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Background: The objective of this study was to characterize the prototypical phenotype of patients with amyotrophic lateral sclerosis (ALS) associated with PFN1 mutations in profilin 1 (PFN1) and to determine clinical indications to test for mutations in this gene. Material and methods: The phenotype of three relatives carrying the M114V PFN1 mutation are detailed here and are compared with those of patients with ALS linked to PFN1 previously reported in the literature. Results: In this pedigree and in the literature, the main clinical findings which best describe familial ALS linked to PFN1 might be the following characteristics: pedigrees over five cases, age of onset around 50 years, site of onset systematically lower limbs and the absence of cognitive impairment. Conclusion: First, the infrequent incidence of patients with ALS linked to PFN1 mutation supports the pursuit of a precise characterization of the phenotype linked to PFN1 mutations. Then, the numerous similarities between the phenotype amongst patients linked to SOD1 and PFN1 mutations and between histological features amongst both mice models prompts a review of the current ALS classifications, taking into consideration both phenotype and genotype. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family. Objectives: To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients. Patients and Methods: Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected. Results: Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121G) and one repeat expansion in the C9ORF72 gene. Three patients had abnormal SMN1 copy numbers. Conclusions: While the high proportion of familial history of ALS cases in these ALS-SMA pedigrees could have suggested that these familial clusters of the two most frequent MND rely on a genetic background, we failed to exclude that this occurred by chance. [ABSTRACT FROM AUTHOR]

Although amyotrophic lateral sclerosis (ALS) typically occurs around 60 years, numerous publications report an onset of ALS before the age of 25 years that define juvenile ALS (jALS). Over the last decade, growing literature mentioned jALS with an aggressive evolution which are mainly linked to the FUS gene. We report here the case of a 25-year-old woman with a bulbar onset ALS that progressed in less than 12 months to invasive ventilation due to respiratory failure; Genetic screening identified a new mutation in the FUS gene that lies within the last codon. After reading the literature, it might be legitimate to consider that jALS linked to FUS mutations represent a specific entity different from both classical jALS and adult ALS linked to FUS gene. This should encourage clinician to firstly screen the FUS gene in the presence of a sporadic ALS that occurs before the age of 25 and with an aggressive profile of evolution. [ABSTRACT FROM AUTHOR]

Mutations in the TAR-DNA Binding Protein-43 (TDP-43) encoding the TARDBP gene are present in amyotrophic lateral sclerosis (ALS). TDP-43 is the major component of ubiquitin-positive inclusions in motor neurons in ALS patients. We report here a novel heterozygous missense mutation in TARDBP in an ALS patient presenting a rapid form of ALS. This mutation p.N259S is located within the RNA recognition motif 2 (RRM2) in very close proximity with nucleotides in RNA. It is the first time a mutation was reported in this RRM2 domain of TDP-43. Expression of TDP-43N259S in neuronal cells NSC-34 and in primary cultures of motor neurons was associated with cytoplasmic TDP-43/ubiquitin positive inclusions. Our findings identified for the first time a mutation in ALS in the RRM2 domain of TDP-43, reinforcing the link between this RNA-binding protein, perturbations in RNA metabolism, disruption in protein homeostasis and ALS. [ABSTRACT FROM AUTHOR]