Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies

doi:10.1016/j.tins.2014.05.006

Trends in Neurosciences

Volume 37, Issue 8, August 2014, Pages 433-442

https://doi.org/10.1016/j.tins.2014.05.006 Get rights and content

Highlights

•
The pathophysiological mechanisms underlying amyotrophic lateral sclerosis (ALS) are multifactorial.
•
Genetic factors and dysfunction of vital molecular pathways underlie ALS pathogenesis.
•
Novel therapeutic approaches have been developed in ALS.

Amyotrophic lateral sclerosis (ALS) is the most frequently occurring of the neuromuscular degenerative disorders, with a median survival time of 3–5 years. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. To date 16 genes and loci have been associated with ALS, with mutations in DNA/RNA-regulating genes including the recently described c9orf72 (chromosome 9 open reading frame 72) gene, suggesting an important role for dysregulation of RNA metabolism in ALS pathogenesis. Further, dysfunction of molecular pathways, including glutamate-mediated excitotoxicity, has been identified in sporadic and familial ALS, indicating the existence of a common pathogenic pathway. These pathophysiological insights have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS.

Section snippets

Advances in ALS

ALS, colloquially known as Lou Gehrig's disease, is a rapidly progressive and universally fatal neurodegenerative disorder of the human motor system, first described in the mid-19th century [1]. Although ALS is heterogeneous in age and site of disease onset, as well as rate of disease progression, clinically ALS is characterized by progressive neurological deterioration and coexistence of upper and lower motor neuron signs, suggesting that ALS is ‘one disease’. Despite the clinical

Clinical features and diagnosis

ALS exhibits a diverse and complex clinical phenotype that is crucial to understanding disease pathophysiology and diagnosis. Clinically, ALS is characterized by the coexistence of upper (UMN) and lower motor neuron (LMN) signs encompassing multiple body regions, with evidence of progressive deterioration [5]. Atypical ALS phenotypes include the ‘pure’ LMN-type progressive muscle atrophy (PMA), ‘pure’ UMN-type primary lateral sclerosis (PLS), and predominant bulbar palsy (PBP). One-third of PMA

ALS pathophysiology

Although the mechanisms underlying ALS pathogenesis remain to be fully elucidated, emerging evidence suggests the importance of genetic factors and dysfunction of vital molecular pathways (Figure 2). A genetic etiology has been identified in up to 20% of apparently sporadic and 60% of familial ALS cases, with at least 16 genes and genetic loci being implicated in ALS pathogenesis [23]. Importantly, these genetic breakthroughs have shed light on the site of disease onset, a controversial aspect

Management of ALS

In the absence of a curative therapy, the management of ALS remains focused on symptom control, with the primary aim of maintaining quality of life (Table 2). Evidence-based management guidelines advise a multidisciplinary model of care, led by a neurologist and clinical nurse consultant working together with physical therapists, occupational therapists, speech pathologists, respiratory physicians, gastroenterologists, psychologists, and social workers to guide patient management. Physical and

Neuroprotection

Although over 30 different therapeutic agents have been investigated in ALS, riluzole has been established as the only effective neuroprotective therapy for ALS, prolonging patient survival by at least 3–6 months, with the beneficial effects of riluzole being most prominent in patients with bulbar-onset disease 74, 81. A potential explanation for therapeutic failure may relate to delay in diagnosis and thereby institution of treatments in later stages of the disease process when these may be

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Trends in Neurosciences

ReviewAdvances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies

Highlights

Section snippets

Advances in ALS

Clinical features and diagnosis

ALS pathophysiology

Management of ALS

Neuroprotection

Neuron

Neuron

Lancet

Lancet Neurol.

Neuron

Neuron

Neuron

Lancet Neurol.

J. Biol. Chem.

Brain Res.

J. Neurol. Sci.

Neuron

Neuron

J. Biol. Chem.

Exp. Neurol.

Neurobiol. Dis.

Exp. Neurol.

Mol. Cell. Neurosci.

Lancet Neurol.

Brain Res. Bull.

Neurobiol. Dis.

Clin. Neurophysiol.

Deux cas d’atrophie musculaire progressive avec lésions de la substance grise et des faisceaux antérolatéraux de la moelle épinière

Arch. Physiol. Norm. Pathol.

Prognosis and epidemiology of amyotrophic lateral sclerosis: analysis of a clinic population, 1997-2011

Neurol. Clin. Pract.

Disease course and prognostic factors of progressive muscular atrophy

Arch. Neurol.

Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS

Neurology

The natural history of primary lateral sclerosis

Neurology

Isolated bulbar phenotype of amyotrophic lateral sclerosis

Amyotroph. Lateral Scler.

Clinical features and associations of 560 cases of motor neuron disease

J. Neurol. Neurosurg. Psychiatry

Incidence of amyotrophic lateral sclerosis in Europe

J. Neurol. Neurosurg. Psychiatry

Dissociated small hand muscle atrophy in amyotrophic lateral sclerosis: frequency, extent, and specificity

Muscle Nerve

Amyotrophic lateral sclerosis. A study of its presentation and prognosis

J. Neurol.

Cramps, muscle pain, and fasciculations: not always benign?

Neurology

Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000

J. Neurol. Neurosurg. Psychiatry

Cause of death and clinical grading criteria in a cohort of amyotrophic lateral sclerosis cases undergoing autopsy from the Scottish Motor Neurone Disease Register

J. Neurol. Neurosurg. Psychiatry

Dyspnea-fasciculation syndrome: early respiratory failure in ALS with minimal motor signs

Amyotroph. Lateral Scler. Other Motor Neuron Disord.

The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study

J. Neurol. Neurosurg. Psychiatry

Are amyotrophic lateral sclerosis patients cognitively normal?

Neurology

Clinical diagnosis and management of amyotrophic lateral sclerosis

Nat. Rev. Neurol.

The overlap of amyotrophic lateral sclerosis and frontotemporal dementia

Neurology

Frontotemporal dementia with amyotrophic lateral sclerosis: a clinical comparison of patients with and without repeat expansions in C9orf72

Amyotroph. Lateral Scler. Frontotemporal Degener.

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

Nat. Rev. Neurol.

P62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS

Acta Neuropathol.

Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis

Ann. Neurol.

hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations

Acta Neuropathol.

TMPyP4 distorts RNA G-quadruplex structures of the disease-associated r(GGGGCC)n repeat of the C9orf72 gene and blocks interaction of RNA-binding proteins

J. Biol. Chem.

TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

Review
Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies