Since its description by Charcot more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis has remained a mystery. Modern genetics has now identified mutations in two genes — SOD1 and ALS2 — as primary causes of the disease, and has implicated others as potential contributors. Insights into these abnormalities, together with errors in the handling of synaptic glutamate and the potential excitotoxic response that this alteration provokes, have provided leads for the development of new strategies to identify an as yet elusive remedy for this progressive, fatal disorder.

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From charcot to lou gehrig: deciphering selective motor neuron death in als

Considerable progress has been made in unraveling the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease and the third most common neurodegenerative disease overall. Here we review genes implicated in the pathogenesis of motor neuron degeneration and how this new information is changing the way we think about this fatal disorder. Specifically, we summarize current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1, and evaluate the information being gleaned from genome-wide association studies. We also outline emerging themes in ALS research, such as next-generation sequencing approaches to identify de novo mutations, the genetic convergence of familial and sporadic ALS, the proposed oligogenic basis for the disease, and how each new genetic discovery is broadening the phenotype associated with the clinical entity we know as ALS.

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State of play in amyotrophic lateral sclerosis genetics.

Superoxide anion radical (O2-.), superoxide dismutases, and related matters.

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 ...

/pdf/efns-guidelines-on-the-clinical-management-of-amyotrophic-23ryvnse4m.pdf

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

We describe 36 patients (six were apparently sporadic cases and 30 were cases from nine families) with amyotrophic lateral sclerosis (ALS) characterized by a distinct phenotype associated with homozygosity for an Asp90Ala mutation in the CuZn-superoxide dismutase gene. The presenting motor manifestation in all patients was paresis in the legs, with slow progression to the upper extremities and finally to the bulbar muscles. The age of ALS onset varied from 20 to 94 years, with a mean of 44 years. Mean survival time was 13 years for the 11 deceased patients. However, this is probably biased and untypical (low) when compared with the disease duration in the surviving patients, and when considering other medical complications in the deceased patients. The rate of progression was highly variable, even within families. All patients showed signs of involvement of both upper and lower motor neurons. Other neurological features included painful muscle spasms and paraesthesiae in the lower extremities. Two-thirds of patients experienced difficulty with micturition. Electrophysiological studies confirmed the slow progression and spatial distribution of clinical symptoms in the peripheral motor system. Furthermore, [corrected] potentials evoked by transcranial magnetic stimulation (MEP) were compared with those evoked by cervical or lumbosacral electrical stimulation and often revealed marked slowing of transmission in central motor pathways. In Sweden and Finland ALS patients homozygous for the Asp90Ala mutation constitute a phenotypically characteristic subset of motor neuron disease.

/pdf/autosomal-recessive-adult-onset-amyotrophic-lateral-4cbilergmr.pdf

Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients

I Tarvainen

Papers

Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients