Is it accurate to classify ALS as a neuromuscular disorder?

ABSTRACT

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of upper and lower motor neurons. ALS has traditionally been classified within the domain of neuromuscular diseases, which are a unique spectrum of disorders that predominantly affect the peripheral nervous system. However, over the past decades compounding evidence has emerged that there is extensive involvement of the central nervous system. Therefore, one can question whether it remains accurate to classify ALS as a neuromuscular disorder.

Areas covered

In this review, the authors sought to discuss current approaches toward disease classification and how we should classify ALS based on novel insights from clinical, imaging, pathophysiological, neuropathological and genetic studies.

Expert opinion

ALS exhibits the cardinal features of a neurodegenerative disease. Therefore, classifying ALS as a neuromuscular disease in the strict sense has become untenable. Diagnosing ALS however does require significant neuromuscular expertise and therefore neuromuscular specialists remain best equipped to evaluate this category of patients. Designating motor neuron diseases as a separate category in the ICD-11 is justified and adequately deals with this issue. However, to drive effective therapy development the fields of motor neuron disease and neurodegenerative disorders must come together.

KEYWORDS:

• Amyotrophic lateral sclerosis (ALS)
• frontotemporal dementia (FTD)
• TDP-43
• neurodegeneration

Article highlights

• ALS is disorder characterized by the loss upper and lower motor neurons. The diagnosis is made by exclusion, which means that alternative causes for lower motor neuron dysfunction (other neuromuscular diseases) need to be ruled out. Hence, ALS patients are commonly seen by neuromuscular specialist.

• Frontotemporal dementia as well as cognitive and behavioral changes within the FTD spectrum are common in ALS and is seen in up to 50% of cases. Many now view ALS and FTD as the phenotypic extremes of a continuum (FTD-MND continuum).

• Aggregation and mislocalization of TDP-43 is the pathological hallmark of ALS.

• The genetic architecture of ALS is highly heterogeneous. Over 30 different genes have now been implicated in ALS, many of which are pleiotropic and are also involved in other neurodegenerative diseases such as FTD, parkinsonism, spinocerebellar ataxia and HSP.

• Current insights from clinical, imaging, neuropathological and genetic studies show that ALS exhibits the cardinal features of a neurodegenerative disease.

• Due to the highly heterogeneous nature of ALS, it seems highly unlikely that we will be able to treat the disease with a single drug. Multiple targeted therapies will need to be developed.

Declaration of interest

MA Van Es received grants from the Netherlands Organization for Health Research and Development (Veni scheme), The Thierry Latran foundation, Motor Neurone Disease Association (MNDA), FIGHT-MND, the Netherlands ALS foundation (Stichting ALS Nederland), the EU Joint Programme —Neurodegenerative Disease Research (JPND), has received travel grants from Shire (formerly Baxalta), consulted for Biogen and currently serves on the ethical review board at the UMC Utrecht, The Netherlands. LH Van den Berg reports grants from Netherlands ALS Foundation, the Netherlands Organization for Health Research and Development (Vici scheme), the Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project), funded through the EU Joint Programme—Neurodegenerative Disease Research, JPND), served on the Scientific Advisory Board of Biogen, Cytokinetics, Prinses Beatrix SpierFonds, and the Latran Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.