Amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis is a progressive, adult-onset neurodegenerative motor-neuron disorder. Both upper and lower motor neurons undergo degeneration. Mean age at onset is approximately 55 years in males and the mid-60s in females, with the overall range extending from
childhood to the ninth decade. Early clinical manifestations are heterogeneous: affected individuals most often present with asymmetric focal weakness of the extremities (stumbling, poor handgrip) or with bulbar findings (dysarthria, dysphagia). Disease progression involves spread to additional
motor regions, with worsening limb weakness, dysarthria, dysphagia and ultimately respiratory compromise; the clinical course shows considerable inter- and intrafamilial variability in age at onset and rate of progression. Cognitive and behavioural changes within the frontotemporal spectrum are reported in up to 45% of affected individuals during the course of illness, ranging from mild executive dysfunction to overt frontotemporal dementia.

The estimated incidence in Europe is approximately 2.1 to 3.8 per 100 000 person-years. Approximately 10% of cases occur in a familial context; the remainder are apparently sporadic.

ALS is genetically heterogeneous, with pathogenic variants in more than 30 genes implicated. The most frequently identified causative genes are C9orf72 (a noncoding hexanucleotide repeat expansion, 39-45% of familial cases and 3-7% of apparently sporadic cases), SOD1 (15-20% of familial cases), FUS (4-8%) and TARDBP (1-4%). Approximately 10% of affected individuals have a positive family history; the identified ALS genes account for at least half of familial cases, with a smaller proportion of apparently sporadic cases attributable to known germline pathogenic variants.

Familial ALS is most commonly inherited in an autosomal dominant manner. Anticipation has been suggested for C9orf72-related ALS/frontotemporal dementia, with reports of earlier age at onset in successive generations and intergenerational increases in repeat size, although ascertainment bias and incomplete characterisation of expansion-size-to-onset relationships leave the magnitude incompletely defined.

Diagnosis rests on clinical recognition of combined upper- and lower-motor-neuron involvement. The revised establish the clinical diagnosis when defined regional combinations of upper- and lower-motor-neuron signs are documented; the and the revised for the ALS-frontotemporal-spectrum disorder supplement this framework. Electromyography demonstrates electrophysiologic evidence of lower-motor-neuron involvement in clinically affected and clinically uninvolved regions; neuroimaging excludes alternative structural disease.

Main differential diagnoses include:

• Spinal and bulbar muscular atrophy (Kennedy disease): X-linked, slowly progressive lower-motor-neuron disorder in males, without upper-motor-neuron or sensory involvement; AR
• : autosomal recessive proximal weakness without upper-motor-neuron involvement, second-to-third-decade onset; SMN1
• Primary lateral sclerosis: slowly progressive, pure upper-motor-neuron syndrome with little or no lower-motor-neuron involvement; ALS2

• Establishing the diagnosis by identifying the underlying pathogenic variant, which confirms the clinical suspicion at the molecular level.
• Enabling specific and individualised clinical management based on the molecular diagnosis, which provides the prerequisite for targeted medical care; management decisions lie with the treating physicians in consultation with the affected individual.
• Informing predictive testing of at-risk relatives, allowing them to make informed reproductive and life decisions.

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• Strong MJ, Abrahams S, Goldstein LH, Woolley S, McLaughlin P, Snowden J, et al. Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(3-4):153-74. doi:10.1080/21678421.2016.1267768. PMID:; PMCID: PMC7409990.