = 0.5008), except between vermis atrophy and UPDRSIII score. CONCLUSION: MCP hyperintensity and HCB sign should be added into the list of additional features of possible MSA-C. MRI signal abnormalities suggestive of MSA-C should be searched for in suitable sequence.

High-intensity intermittent training is as effective as moderate continuous training, and not deleterious, in cardiomyocyte remodeling of hypertensive rats.

Exercise training offers possible nonpharmacological therapy for cardiovascular diseases including hypertension. High-intensity intermittent exercise (HIIE) training has been shown to have as much or even more beneficial cardiovascular effect in patients with cardiovascular diseases than moderate-intensity continuous exercise (CMIE) training. The aim of this study was to investigate the effects of the two types of training on cardiac remodeling of spontaneously hypertensive rats (SHR) induced by hypertension. Eight-week-old male SHR and normotensive Wistar-Kyoto rats (WKY) were divided into four groups: normotensive and hypertensive control (WKY and SHR-C) and hypertensive trained with CMIE (SHR-T CMIE) or HIIE (SHR-T HIIE). After 8 wk of training or inactivity, maximal running speed (MRS), arterial pressure, and heart weight were all assessed. CMIE or HIIE protocols not only increased final MRS and left ventricular weight/body weight ratio but also reduced mean arterial pressure compared with sedentary group. Then, left ventricular tissue was enzymatically dissociated, and isolated cardiomyocytes were used to highlight the changes induced by physical activity at morphological, mechanical, and molecular levels. Both types of training induced restoration of transverse tubule regularity, decrease in spark site density, and reduction in half-relaxation time of calcium transients. HIIE training, in particular, decreased spark amplitude and width, and increased cardiomyocyte contractility and the expression of sarco(endo)plasmic reticulum Ca2+-ATPase and phospholamban phosphorylated on serine 16. NEW & NOTEWORTHY High-intensity intermittent exercise training induces beneficial remodeling of the left ventricular cardiomyocytes of spontaneously hypertensive rats at the morphological, mechanical, and molecular levels. Results also confirm, at the cellular level, that this type of training, as it appears not to be deleterious, could be applied in rehabilitation of hypertensive patients.

Deciphering the causes of sporadic late-onset cerebellar ataxias: a prospective study with implications for diagnostic work.

The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40 years of age were included in the prospective, observational study. 80 patients were included over a 2 year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy (n = 29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich's disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) (n = 9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia (p < 0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia (p = 0.001) and more frequently parkinsonism (p < 0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.

Xeroderma pigmentosum complementation group F: A rare cause of cerebellar ataxia with chorea.

The complementation group F of Xeroderma pigmentosum (XP-F) is rare in the Caucasian population, and usually devoid of neurological symptoms. We report two cases, both Caucasian, who exhibited progressive cerebellar ataxia, chorea, a mild subcortical frontal cognitive impairment, and in one case severe polyneuropathy. Brain MRI demonstrated cerebellar (2/2) and cortical (1/2) atrophy. Both patients had only mild sunburn sensitivity and no skin cancer. Mini-exome sequencing approach revealed in ERCC4, two heterozygous mutations, one of which was never described (c.580-584+1delCCAAGG, exon 3), in the first case, and an already reported homozygous mutation, in the second case. These cases emphasize that XP-F is a rare cause of recessive cerebellar ataxia and can in some cases clinically mimic Huntington's disease due to chorea and executive impairment. The association of ataxia, chorea, and sun hypersensitivity are major guidance for the diagnosis, which should not be missed, in order to prevent skin neoplastic complications.

Frequency and fitness cost of resistance to Bacillus thuringiensis in Chrysomela tremulae (Coleoptera: Chrysomelidae).

The "high dose-refuge" (HDR) strategy is commonly recommended and currently used for delaying or preventing pest adaptation to transgenic plants producing Bacillus thuringiensis (Bt) toxins. The efficiency of this strategy depends, among other factors, on the initial frequency of Bt resistance alleles and on the fitness costs associated with these alleles. Two years ago, an allele conferring resistance to Bt poplar was detected in a French population of the poplar pest Chrysomela tremulae F. Although this pest had never been subjected to Bt selection pressure due to human activities, the frequency of this allele was estimated at 0.0037, with a 95% credible (CI) interval of 0.00045-0.0080. We investigated the frequency of this allele in a second sample of C. tremulae collected more than 500 km from the site of the initial population. The estimated frequency in this sample was 0.0113 (95% CI 0.0031-0.0247), reinforcing the conclusion that resistance to Bt plants may be present at detectable frequencies in pest populations before selection resulting from pest management by humans. The frequency of the Bt resistance allele over the two samples was 0.0049 (95% CI 0.0020-0.0091). We also followed five laboratory lines in which the frequency of this allele was initially fixed at 0.500. After five generations maintained on non-Bt poplar leaves, the frequency of this allele decreased in all lines, whereas allelic frequencies at a neutral locus were unaffected. Thus, the Bt resistance allele detected in French populations of C. tremulae is probably associated with a fitness cost.

