Functional classification of ATM variants in ataxia-telangiectasia patients.

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.

Breathing variability and brainstem serotonergic loss in a genetic model of multiple system atrophy.

Breathing disorders like sleep apnea, stridor, and dysrythmic breathing are frequent in patients with multiple system atrophy (MSA). These observations have been related to neurodegeneration in several pontomedullary respiratory nuclei and may explain the occurrence of sudden death. In this study, we sought to determine whether these functional and neuropathological characteristics could be replicated in a transgenic model of MSA. Mice expressing human wild-type α-synuclein under the control of the proteolipid promoter (PLP-αSYN) were compared with age-matched controls. Using whole-body, unrestrained plethysmography, the following breathing parameters were measured: inspiratory and expiratory times, tidal volume, expiratory volume, peak inspiratory and expiratory flows, and respiratory frequency. For each category, the mean, coefficient of variation, and irregularity score were analyzed. Brains were then processed for stereological cell counts of pontomedullary respiratory nuclei. A significant increase in the coefficient of variation and irregularity score was observed for inspiratory time, tidal volume, and expiratory volume in PLP-αSYN mice (P < 0.05). Glial cytoplasmic inclusions were found in the medullary raphe of PLP-αSYN mice, together with a loss of serotonergic immunoreactivity in the raphe obscurus (P < 0.001) and pallidus (P < 0.01). There was a negative correlation between α-synuclein burden and raphe pallidus cell counts (P < 0.05). There was no significant neuronal loss in the pre-Botzinger complex. The PLP-αSYN mouse model replicates the breathing variability and part of the neuronal depletion in pontomedullary respiratory nuclei observed in patients with MSA. Our findings support the use of this model for future candidate drugs in the breathing disorders observed in MSA.

[Multidisciplinary care of patients with Myotonic Dystrophy type 1 (DM1) in South Aquitaine]. / Le suivi multidisciplinaire de patients adultes atteints de dystrophie myotonique de type 1 dans le Sud Aquitain.

DM1 is characterized by a multisystemic involvement. Our objective was to determine the proportion of adequate follow-up for each affected organ in DM1 patients based on the recently published American and Spanish recommendations. To this end, we conducted a descriptive cross-sectional survey by phone in adult, genetically proven DM1 patients followed in the two French neuromuscular centers of Bayonne and Hendaye located in South Aquitaine, France. The questionnaire selected the most stringent criteria of the two international recommendations for each item of follow-up. Seventy-three patients were included, 55% of which were women (mean age of 48 years) with an average number of 467 CTG repeats. The proportion of patients receiving clinical follow-up in accordance with the recommendations was 90% in cardiology, 60% in neurology, 68% in ophthalmology, 53% in physiotherapy, 23% in pneumology, and 12% in rehabilitation. The high rate of neurological, cardiological, and ophthalmological monitoring might be explained by a locally dense medical demography whereas low rate of respiratory follow up and rehabilitation may reflect an incomplete knowledge of both the disease and the questionnaire. These results should be carefully interpretated as cognitive status may influence such a declarative study. Our study nevertheless disclosed important disparities according to the recommended multidisciplinary follow-up criteria in this French cohort of adult DM1 patients. These results highlight the major role of a multidisciplinary care and monitoring in DM1.

Impact of sleep apnea syndrome on survival in patients with multiple system atrophy.

INTRODUCTION: Sleep apnea is very frequent in multiple system atrophy (MSA) and may contribute to the poor prognosis. The aim of the present study was to prospectively assess the relation between sleep apnea and survival in 30 consecutive MSA patients recruited at the French Reference Center for MSA. METHODS: Patients with "probable" MSA according to current consensus diagnosis criteria were enrolled in this prospective cohort study. All patients received full polysomnography at baseline and were then followed for up to 4.5 years. The prognostic role of sleep apnea was assessed by a Cox model in an univariate analysis and then adjusted on other potential factors. RESULTS: Analyzable polysomnographic recordings were available for 28 patients. Sleep apnea was found in 11 patients. During follow-up, 15 patients died, including 9 with baseline sleep apnea. In an univariate analysis, sleep apnea, Unified MSA Rating Scale I + II score at baseline and at year one, and disease duration were associated with mortality. However, when adjusting for disease duration and baseline Unified MSA Rating Scale score, the association between sleep apnea and mortality was no longer significant. CONCLUSIONS: Sleep apnea was not an independent factor associated with mortality in this prospective cohort study.

