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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]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons. Mutations in the SOD1 gene encoding the superoxide dismutase 1 are present in 15% of familial ALS cases and in 2% of sporadic cases. These mutations are associated with the formation of SOD1-positive aggregates. The mechanisms of aggregation remain unknown, but posttranslational modifications of SOD1 may be involved. Here, we report that NSC-34 motor neuronal cells expressing mutant SOD1 contained aggregates positive for small ubiquitin modifier-1 (SUMO-1), and in parallel a reduced level of free SUMO-1. CLEM (correlative light and electron microscopy) analysis showed nonorganized cytosolic aggregates for all mutations tested (SOD1A4V , SOD1V31A , and SOD1G93C ). We next show that preventing the SUMOylation of mutant SOD1 by the substitution of lysine 75, the SUMOylation site of SOD1, significantly reduces the number of motor neuronal cells with aggregates. These results support the need for further research on the SUMOylation pathways, which may be a potential therapeutic target in ALS. [ABSTRACT FROM AUTHOR]

Mutations in the SOD1 gene encoding the Cu/Zn superoxide dismutase-1 protein are responsible for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. To date a large number of mutations have been reported in SOD1, but only few of them have been studied and validated by functional studies. We present a novel mutation in SOD1 in a female suffering from slowly progressive ALS. This dominant mutation (c.365A > G) in exon 5 resulted in a substitution of a highly conserved amino acid (p.E121G) of the protein. Functional studies in the motor neuronal cell line NSC34 and in primary culture of mouse motor neurons revealed that this mutation p.E121G induced aggregates positive for SOD1 and ubiquitin, as well as reduced cell viability. These findings identified a novel causal mutation in ALS in close proximity with one of the three histidine residues (H120) of SOD1 interacting with copper. [ABSTRACT FROM AUTHOR]

More than 40 human diseases, mainly diseases affecting the central nervous system, are caused by the expansion of unstable nucleotide repeats. Repeats of sequences like (CAG) n present in different genes can be responsible for various diseases of the central nervous system. An expanded hexanucleotide repeat (GGGGCC) n in the C9ORF72 gene has been characterized as the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar dementia. In this study, we performed a genome-wide analysis in the human genome and identified 74 genes containing this precise hexanucleotide repeat, with a preference for a location in exon 1 or intron 1, similar to the C9ORF72 gene. A total of 36 of these 74 genes may be of interest as candidates in neurodevelopmental or neurodegenerative diseases, based on their function. • Presence of hexanucleotide repeats in many genes in the human genome. • Genes already involved in neurological diseases and with hexanucleotide repeats. • Repeats in genes involved in ion transmembrane transport, calcium ion import, membrane depolarization, and ubiquitin pathway. [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.

The SOD1 gene encoding the superoxide dismutase 1 (SOD1) protein is mutated in approximately 15% of familial amyotrophic lateral sclerosis (ALS) and 3% of sporadic ALS. We identified a novel mutation in SOD1 in a man who presented at age 49 with lower limb stiffness, and at age 53, a spastic paraparesia with distal muscular atrophy in the lower limbs and fasciculations in the quadriceps. A diagnosis of ALS was established. Eleven years after disease onset his condition continues gradually and slowly to deteriorate. The heterozygous mutation observed in exon 2 resulted in a valine to alanine substitution at position 31 in the β-barrel domain of the SOD1 protein. Functional analysis in NSC34 cells showed that the overexpression of the mutant form of SOD1(V31A) induced aggregates and decreased cell viability. This mutation is located outside of the regions carrying most of the ALS-related mutations (i.e., the catalytic center, the region of dimerization, and the loops between the β-strands of the β-barrel). In conclusion, we identified a novel SOD1 mutation in a patient with slow disease progression and supported the idea that different SOD1 mutations can lead to distinct ALS phenotypes., (Copyright © 2013 Elsevier Inc. All rights reserved.)