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

Abstract

Hereditary amyotrophic lateral sclerosis (ALS) encompasses a group of genetic disorders characterized by adult-onset loss of the lower and upper motor neuron systems, often with involvement of other parts of the nervous system. Cases of hereditary ALS have been attributed to mutations in 12 different genes, the most common being SOD1, FUS and TARDBP—mutations in the other genes are rare. The identified genes explain 25–35% of cases of familial ALS, but identifying the remaining genes has proved difficult. Only a few genes seem to account for significant numbers of ALS cases, with many others causing a few cases each. Hereditary ALS can be inherited in an autosomal dominant, autosomal recessive or X-linked manner, and families with low disease penetrance are frequently observed. In such families, the genetic predisposition may remain unnoticed, so many patients carry a diagnosis of isolated or sporadic ALS. The only clinical feature that distinguishes recognized hereditary from apparently sporadic ALS is a lower mean age of onset in the former. All the clinical features reported in hereditary cases (including signs of extrapyramidal, cerebellar or cognitive involvement) have also been observed in sporadic cases. Genetic counseling and risk assessment in relatives depend on establishing the specific gene defect and the disease penetrance in the particular family.

Key Points

  • Familial amyotrophic lateral sclerosis (ALS) is frequently underdiagnosed, and apparently sporadic ALS may, in many cases, be familial ALS with reduced disease penetrance

  • A few genes are associated with a substantial proportion of ALS cases, and many others probably contribute to only a few cases

  • Mutations in 12 genes have been found to cause familial ALS, the most common being SOD1, followed by FUS and TARDBP

  • All genes mutated in familial ALS have also been found mutated in patients diagnosed with sporadic ALS and, besides a lower mean age of onset, no clinical difference exists between the two groups

  • No ALS gene has exclusively been associated with an ALS-only motor phenotype, suggesting that ALS is a multisystem neurodegenerative syndrome with a propensity for targeting the motor system

  • Most ALS cases are probably attributable to oligogenic inheritance, perhaps in combination with environmental factors, but monogenic inheritance with a mutation private to each individual is also possible

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Figure 1: Patterns of inheritance in ALS.
Figure 2: Why complex inheritance leads to familial clustering.
Figure 3: Pleiotropy of genes associated with ALS.

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Both authors researched data for the article, made substantial contributions to discussions of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Supplementary information

Supplementary table 1

Frequency of FALS in epidemiological studies (PDF 115 kb)

Supplementary Table 2

Frequency of SOD1 mutations in ALS (PDF 106 kb)

Supplementary Box 1

Guidelines for presymptomatic genetic testing in amyotrophic lateral sclerosis (PDF 88 kb)

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Andersen, P., Al-Chalabi, A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know?. Nat Rev Neurol 7, 603–615 (2011). https://doi.org/10.1038/nrneurol.2011.150

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