Abstract
Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, affecting the upper and/or lower motor neurons. However, extramotor symptoms can also occur; cognitive deficits are present in more than 40% of patients and 5–8% of ALS patients develop frontotemporal dementia. There is no effective treatment for ALS and median survival is 2–3 years after onset.Amyotrophic lateral sclerosis is a genetically heterogeneous disorder with monogenic forms as well as complex genetic etiology. Currently, complex genetic risk factors are of minor interest for routine diagnostic testing or counseling of patients and their families. By contrast, a monogenic cause can be identified in 70% of familial and 10% of sporadic ALS cases. The most frequent genetic cause is a noncoding hexanucleotide repeat expansion in the C9orf72 gene. In recent years, high-throughput sequencing technologies have helped to identify additional monogenic and complex risk factors of ALS.Genetic counseling should be offered to all ALS patients and their first- and possibly second-degree relatives, and should include information about the possibilities and limitations of genetic testing. Routine diagnostic testing should at least encompass the most frequently mutated disease genes (C9orf72, SOD1, TDP-43, FUS). Targeted sequencing approaches including further disease genes may be applied. Caution is warranted as the C9orf72 repeat expansion cannot be detected by routine sequencing technologies and testing by polymerase chain reaction (PCR) is failure-prone.Predictive testing is possible in families in which a genetic cause has been identified, but the limitations of genetic testing (i. e., the problems of incomplete penetrance, variable expressivity and possible oligogenic inheritance) have to be explained to the families.
Highlights
Introduction and clinical aspectsAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the upper and lower motor neurons
The initial presentation varies between patients, depending on the affected motor neurons
Muscle paresis of the limbs is seen in spinal-onset disease (>75% of patients), whereas dysarthria is usually the first symptom in patients with bulbar onset
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the upper and lower motor neurons. The initial presentation varies between patients, depending on the affected motor neurons. Regarded as distinct diseases, both primary lateral sclerosis (PLS), which affects only upper motor neurons, and progressive muscular atrophy (PMA), which affects only lower motor neurons, are nowadays considered variants of ALS [27]. According to the revised Escorial criteria, diagnosis relies onthe identification of upper and lower motor neuron signs in clinical, electrophysiological, and neuropathological examinations, as well as the progressive spread of signs, whereas differential diagnoses are excluded [27]. This review gives an overview of the most frequently as well as newly identified monogenic causes as well as genetic risk factors of ALS and will discuss ALS-specific aspects of genetic counseling of patients and their families. AD autosomal-dominant, AR autosomal-recessive, DN de novo, XL X-linked, NA not available
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
