Exploring the diagnosis delay and ALS functional impairment at diagnosis as relevant criteria for clinical trial enrolment.

Objectives were: i) to describe the phenotypic heterogeneity of incident amyotrophic lateral sclerosis (ALS) patients diagnosed in 2012 in French ALS centres; ii) to look at the associations between ALSFRS-R score and ALSFRS-R slope (ΔFS) at time of diagnosis with diagnosis delay, ALS phenotypes and Airlie House diagnosis criteria (AHDC); iii) to describe the rate of progression on ΔFS, according to diagnosis delay. METHODS: Incident ALS cases diagnosed in French ALS centres were included. The rate of progression was evaluated as follows: ΔFS = (48 - ALSFRS-R at time of diagnosis)/duration from onset to diagnosis (months). Fast and slow progressors were defined by ΔFS >1 and <0.5, respectively. RESULTS: At time of diagnosis, 476 patients were classified into eight phenotypes: bulbar (33.0%), spinal lumbar (28.2%), spinal cervical (23.1%), flail leg (4.4%), ALS/FTD (4.2%), possible flail arm (4.0%), respiratory (2.1%), dropped-head (1.0%). Median ΔFS (n = 358/476) was 1.0 [0.5-2.0]. ΔFS was associated with AHDC (p = 0.009), but not with clinical phenotype (p = 0.902). Stratification on diagnosis delay (<12 months or ≥18 months) allowed to differentiate fast progressors from slow progressors. CONCLUSION: At time of inclusion in therapeutic trial closed to diagnosis, ΔFS or diagnosis delay may discriminate the rate of progression.

Rural environment and risk factors of amyotrophic lateral sclerosis: a case-control study.

The aetiology of sporadic ALS is still unknown. Links with several environmental factors have been suggested, and some epidemiological studies have shown an increased incidence of ALS in rural populations. This study was designed to investigate risk exposures in a well-delimited rural population and to assess whether rural residency or occupations, such as farming, were associated with an increased risk of developing ALS. A prospective case-control-study of 108 sporadic ALS cases matched by age and sex to 122 controls was performed in Brittany from 2006 to 2008. A strong association was found between agricultural activity and ALS (odds ratio: 2.919; p = 0.01), while rural residence itself did not influence the risk of the disease. Bulbar forms of onset prevailed among agricultural workers as compared with other occupations (55 vs. 26%; p = 0.009). These results suggest a potential role of exposure to agricultural chemicals or contact with animals linked to agricultural work. The prevalence of bulbar forms of onset in agricultural workers has not been reported before. In addition to variable methodological approaches, differences in agricultural practices could explain the discrepancy between these findings and other studies.

OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.

Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA 'plus' phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability.

Clinical, electrophysiological and molecular genetic studies in a family with X-linked dominant Charcot-Marie-Tooth neuropathy presenting a novel mutation in GJB1 Promoter and a rare polymorphism in LITAF/SIMPLE.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of neuropathies. In the demyelinating form of Charcot-Marie-Tooth disease with dominant inheritance, five genes have been incriminated: PMP22, MPZ, LITAF/SIMPLE, EGR2 (CMT1A to D), and GJB1 (CMTX). Here, we report clinical, electrophysiological and molecular genetic studies in a family with a Charcot-Marie-Tooth disease variable phenotype, ranging from asymptomatic to moderately affected. The absence of male-to-male transmission as well as the results of systematic electrophysiological studies suggested a CMTX secondary to a GJB1 mutation. Screening for mutations in the coding regions of PMP22, MPZ, EGR2 and GJB1 was negative. We identified (1) a LITAF/SIMPLE substitution (T49M), absent in 1000 control chromosomes, but which was thought to be a polymorphism because of discrepancies of segregation when considering the results of electrophysiology; and (2) a novel substitution T>C in the P2 promoter of GJB1 at position -529, in the SOX10 binding site S2. The transmission of this second mutation was consistent with the electrophysiological data. We emphasise the role of electrophysiological studies that help to discriminate between asymptomatic subjects and that bring some additional valuable data to the genetic approach.

Subjective signs in premotor epilepsy: confirmation by stereo-electroencephalography.

Subjective manifestations inaugurating frontal seizures are less well known than those observed in temporal seizures. We report eleven consecutive patients who underwent surgery for premotor epilepsy. Six of them had focal cortical dysplasia. Ictal symptomatology was analysed to establish electroclinical correlations. The localisation of the epileptogenic zone was assessed by stereoelectroencephalographic studies. Subjective manifestations were described in all cases, more frequently in a sensory rather than an emotional or psychological fashion. Focal seizures limited to subjective features were recorded in two patients. In one, psychological illusions and visual hallucinations were related to the superior frontal sulcus. Another presented isolated paraesthesia in the left arm with the implication of the supplementary motor area. Electrical stimulation of an electrode located in the premotor area evoked isolated subjective manifestations in three other patients. One patient reported sensory manifestations and another, ideational manifestations. Cephalic sensations and emotional manifestations were associated in one case. Subjective manifestations were observed in all patients, and were proved to be related to a discharge restricted to the premotor area in five. These were non-specific signs, but were always the same in a given patient. Spontaneous, isolated sensations and stimulation data tended to be contradictory. This illustrates the complexity of analyzing subjective signs, as well as the complexity of the neuronal networks participating in the propagation of discharges arising in the premotor frontal area.