Genetics of amyotrophic lateral sclerosis: A review

doi:10.1016/j.jns.2019.02.030

Journal of the Neurological Sciences

Volume 399, 15 April 2019, Pages 217-226

https://doi.org/10.1016/j.jns.2019.02.030 Get rights and content

Highlights

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Familial amyotrophic lateral sclerosis (FALS) represents <10% of the total ALS patients.
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FALS are mainly due to the mutations of four genes: C9ORF72, SOD1, FUS and TDP-43.
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The increased number of genes has clearly contributed to a better understanding of the pathophysiology of ALS.
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This increased number of genes also risk to led to difficulties to their classification.
•
Gene therapy is probably a therapeutic way to explore in ALS.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor pathways, invariably leading to death within a few years of onset. Most cases of ALS are sporadic, but familial forms of the disease (FALS) constitute 10% of the cases. Since the first identification of a causative gene in the 1990s and with recent advances in genetics, more than twenty genes have now been linked to FALS. This increased number of genes led to a tremendous amount of research, clearly contributed to a better understanding of the pathophysiology of this disorder, and paved the way for the development of new therapeutics and new hope for this fatal disease.

Introduction

Amyotrophic lateral sclerosis (ALS) has become a well-identified disease since the end of the 19th century, but its pathogenesis is still poorly understood despite the considerable efforts made in recent years [1]. Although the global incidence of ALS has tended to increase slightly over the years, especially in Western societies (probably in part due to the progressive aging of the population), ALS remains rare; its incidence is estimated to be 2–3 per 100,000 individuals in Europe and 0.7–0.8 per 100,000 individuals in Asia [2]. This neurodegenerative disorder is usually fatal within 2–5 years [3], with an estimated worldwide mortality of 30,000 patients a year [1]. The mean age of onset is 65, even if younger patients may be affected [4]. Primarily affecting the motor pathways, ALS is characterized by a combination of both upper and lower motor neuron degeneration [5]. Nevertheless, non-motor signs may also be associated with this disorder (cognitive dysfunction, frontotemporal dementia, extrapyramidal features, etc.), so ALS is currently widely regarded as a multisystem degeneration [6]. Moreover, several clinical variants of the disease are still known under the term ‘ALS’, broadening the phenotypical spectrum of the disease [5].

Our knowledge about ALS has progressively increased over the years, though no unifying hypotheses for its pathogenesis have emerged thus far. Most cases of ALS are sporadic (SALS), but a few have clearly been classified as ‘familial ALS’ (FALS) due to the identification of some causative genes over the three last decades. Many new pathophysiological concepts have emerged from the study of these genetic forms, and new therapeutic perspectives have appeared.

Section snippets

Genetics and amyotrophic lateral sclerosis: an old concept

In the middle of the 19th century, some authors, such as Jean Cruveilhier (1791–1874) [7] and Jacob Augustus Lockhart Clarke (1817–1880) [8], elaborated on the concept of ‘progressive muscular atrophy’. In relation to this clinical syndrome, some cases have been identified as having degeneration of the anterior horn of the spinal cord, corresponding to ‘amyotrophic lateral sclerosis’, a neurodegenerative disorder that was finally fully clinicopathologically described by Jean-Martin Charcot

Recent knowledge of the genetics of ALS

Although most cases of ALS are sporadic, FALS may represent 5–10% of the total number of the ALS cases. However, this prevalence may be underestimated (due to the variable definitions used), with not always a clear delineation between clinically defined FALS and SALS. If large-scale genetic screening becomes more accessible and increasingly more available in routine clinical practice, the genetic diversity and complexity of ALS still forces clinicians to refer to specific genetic testing and to

Genes most frequently implicated in familial amyotrophic lateral sclerosis

All the genes implicated in FALS are mentioned in Table 1 and Table 2. The localization of the targets (proteins) of the main causative genes of FALS appears in Fig. 1.

Are there genetic susceptibility factors in amyotrophic lateral sclerosis?

As many causative genes of ALS have been identified, other genes seem to be involved in ALS susceptibility. The first example was given in 2010 of ATXN2, encoding the ataxin-2 protein. As TDP-43, ataxin-2 is mislocalized in the neurons of ALS patients. High-length polyglutamine (polyQ) expansions (>34 Qs) in ATXN2 cause spinocerebellar ataxia type 2 (SCA2) [104] and rarely familial parkinsonism [105], whereas intermediate-length polyQ expansions (27–33) represent a genetic risk factor for

Challenges for the classification of genetic forms of amyotrophic lateral sclerosis

Because FALS may sometimes be apparent SALS, the term ‘inherited ALS’ is probably more appropriate than ‘FALS’. >30 forms of inherited ALS have been identified so far (Table 1), and additional genes remain to be discovered in the future. Since the first gene was identified in 1993 (SOD1), FALS has been renamed as ‘ALS’ associated with a number (ALS1, ALS2, etc), and the last number used currently is ‘23’ (OMIM), while some genes have no clear denomination yet (DAO, etc.). Initially, only

Gene therapy: a therapeutic way to explore in amyotrophic lateral sclerosis?

