Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Next-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.

Newly-diagnosed epileptic seizures in three populations: Geneva (EPIGEN), Martinique (EPIMART), and the Reunion Island (EPIREUN).

AIM: The objective was to analyse and discuss data from three studies of newly-diagnosed epileptic seizures (provoked and unprovoked) conducted in Geneva, Martinique, and the Reunion Island, in which the same methodology was used. METHODS: We extracted data from three studies in which the incidence of seizures was estimated and aetiologies identified. Data was extracted and analysed using STATA. Group comparison was performed firstly for each study as a single group, and secondly by considering Martinique and the Reunion Island as an overseas group, in comparison with Geneva, considered as a mainland group. Uncorrected χ(2)was used and statistical significance (two-sided, p=0.05) was determined for each aetiology per cohort. RESULTSThe incidence of newly-diagnosed epileptic seizures per 100,000 was 71.0, 80.6, and 100.4 in Geneva, Martinique, and the Reunion Island, respectively. A bimodal distribution and predominance of generalised seizures was noted. The male to female ratio was higher in Martinique (∼2.0) than other populations (∼1.5). Status epilepticus was noted in Geneva and more so in the Reunion Island. The incidence of provoked seizures per 100,000 was 25.2, 16.4, and 17.7, and for unprovoked seizures was 45.6, 64.1, and 81.2 in Geneva, Martinique, and the Reunion Island, respectively. There was a greater risk of provoked seizures in Geneva relative to the overseas group, which was due to tumours, use of toxic substances, and drug abuse. The risk of unprovoked seizures in Geneva was due to trauma and infections. In Martinique, alcoholism and HIV were foremost factors for provoked and unprovoked seizures, and stroke was an important aetiology in both Martinique (provoked seizures) and the Reunion Island (unprovoked seizures). CONCLUSION: The risk of provoked seizures was greatest in Geneva and risk of unprovoked seizures was greatest in the Reunion Island. Toxic substances, alcohol, infection, and trauma constituted major factors for epileptic seizures in Geneva, while alcoholism, HIV, and stroke were major factors in the overseas group. Relative eradication of tropical infections has paved a way for the emergence of non-communicable aetiologies (stroke, alcoholism). Males from Martinique demonstrated the greatest risk of epileptic seizures, signifying the importance of alcoholism, HIV, etc. Three steps should follow: follow-up studies (mortality), strong mechanisms for prevention (or control) of risk factors, guidelines on whether to treat or not.

Newly diagnosed epileptic seizures: focus on an elderly population on the French island of Réunion in the Southern Indian Ocean.

PURPOSE: To describe seizure types and risk factors among elderly people with newly diagnosed epileptic seizures living on La Réunion, a French Island in the Southern Indian Ocean. METHODS: We describe an elderly population with newly diagnosed epileptic seizures using data from the EPIREUN study conducted between July 1, 2004 and June 30, 2005. The methodology is described in detail in the EPIREUN study report (Mignard et al., 2009). KEY FINDINGS: There were 153 single unprovoked seizures (84.1%); their incidence was 278.1 [95% confidence interval (CI) 237.4-325.9] per 100,000. The incidence of newly diagnosed epilepsy was 125.4 (95% CI, 99.1-158.8) per 100,000. Twenty-eight acute symptomatic seizures occurred (15.4%); the incidence was 50.9 (95% CI 35.1-73.7) per 100,000. The annual incidence of newly diagnosed epileptic seizure in the elderly was 330.8 (95% CI 286.1-382.6) per 100,000: 403.0 (95% CI 328.5-494.3) per 100,000 in men and 279.6 (95% CI, 227.4-343.8) per 100,000 in women. Sex had a significant (p = 0.014) effect on incidence: elderly men had a risk ratio of 1.44 compared to women of developing a newly diagnosed epileptic seizure. The etiology of single unprovoked seizure was as follows: stroke, 77 cases (50.3%); cryptogenic, 36 (23.5%); alcoholism, 10 (6.6%); a combination of several causes such as polypathology, 9 (5.9%); degenerative disease, 6 (4.0%); HIV infection, 2 (2.0%), and undetermined causes (2.7%). Most patients (170; 93.4%) were hospitalized, and 110 (60.8%) were treated. Among patients treated, 49 (44.5%) were given sodium valproate, 25 (22.7%) benzodiazepines, 12 (10.9%) phenytoin, 9 (8.2%) lamotrigine, 8 (7.3%) Trileptal, and 7 (6.4%) gabapentin. SIGNIFICANCE: Our findings show that the incidences of newly diagnosed epileptic seizures and newly diagnosed epilepsy were high in the elderly population of La Réunion. These incidences were significantly higher in men than in women. These results may be attributable to the high incidence of cerebrovascular diseases and comorbidities in this population.

Incidence of newly diagnosed epileptic seizures in a French South Indian Ocean Island, La Réunion (EPIREUN).

