Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.

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Molecular biology of amyotrophic lateral sclerosis: insights from genetics.

Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and ...

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EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) : revised report of an EFNS task force

Copper-zinc superoxide dismutase (CuZnSOD, SOD1 protein) is an abundant copper- and zinc-containing protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial intermembrane space of human cells. Its primary function is to act as an antioxidant enzyme, lowering the steady-state concentration of superoxide, but when mutated, it can also cause disease. Over 100 different mutations have been identified in the sod1 genes of patients diagnosed with the familial form of amyotrophic lateral sclerosis (fALS). These mutations result in a highly diverse group of mutant proteins, some of them very similar to and others enormously different from wild-type SOD1. Despite their differences in properties, each member of this diverse set of mutant proteins causes the same clinical disease, presenting a challenge in formulating hypotheses as to what causes SOD1-associated fALS. In this review, we draw together and summarize information from many laboratories about the characteristics of the individual mutant SOD1 proteins in vivo and in vitro in the hope that it will aid investigators in their search for the cause(s) of SOD1-associated fALS.

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Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.

Hereditary amyotrophic lateral sclerosis (ALS) encompasses a group of genetic disorders characterized by adult-onset loss of the lower and upper motor neuron systems, often with involvement of other parts of the nervous system. Cases of hereditary ALS have been attributed to mutations in 12 different genes, the most common being SOD1, FUS and TARDBP-mutations in the other genes are rare. The identified genes explain 25-35% of cases of familial ALS, but identifying the remaining genes has proved difficult. Only a few genes seem to account for significant numbers of ALS cases, with many others causing a few cases each. Hereditary ALS can be inherited in an autosomal dominant, autosomal recessive or X-linked manner, and families with low disease penetrance are frequently observed. In such families, the genetic predisposition may remain unnoticed, so many patients carry a diagnosis of isolated or sporadic ALS. The only clinical feature that distinguishes recognized hereditary from apparently sporadic ALS is a lower mean age of onset in the former. All the clinical features reported in hereditary cases (including signs of extrapyramidal, cerebellar or cognitive involvement) have also been observed in sporadic cases. Genetic counseling and risk assessment in relatives depend on establishing the specific gene defect and the disease penetrance in the particular family.

Clinical genetics of amyotrophic lateral sclerosis: what do we really know?

Toxicity of Familial ALS-Linked SOD1 Mutants from Selective Recruitment to Spinal Mitochondria

OBJECTIVE: Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations.METHODS: Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations.RESULTS: One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease‐associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S59I, V87A, T88ΔTAD, A89T, V97M, S105ΔSL, V118L, D124G, G141X, G147R, I151S) were found, bringing the total number of SOD1 gene mutations in ALS to 105.CONCLUSIO...

Hedvika U. Heinicke

Papers

Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes.

Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis