Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The prognostic value of serum neurofilament light chain (sNfL), a biomarker of neurodegeneration, compared to other prognostic factors of amyotrophic lateral sclerosis (ALS) at the time of diagnosis, remains unclear. METHODS: Sera from ALS patients were prospectively collected at the first diagnostic visit in our centre. sNfL levels were determined by single molecule array in 207 ALS patients and in 21 healthy controls. The prognostic value of sNfL was compared with that of other known clinical prognostic factors using a Cox regression model and multivariate analysis. RESULTS: Serum neurofilament light chain levels were higher in ALS patients than in controls (P < 0.0001). Seven parameters were predictive of death in ALS: older age, bulbar onset, higher ALS Functional Rating Scale revised (ALSFRS-R) score, greater weight loss, lower maximal inspiratory pressure, forced vital capacity and higher sNfL levels. A Cox regression model showed that sNfL (P < 0.0001), weight loss (P = 0.040) and site at onset (P = 0.048) were independent predictive factors of death. In a sub-cohort restricted to 139 patients with complete spirometry data, sNfL level (P < 0.005) and forced vital capacity (P = 0.022) were independent factors predictive of death. In a subgroup of 142 patients in whom ALSFRS-R score was available at several time points, sNfL levels positively correlated with ALSFRS-R rate of decline (r = 0.571, P < 10-12 ). CONCLUSIONS: Higher sNfL concentration is a strong and independent prognostic factor of death in ALS as early as the time of diagnosis.

Adult-onset spinal muscular atrophy: An update.

Spinal muscular atrophy (SMA) refers to a group of disorders affecting lower motor neurons. The age of onset of these disorders is variable, ranging from the neonatal period to adulthood. Over the last few years, there has been enormous progress in the description of new genes and phenotypes that throw new light on the molecular pathways involved in motor neuron degeneration. Advances in our understanding of the pathophysiology of the most frequent forms, SMA linked to SMN1 gene mutations and Kennedy disease, has led to the development of therapeutic strategies currently being tested in clinical trials. This report provides a general overview of the clinical features and pathophysiological mechanisms in adult-onset genetic SMA disorders in which the causative gene has been identified (SMN1-related SMA, Kennedy disease, CHCHD10, TRPV4, DYNC1H1 and BICD2). Sporadic lower motor neuron disease, also known as progressive muscular atrophy (PMA), is also discussed. The finding of TDP-43 aggregates in immunohistochemical studies of PMA strongly supports the idea that it is a phenotypic variant of amyotrophic lateral sclerosis (ALS).

Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations.

OBJECTIVE: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. METHODS: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. RESULTS: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). CONCLUSION: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.

Respiratory onset in an ALS family with L144F SOD1 mutation.

Familial amyotrophic lateral sclerosis (FALS) cases linked to SOD1 mutations may sometimes present with unusual clinical features such as pure lower motor neuron involvement or sensory signs. The authors describe a FALS pedigree with the L144F SOD1 mutation in which all cases had respiratory involvement as a first symptom. Although atypical clinical features are not rare in ALS families, this is the first pedigree with respiratory-onset in three affected members. This unusual presentation led to delayed diagnosis in the proband and highlights the fact that respiratory-onset can occur in familial ALS cases carrying SOD1 mutation.

Hypocretinergic dysfunction in neuromyelitis optica with coma-like episodes.

Devic's neuromyelitis optica (NMO) is a severe demyelinating disease of the central nervous system, often misdiagnosed as multiple sclerosis, and involving mainly optic nerves and the spinal cord. We report on a peculiar case of relapsing NMO with severe recurrent dysautonomia and hypersomnia, in which we had the opportunity to observe a dramatic decrease in hypocretin/orexin cerebrospinal fluid level.

[Involuntary motor activity or alien hand syndrome following ischemic lesion sparing medial frontal cortex]. / Activité motrice involontaire ou "alien hand syndrome" à l'issue d'une lésion ischémique respectant le cortex frontal médian.

We report a case of a left alien hand syndrome without grasp reflex, inter-manual conflict or sensory impairement after an infarction involving the striatum, premotor lateral cortex and colossal fibers but sparing medical premotor cortex. According to the location of the lesion, the mechanism underlying this clinical feature might mainly involve cortico-putamino-thalamo-cortical loop which links extrapyramidal system to medial premotor cortex.

[A multivariate analysis approach to antineoplastic and antiviral structure-activity relationships to a series of podophyllotoxins]. / Approche par analyse multivariée des relations structure-activités antitumorale et antivirale dans la série de la podophyllotoxine.

In this work, the authors have used technics of multivariate analysis to determine the structure-activity relationships of 46 podophyllotoxin derivatives and analogs studied for their antineoplastic and antiviral activities. The obtained results allow to envisage the possible synthesis of more specific molecules by making modifications in the structure of the model molecular archetype.