PURPOSE: To assess the incidence of newly diagnosed epileptic seizures in the population of La Réunion. METHODS: From July 1, 2004 to June 30, 2005, we conducted a prospective, observational, and multicenter epidemiologic study to identify patients with newly diagnosed epileptic seizures. Febrile and neonatal seizures were excluded. RESULTS: Seven hundred sixty-six patients were included. The standardized (2000 U.S. population) incidence rate of all suspected cases of newly diagnosed (provoked and unprovoked) epileptic seizures was 115.4/100.000 person-years [95% confidence interval (CI) 106.7-124.0]. We observed a bimodal distribution: The crude incidence was 99.5/100,000 in the group aged 0-14 years and 330.8/100,000 in those older than 65 years. One hundred thirty-five cases were classified as provoked seizures (17.6%; incidence 17.7/100,000). Alcohol consumption, cranial trauma, and cerebrovascular disease were the most frequent causes (27.4%, 11.1%, and 10.4%, respectively). Six hundred twenty cases were classified as unprovoked seizures (single and recurrent) (80.9%; incidence, 81.2/100,000). Two hundred sixty cases of seizures were due to stable neurologic conditions (incidence, 34.1/100,000) and the most common causes were cerebrovascular disease (46.2%), alcoholism (20.4%), and cranial trauma (5.4%). Evolutive neurologic conditions contributed to 23 cases (incidence, 3.0/100,000). Lastly, unprovoked seizures with unknown etiology were 337 (incidence, 44.2/100,000). CONCLUSIONS: The global incidence rate of newly diagnosed epileptic seizures in La Réunion was clearly higher than those observed in industrialized countries and similar to those observed in developing countries. The major risk factors were represented by cerebrovascular disease, alcohol consumption, and cranial trauma. Surprisingly, there were few infections.

Natural history of LGMD2A for delineating outcome measures in clinical trials.

OBJECTIVE: Limb-girdle muscular dystophy 2A (LGMD2A, OMIM) is a slowly progressive myopathy caused by the deficiency in calpain 3, a calcium-dependent cysteine protease of the skeletal muscle. METHODS: In this study, we carried out an observational study of clinical manifestations and disease progression in genetically confirmed LGMD2A patients for up to 4 years. A total of 85 patients, aged 14-65 years, were recruited in three centers located in metropolitan France, the Basque country, and the Reunion Island. They were followed up every 6 months for 2 years and a subgroup was assessed annually thereafter for two more years. Data collected for all patients included clinical history, blood parameters, muscle strength assessed by manual muscle testing (MMT) and quantitative muscle testing, functional scores, and pulmonary and cardiac functions. In addition, CT scans of the lower limbs were performed in a subgroup of patients. RESULTS: Our study confirms the clinical description of a slowly progressive disorder with onset in the first or second decade of life with some degree of variability related to gender and mutation type. The null mutations lead to a more severe phenotype while compound heterozygote patients are the least affected. Muscle weakness is remarkably symmetrical and predominant in the axial muscles of the trunk and proximal muscles of the lower limb. There was a high correlation between the weakness at individual muscle level as assessed by MMT and the loss of density in CT scan analysis. INTERPRETATION: All the generated data will help to determine the endpoints for further clinical studies.

First-ever population-based study on status epilepticus in French Island of La Reunion (France) - incidence and fatality.

PURPOSE: We aimed to determine the incidence and case-fatality of first-ever status epilepticus (SE) among the general population living in La Reunion Island, a French overseas territory in the Indian Ocean near Madagascar. METHODS: We recruited cases (1st July 2004-30th June 2005) in a population-based manner using neurology, neurosurgery, electroencephalogram, emergency, paediatric and neuroradiology services; emergency medical aid service; emergency and admission service of private and public clinics; neurologists (public and private); private paediatricians and practitioners of various rural hospitals. All cases had an electroencephalogram (EEG) and were assessed by an epileptologist. Standard definition and classification schemes were used. Those with known epilepsy were not part of this analysis. RESULTS: Sixty-five cases (males: n=41, 63.1%) had epileptologist-confirmed SE, with 38.5% (n=25) being >60 years of age. Global incidence rate was 8.52/100 000 (95% confidence interval 6.5-10.5). A bimodal age distribution with high frequency and incidence among young (<10 years age) (frequency: 12.3%; incidence 6.6/100,000) and aged (>60 years) (frequency: 40.0%; incidence 35.0/100,000) was observed. We found that 60%, 32.3%, 6.7% had convulsive, partial and non-convulsive SE respectively (1% remained unclassified). Of the cases identified, 44.6%, 38.5%, 16.9% had unprovoked, provoked or cryptogenic seizures respectively. The most important aetiological factors identified included: stroke (27.7%), alcoholism/toxicity (18.5%), cryptogenic (16.9%), infections (10.8%). Mortality was 18.5%. CONCLUSION: The incidence of SE incidence in La Reunion Island was lower than that described elsewhere. The status type was found to be dependent on aetiology and age. The study confirms that SE is more frequent in men and in older adults and is associated with significant short-term case mortality.