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.
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Approximately 10% of ALS cases are familial with autosomal dominant inheritance of mutations reported in at least 15 genes, including SOD1, TARDBP, FUS, ANG, and OPTN, and an expanded hexanucleotide repeat of GGGGCC in a noncoding region of the C9ORF72 gene.
“Approximately 10% of ALS cases are familial with autosomal dominant inheritance of mutations reported in at least 15 genes, including to name a few SOD1 , TARDBP , FUS , ANG , and OPTN (11, 18, 174, 465), and an expanded hexanucleotide repeat of GGGGCC in a noncoding region of the C9ORF72 gene (140, 497).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [18]
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- Authors
- Andersen, P. M., & Al-Chalabi, A.
- Affiliations
- Umeå University (SE)
- Corresponding author
- Andersen, Peter M.
- ORCID
- Andersen, Peter M.
- Venue
- Nature Reviews Neurology
- Published
- 2011-10-11
- Volume
- 7
- Issue
- 11
- Pages
- 603-615
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- OpenAlex
- W2055456084
- Cited by
- 687
- References
- 4
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 29 · 2023: 28 · 2022: 40 · 2021: 28 · 2020: 41 · 2019: 41 · 2018: 45 · 2017: 55 · 2016: 53 · 2015: 68 · 2014: 65 · 2013: 90 · 2012: 65
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- amyotrophic lateral sclerosis, sporadic ALS, SOD1 mutations, FUS mutations, TARDBP mutations, motor neuron disease, genetic counseling, penetrance, mode of inheritance, age of onset, cognitive engagement, genetic risk prediction
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Humans, Genetic Predisposition to Disease
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