The emergence of multidisciplinary, specialized ALS clinics has increased both the quality of life and the survival of ALS patients, respiratory management through early non-invasive ventilation being probably one of the most important determinants of survival; however, there is still no curative treatment for ALS patients [5]. Gene therapy approaches, including antisense oligonucleotides (ASOs) and viral-directed gene delivery, have shown enormous potential to enable therapeutic modulation of

Conclusions

ALS is an old but mysterious disease that is sporadic in most cases. FALS has been observed for many decades, with currently more than thirty causative genes having been discovered. Even if inherited forms of ALS represent only 10% of ALS cases, genetic advances contribute to a better understanding of the pathophysiology of the disease, leading to new potential treatments in the future for this neurodegenerative disorder, which is still fatal. Based on the recent successes observed in spinal

Competing interests

The authors declare that they have no competing interests.

Funding

For the remaining authors (SM, CG, AS, JMV and GLM), none were declared.

Acknowledgements

We thank Mrs Jackie Stewart for the design of the Figure 1.

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Review ArticleGenetics of amyotrophic lateral sclerosis: A review

Highlights

Abstract

Introduction

Section snippets

Genetics and amyotrophic lateral sclerosis: an old concept

Recent knowledge of the genetics of ALS

Genes most frequently implicated in familial amyotrophic lateral sclerosis

Are there genetic susceptibility factors in amyotrophic lateral sclerosis?

Challenges for the classification of genetic forms of amyotrophic lateral sclerosis

Gene therapy: a therapeutic way to explore in amyotrophic lateral sclerosis?

Conclusions

Competing interests

Funding

Acknowledgements

Lancet Neurol.

Lancet.

Neuron.

Neuron.

Prog. Neurobiol.

Adv. Biol. Regul.

Neurobiol. Dis.

J. Biol. Chem.

Neuron.

Cell.

Lancet Neurol.

Cell Rep.

Neuroimage.

Lancet Neurol.

Genomics.

Curr. Biol.

J. Biol. Chem.

Am. J. Hum. Genet.

Neuron.

ALS clinical trials review: 20 years of failure. Are we any closer to registering a new treatment?

Front. Aging Neurosci.

Amyotrophic lateral sclerosis

Nat. Rev. Dis. Primers.

Management and therapeutic perspectives in amyotrophic lateral sclerosis

Expert. Rev. Neurother.

Amyotrophe Lateralsklerose. Eine Multisystemdegeneration

Nervenarzt

Sur la paralysie musculaire progressive atrophique

Arch. Gen. Med.

An important case of paralysis and muscular atrophy with disease of the nervous centres

Brit. Foreign. Med. Chir. Rev.

De la sclérose latérale amyotrophique

Progr. Med

Amyotrophic lateral sclerosis; fifty cases observed on Guam

J. Nerv. Ment. Dis.

Epidemiologic investigations of amyotrophic lateral sclerosis. 2. Familial aggregations indicative of dominant inheritance. I

Neurology

Epidemiologic investigations of amyotrophic lateral sclerosis. 2. Familial aggregations indicative of dominant inheritance. II

Neurology

Amyotrophische Lateralsklerose. Klinisch-pathologische und genetisch-demographische Studie

Etude clinique et évolutive de 125 cas de sclérose latérale amyotrophique

Presse Med.

Hereditary amyotrophic lateral sclerosis transmitted for five generations

Clin. Genet.

An inherited disease similar to amyotrophic lateral sclerosis with a pattern of posterior column involvement. An intermediate form?

Brain

Prognosis in hereditary amyotrophic lateral sclerosis

Arch. Neurol.

Chronic progressive disorders of the lower motor neuron

The central nervous system in motor neurone disease

J. Neurol. Neurosurg. Psychiatry

Familial amyotrophic lateral sclerosis: features of multisystem degeneration

Acta Neuropathol.

Amyotrophic lateral sclerosis. Clinicopathological studies of a family

Arch. Neurol.

Anatomische Untersuchung eines Falles von amyotrophischer Laterosklerose

Neurol. Centralblatt.

Presenile dementia with motor neuron disease in Japan. A new entity?

Arch. Neurol.

Classic amyotrophic lateral sclerosis with dementia

Arch. Neurol.

Etude clinique des formes familiales de sclérose latérale amyotrophique. Revue de la littérature

Rev. Neurol. (Paris)

Familial motor neuron disease. Evidence for at least three different types

Neurology

Review Article
Genetics of amyotrophic lateral sclerosis: A review