Elsevier

The Lancet Neurology

Volume 12, Issue 3, March 2013, Pages 310-322
The Lancet Neurology

Review
Controversies and priorities in amyotrophic lateral sclerosis

https://doi.org/10.1016/S1474-4422(13)70036-XGet rights and content

Summary

Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.

Introduction

In the autumn of 2011, a monumental discovery changed the way we understand amyotrophic lateral sclerosis (ALS). Some 150 years after Charcot provided the first description of ALS, a genetic variant was discovered that meant neuroscientists must revisit what they knew, or think they knew, about the disorder. Understanding of the cause of this therapeutically resistant neurodegenerative disorder has entered a new phase with the discovery of linkage to an expansion of an intronic hexanucleotide repeat in the previously unknown gene C9orf72.1, 2 At the most basic level, this breakthrough provides incontrovertible evidence that ALS and frontotemporal dementia are manifestations of a clinicopathological spectrum. Most tantalising however is the emergence of a unifying pathogenic theme of nuclear protein mishandling in ALS. The apparent RNA binding function of the C9orf72 expansion adds to known mutations in other key RNA-processing and proteosomal genes linked to ALS, notably the transactive-region DNA-binding protein gene TARDBP,3 the fused in sarcoma gene FUS (also known as translocated in liposarcoma, TLS),4 and the ubiquilin-2 gene UBQLN2,5 whose proteins are widely expressed in human cells, with fundamental physiological roles.

The recent C9orf72 genetic breakthrough further reinforces the concept that ALS pathogenesis involves multiple pathways.6 To date, models of disease have largely centred around mutant superoxide dismutase-1 (SOD1), discovered 20 years ago7 (figure 1). This genetic discovery heralded development of the first animal model of ALS,8 and the availability of a coherent strategy for development of successful therapy. Recent seminal findings including a recognition of the importance of TDP-43 deposition in most forms of ALS and some forms of frontotemporal dementia,9 although not in SOD1-related disease,9 and the likely role of RNA dysregulation in disease pathogenesis, suggest that translation of findings from the SOD1 model to benefit patients living with ALS might be more restricted than previously thought. Fundamental aspects of ALS, not least its striking clinical heterogeneity, still puzzle clinicians as much now as at the turn of the 20th century and remain the subject of debate. The juxtaposition of the new and exciting discovery of a major ALS gene, with the emergent problems in the translation of findings from the SOD1 mouse model, provided the backdrop to our debate, held as part of the 22nd International Symposium on ALS/MND with the specific aim of highlighting areas that with future research and prioritisation might lead to the development of treatments. To better guide this therapeutic potential, we considered the clinical scope of ALS, dealing with concepts of heterogeneity, while also dissecting arguments concerning focality of disease onset, methods to identify patterns of disease spread, and predictors of prognosis, with implications for the design of future clinical trials. Recent genetic discoveries and controversies concerning heritability and the current models of ALS were incorporated into the discussion, in the context of emergent technology, with consideration of priorities for future ALS research.

Section snippets

Has the concept of ALS as one disease become untenable?

From a clinical viewpoint, ALS has been identified by most neurologists as a single entity because it characteristically involves a recognised pattern of progressive motor neuronopathy, with respiratory failure as the mode of death for most patients. This core phenotype is confidently diagnosed by an experienced clinician when progression is rapid, although the mean diagnostic delay has stubbornly remained around 1 year from symptom onset,10 reflecting the reality of more slowly progressing

Should ALS even be regarded as a neuromuscular disease?

Many ALS physicians are also specialists in neuromuscular disease, and the characteristic presence of progressive muscle wasting, weakness, and fasciculations clearly reflects degeneration of anterior horn cells and lower motor neurons. The electromyogram is an adjunct to clinical evaluation, and the Awaji criteria, based on features of denervation and reinnervation, have recently been established as a useful diagnostic aid.32 However, as originally recognised by Charcot, corticospinal tract

Can apparently sporadic ALS be inherited?