Is optic flow used to guide walking while wearing a displacing prism?

Rushton et al (1998 Current Biology 8 1191 - 1194) recently showed that walkers wearing displacing prisms follow curved trajectories determined by the perceived direction of their target. This suggests that optic flow is not important in guidance, since flow cues are unaffected by the prism and should allow a straight, direct trajectory. We replicated Rushton et al's result but also tried to rule out an important artifact associated with the prism. Prisms restrict the field of view and, particularly, access to the foreground optic flow that is likely to be important in providing guidance cues. We found that performance did not improve when walkers directed their gaze to include the foreground flow, suggesting that Rushton et al's results were not due to this artifact. On the other hand, performance did reliably improve when subjects reduced their viewing height by crawling towards the target. This improvement may be due to coarsening of the visual texture or to increased salience of alignment and motion-parallax cues. Whatever its cause, the improvement demonstrates that guidance is not determined only by perceived target direction and that, under some conditions, flow may be important.

Glutamatergic activation of the medial septum complex: an enhancement of the dentate gyrus population spike and accompanying EEG and unit changes.

A large number of cells from the medial septum complex (MSC) innervate the dentate gyrus of the hippocampus. Electrical prestimulation of the MSC enhances perforant path-dentate gyrus evoked field potentials. Considering the large number of fibres that pass through this region, the effects glutamatergic stimulation of the MSC had on dentate gyrus field potentials, and accompanying changes in units, and EEG, was investigated in urethane-anaesthetized rats. The perforant path was stimulated at a rate of 0.1 Hz, evoking an EPSP and a population spike recorded in the dentate gyrus granule cell layer. L-glutamate was delivered by pressure ejection. Glutamate ejection to the MSC produced a significant enhancement of the population spike. The duration of enhancement ranged from 1 to 49 min ( approximately =10.5 min). A consistent, but relatively short increase in the EPSP slope was also demonstrated. MSC activation induced a theta rhythm in 7 of 10 animals (duration=20-112 s). Theta rhythm induction preceded spike enhancement and occurred for a shorter duration than the enhancement. The effects on spontaneous unit activity were mixed. However, all changes in firing rate preceded spike enhancement, and their duration rarely coincided with the duration of the spike enhancement. The population spike enhancement usually occurred without evidence of a change in paired-pulse inhibition.

Two distinct truncated variants of ankyrin associated with hereditary spherocytosis.

We present two distinct truncated variants of ankyrin associated with mild to moderate hereditary spherocytosis. Ankyrin Saint-Etienne 1 was manifested by an additional band located between bands 2.1 and 2.2. It was associated with a nonsense mutation in exon 39: TGG-->TGA; W1721X. Ankyrin Saint-Etienne 2 appeared as two faint bands underlining bands 2.1 and 2.2. It was associated with a nonsense mutation in exon 41: CGA-->TGA; R1833X. Overall ankyrin was diminished in splenectomized patients. Messenger RNAs Saint-Etienne 1 and 2 amounted to 20 and 37% of the total ankyrin mRNA, respectively. Ankyrin molecules truncated in their C-terminal region retain some ability to bind to the membrane whereas the bulk of nonsense mutations, located in more upstream regions, result in the mere disappearance of one haploid set of ankyrin. In the present cases, it was not possible to apportion the roles of ankyrin reduction and truncation in the pathogenesis of hereditary spherocytosis.

Hereditary spherocytosis with band 3 deficiency. Association with a nonsense mutation of the band 3 gene (allele Lyon), and aggravation by a low-expression allele occurring in trans (allele Genas).

We describe an 18-year-old with moderate hereditary spherocytosis. The condition was associated with a 35% decrease in band 3. The underlying mutation was Arg to stop at codon 150 (CGA-->TGA) and was designated R150X, which defined allele Lyon of the EPB3 gene. The inheritance pattern was dominant. However, the mother, who also carried the allele Lyon, had a milder clinical presentation and only a 16% decrease of band 3. We suggested that the father had transmitted a modifying mutation that remained silent in the heterozygous state. Nucleotide sequencing after single strand conformation polymorphism analysis of the band 3 cDNA and promoter region revealed a G-->A substitution at position 89 from the cap site in the 5'-untranslated region, designated 89G-->A, which defined allele Genas. A ribonuclease protection assay showed that (1) the allele Genas (father) resulted in a 33% decrease in the amount of band 3 mRNA, (2) the reduction caused by the allele Lyon (mother) was 42%, and (3) the compound heterozygous state for both alleles (proband) resulted in a 58% decrease. These results suggest that some mildly deleterious alleles of the EPB3 gene are compensated for by the normal allele in the heterozygous state. They are shown through the aggravation of the clinical picture, based on more obvious molecular alterations when they occur in trans to an allele causing a manifest reduction of band 3 membrane protein concentration.

Population spike facilitation in the dentate gyrus following glutamate to the lateral supramammillary nucleus.

Glutamate stimulation of the lateral supramammillary nucleus (SUL) in urethane anaesthetized rats produced a substantial increase in the amplitude of the perforant path-evoked population spike in the dentate gyrus, without affecting the population EPSP slope. One third of the spike enhancements lasted longer than 20 min. These data suggest that SUL afferents provide a mechanism for both short- and long-lasting heterosynaptic modulation of hippocampal throughput.

Impact of human immunodeficiency virus type 1 on tuberculosis in rural Haiti.

We conducted a case-control study to determine the relative and attributable risk of HIV seropositivity for bacillary-positive (smear and/or culture) pulmonary tuberculosis in Haiti. There were 274 patients with tuberculosis and an equal number of control subjects. Antibodies to HIV were present in 67 (24%) patients and eight (3%) control subjects. Odds ratios suggested that the risk of pulmonary tuberculosis was 15.7 times as great (95% confidence interval, 4.8 to 5.0; p less than 0.05) in patients 20 to 39 yr of age who were HIV-seropositive than in HIV-seronegative patients. In contrast, the relative risk in those 40 to 59 yr of age was elevated (3.0 times), though not significantly (lower 95% confidence interval, 0.8). In the 20- to 39-yr age group, 31% of tuberculosis was attributable to HIV infection (95% confidence interval between 23 and 39%). HIV-seropositive and HIV-seronegative patients did not differ with respect to sputum smear positivity. HIV-seronegative patients were twice as likely to be infected with resistant organisms, though this was not significant. We conclude that HIV infection is a major risk factor for pulmonary tuberculosis in young adult residents of Haiti. This, together with the fact that similar proportions of HIV-seropositive and HIV-seronegative patients were potentially infectious, suggests that without vigorous counteraction tuberculosis will become a greater problem for Haiti.

Antituberculous drug resistance in central Haiti.

To determine the prevalence of antituberculous drug resistance in Haiti, we conducted a 1-yr survey in a central district. From a bacillary positive (smear and/or culture positive) case rate of 80/100,000, there were 282 patients from whom Mycobacterium tuberculosis was cultured. Each isolate was packaged and delivered to Canada where speciation and drug susceptibility testing were performed. Reported resistances are those using the proportions method (Laboratory Center for Disease Control, Ottawa, Canada). Resistance to one or more drugs was found in 22% of isolates. Age was the most important predictor of resistance in Haiti; resistance rates for age groups less than 14, 14 to 29, 30 to 44, greater than or equal to 45 were 8, 19, 22, and 31%, respectively. In patients not known to have received antituberculous drugs in the past, resistances were isoniazid (19%), streptomycin (5%), ethambutol (2%), ethionamide (2%), rifampin (1%). We conclude that antituberculous drug resistance is prevalent in Haiti, especially in older age groups, and that in persons with no known antituberculous drug use in the past, resistance to isoniazid is significant.

DSP-4 treatment accelerates kindling.

Norepinephrine depletion of the central nervous system by peripheral N-(2-chloroethyl)-N-ethyl bromobenzylamine administration accelerates the development of seizures kindled by repeated stimulation of the amygdala. These data, in conjunction with previous 6-hydroxydopamine data, demonstrate the robustness of this phenomenon and emphasize the importance of noradrenergic innervation originating from the locus ceruleus in the suppression of seizure development.

Biotin dependent multiple carboxylase deficiency presenting as a congenital lactic acidosis.

Two patients presented in early childhood with (i) alopecia, skin rashs, and dermatitis, (ii) severe hypotonia, ataxia and motor retardation, (iii) frequent episodes of ketoacidosis with hyperlactacidemia. Propionic and methylcrotonic aciduria only appeared on high protein diet. Mitochondrial biotin-dependent carboxylase activities were decreased in the liver and leukocytes, but were similar to control values in fibroblasts cultured in a biotin-free medium. In addition, the plasma biotin was found to be significantly lower than in control subjects. These disorders responded to biotin administration, pointing to biotin-dependent multiple carboxylase deficiencies (MCD). Our report stresses the polymorphism of MCD and suggests that MCD could be of two types: impaired vitamin metabolism (absorption, plasma transport), might result in low plasma biotin with generalized MCD involving acetyl CoA carboxylase. Defective mitochondrial holocarboxylase synthetase might lead to a pure mitochondrial MCD, with fibroblastic deficiency and presumably normal biotin metabolism.