Current Concepts in the Treatment of Multiple System Atrophy.

MSA is a progressive neurodegenerative disorder characterized by autonomic failure and a variable combination of poor levodopa-responsive parkinsonism and cerebellar ataxia (CA). Current therapeutic management is based on symptomatic treatment. Almost one third of MSA patients may benefit from l-dopa for the symptomatic treatment of parkinsonism, whereas physiotherapy remains the best therapeutic option for CA. Only midodrine and droxidopa were found to be efficient for neurogenic hypotension in double-blind, controlled studies, whereas other symptoms of autonomic failure may be managed with off-label treatments. To date, no curative treatment is available for MSA. Recent results of neuroprotective and -restorative trials have provided some hope for future advances. Considerations for future clinical trials are also discussed in this review.

TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts.

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.

Semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis, are predominant frontotemporal lobar degeneration phenotypes in TBK1 carriers.

INTRODUCTION: TBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far. METHODS: We describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes. RESULTS: Two carriers initially presented semantic variant of FTLD (svFTLD); two other developed nonfluent variant of FTLD (nfvFTLD) and corticobasal syndrome (CBS), associated with severe anterior temporal and opercular atrophy. All secondarily developed ALS. DISCUSSION: This study enlarges the phenotypic spectrum of TBK1 mutations, including svFTLD and nfvFTLD/CBS, not reported so far. Aphasic presentations seem to be more evocative of TBK1 genotype than behavioral variant of FTLD, and TBK1 should be analyzed in patients with isolated FTLD at onset, particularly in rare aphasic cases secondarily associated with ALS.

Accuracy of portable polygraphy for the diagnosis of sleep apnea in multiple system atrophy.

OBJECTIVE: To assess the diagnostic accuracy of portable polygraphy (PG) for the detection of sleep apnea (SA) in multiple system atrophy (MSA). METHODS: Thirty consecutive patients with probable MSA underwent PG (overnight recording of nasal flow, thoracic/abdominal movements and pulse oximetry), followed 4 weeks later by full polysomnography (PSG) (reference standard). The accuracy of PG was first assessed using the same threshold as for PSG (apnea-hypopnea index [AHI]≥5), then for all possible AHI thresholds using the area under the receiver operating characteristics (AUROC) curve. Inter-rater reliability of PG was assessed using the kappa coefficient. RESULTS: Among 30 patients enrolled, seven were excluded for technical problems on PG or PSG and 23 were included in the main analysis. Eight out of 23 had an AHI≥5 on PSG. With the same threshold, sensitivity, specificity, positive and negative predictive values of PG for the diagnosis of SA were 87.5% (95% confidence interval: 47-99), 80% (52-96), 70% (35-93) and 92.3% (64-99), respectively. The kappa between PG raters was 0.75 (0.49-1.00) indicating good agreement. The AUROC was 0.93 (0.82-1.00). No association was found between sleep and excessive daytime sleepiness questionnaires and SA. CONCLUSION: Portable PG seems to be valuable for ruling out SA in MSA.

Multiple system atrophy: current and future approaches to management.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder without any effective treatment in slowing or stopping disease progression. It is characterized by poor levodopa responsive Parkinsonism, cerebellar ataxia, pyramidal signs and autonomic failure in any combination. Current therapeutic strategies are primarily based on dopamine replacement and improvement of autonomic failure. However, symptomatic management remains disappointing and no curative treatment is yet available. Recent experimental evidence has confirmed the key role of alpha-synuclein aggregation in the pathogenesis of MSA. Referring to this hypothesis, transgenic and toxic animal models have been developed to assess candidate drugs for MSA. The standardization of diagnosis criteria and assessment procedures will allow large multicentre clinical trials to be conducted. In this article we review the available symptomatic treatment, recent results of studies investigating potential neuroprotective drugs, and future approaches for the management in MSA.