In populations of European origin, only 5–10% of patients with ALS report a family history of the disease (figure 2). It seems likely that there is a complex set of genetic determinants, each with potentially small but significant effect.15 Standard practice has been to reassure patients without an apparent family history of ALS. However, early studies of the C9orf72 hexanucleotide repeat expansion suggest that the repeat expansion is also present in a sizeable minority of apparently sporadic

Is there a premorbid phenotype that reflects vulnerability to ALS?

Despite conflicting results regarding premorbid athleticism from case-control studies,62, 63 a clinical impression remains that patients who develop ALS frequently have a higher than average level of physical activity or fitness, perhaps best exemplified by the American baseball player Lou Gehrig. Whether the findings of reduced coronary artery disease premorbidly in patients with ALS,64 and a cardioprotective vascular profile of patients65 and their first degree relatives,66 are significant in

When does ALS begin?

Longitudinal studies in presymptomatic individuals carrying pathogenic SOD1 mutations have shown apparently abrupt changes in both lower motor neuron loss76 and the development of cortical hyperexcitability77 within a year of symptom onset. Whether the nervous system of people who later develop ALS was normal immediately before disease onset or whether, like in Alzheimer's and Parkinson's diseases, a more prolonged presymptomatic phase of disease might have been detectable, seems uncertain. In

How does ALS spread?

Typically, ALS has a striking focal clinical presentation, although this view must be interpreted with the understanding that most biological systems have a degree of redundancy and also in view of emerging data covering presymptomatic changes. For example, at least a third of muscle fibres have already been lost before clinical wasting occurs in ALS.81 Nonetheless, post-mortem studies suggest that the pathological changes in ALS radiate from an area in which maximum upper motor neuron and

How can the course of ALS be predicted and the design of therapeutic clinical trials improved?

Prediction of the rate of progression in a heterogeneous disorder such as ALS has clear value in care-planning, but also in the assessment of potential therapeutic agents. Typical inclusion criteria for therapeutic trials have tended to be based on time from symptom onset (typically with a cutoff less than 3 years) and a minimum level of respiratory function as measured by vital capacity. Within only these criteria there will inevitably be a wide range of prognoses, thereby greatly reducing

Has the SOD1 mouse model outlived its usefulness?

The transgenic mouse model overexpressing SOD1 contains multiple copies of mutant human DNA. The model has been used extensively to dissect the likely pathogenic mechanisms of mutant SOD1 and to evaluate the possible benefits of new therapeutic agents. There has been a disappointing lack of drugs that meaningfully affect disease progression in the model and also in the translation of any modest disease-delaying benefits from mouse to human ALS. The repeated failures of phase 2 and 3 trials in

Novel approaches to understanding of ALS pathogenesis

The cost of whole-genome sequencing is falling exponentially to a level that will soon make this approach feasible for a large number of patient samples. An internationally collaborative approach to sequence whole genomes from large cohorts of well characterised patients with ALS seems the next logical step. As a result, the characterisation of the genetic architecture of ALS might soon be complete, but is likely to be only the first step towards identification of key pathways amenable to

Conclusion

The enormous advances in scientific research during the past two decades have revealed the complexity of ALS pathogenesis (figure 3), which might have been underestimated at the time of the discovery of SOD1. Developments in molecular biology, particularly the discovery of C9orf72, when combined with new approaches in clinical neurophysiology and neuroimaging have accentuated rather than lessened the importance of detailed clinical assessment. The multiple pathogenic processes support the view

Search strategy and selection criteria

We searched PubMed (1966, to Dec 31, 2012), Embase (1980, to Dec 31, 2012), and the Cochrane Library using the search terms “amyotrophic lateral sclerosis” or “motor neuron disease” in combination with “diagnosis”, “epidemiology”, “fronto-temporal dementia”, “imaging”, “neurophysiology”, “management”, and “neuroprotection”. Further articles were included from reference lists, review articles, and major textbook chapters. Abstracts and reports from relevant meetings were also included. The final

References (123)

  • TH Bak et al.

    What wires together dies together: verbs, actions and neurodegeneration in motor neuron disease

    Cortex

    (2012)
  • M Polymenidou et al.

    The seeds of neurodegeneration: prion-like spreading in ALS

    Cell

    (2011)
  • J Sreedharan et al.

    TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

    Science

    (2008)
  • C Vance et al.

    Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6

    Science

    (2009)
  • HX Deng et al.

    Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia

    Nature

    (2011)
  • JD Rothstein

    Current hypotheses for the underlying biology of amyotrophic lateral sclerosis

    Ann Neurol

    (2009)
  • DR Rosen et al.

    Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

    Nature

    (1993)
  • M Neumann et al.

    Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

    Science

    (2006)
  • JD Mitchell et al.

    Timelines in the diagnostic evaluation of people with suspected amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)—a 20-year review: can we do better?

    Amyotroph Lateral Scler

    (2010)
  • MR Turner et al.

    Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990–2002

    J Neurol Neurosurg Psychiatry

    (2003)
  • A Chio et al.

    Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study

    J Neurol Neurosurg Psychiatry

    (2011)
  • BR Brooks et al.

    El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis

    Amyotroph Lateral Scler Other Motor Neuron Disord

    (2000)
  • BJ Traynor et al.

    Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study

    Arch Neurol

    (2000)
  • PM Andersen et al.

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

    Nat Rev Neurol

    (2011)
  • T Juneja et al.

    Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase

    Neurology

    (1997)
  • D Baumer et al.

    Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations

    Neurology

    (2010)
  • A Chio et al.

    Extensive genetics of ALS: a population-based study in Italy

    Neurology

    (2012)
  • IR Mackenzie et al.

    Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations

    Ann Neurol

    (2007)
  • S Al-Sarraj et al.

    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

    (2011)
  • J Phukan et al.

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

    J Neurol Neurosurg Psychiatry

    (2012)
  • M Elamin et al.

    Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia

    Neurology

    (2011)
  • J Raaphorst et al.

    Cognitive dysfunction in lower motor neuron disease: executive and memory deficits in progressive muscular atrophy

    J Neurol Neurosurg Psychiatry

    (2011)
  • GM Grace et al.

    Neuropsychological functioning in PLS: a comparison with ALS

    Can J Neurol Sci

    (2011)
  • PH Gordon et al.

    The natural history of primary lateral sclerosis

    Neurology

    (2006)
  • J Visser et al.

    The history of progressive muscular atrophy: syndrome or disease?

    Neurology

    (2008)
  • RM Van den Berg-Vos et al.

    A long-term prospective study of the natural course of sporadic adult-onset lower motor neuron syndromes

    Arch Neurol

    (2009)
  • CE Pringle et al.

    Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria

    Brain

    (1992)
  • S Vucic et al.

    Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis

    J Neurol Neurosurg Psychiatry

    (2007)
  • NK Iwata et al.

    White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis

    Brain

    (2011)
  • J Costa et al.

    Awaji criteria for the diagnosis of amyotrophic lateral sclerosis: a systematic review

    Arch Neurol

    (2012)
  • SM Chou et al.

    Amyotrophic lateral sclerosis: lower motor neuron disease spreading to upper motor neurons

    Muscle Nerve

    (1993)
  • M Dadon-Nachum et al.

    The “dying-back” phenomenon of motor neurons in ALS

    J Mol Neurosci

    (2010)
  • A Eisen et al.

    Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron?

    Muscle Nerve

    (1992)
  • A Eisen

    Amyotrophic lateral sclerosis—evolutionary and other perspectives

    Muscle Nerve

    (2009)
  • O Sporns

    The human connectome: a complex network

    Ann NY Acad Sci

    (2011)
  • SM Smith et al.

    Correspondence of the brain's functional architecture during activation and rest

    Proc Natl Acad Sci USA

    (2009)
  • G Douaud et al.

    Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis

    Brain

    (2011)
  • E Verstraete et al.

    Impaired structural motor connectome in amyotrophic lateral sclerosis

    PLoS One

    (2011)
  • S Byrne et al.

    Absence of consensus in diagnostic criteria for familial neurodegenerative diseases

    J Neurol Neurosurg Psychiatry

    (2012)
  • MF Hanby et al.

    The risk to relatives of patients with sporadic amyotrophic lateral sclerosis

    Brain

    (2011)
  • Cited by (421)

    View all citing articles on Scopus
    View full text