ALS arises from progressive motor neuron degeneration, with both genetic and non-genetic forms recognized. Four genes are documented in this packet as associated with ALS: SOD1 (chromosome 21), C9ORF72 (chromosome 9), FUS (chromosome 16), and TARDBP (chromosome 1). These genetic associations account for a recognized proportion of familial ALS cases. For TARDBP-related ALS-FTD, GeneReviews documents that pathogenic missense variants in TARDBP show high penetrance, with males and females similarly affected and notable intra- and interfamilial variability in age of onset and clinical presentation (GeneReviews: TARDBP-Related ALS-FTD). The frequency of TARDBP pathogenic variants is documented as approximately twice as high in individuals with a family history of ALS and/or frontotemporal dementia (approximately 3%–4%) compared to those without such a family history (approximately 1.5%) (GeneReviews: TARDBP-Related ALS-FTD). The specific inheritance mode for each gene-linked familial ALS subtype is not enumerated in the current packet. The majority of ALS cases are sporadic, occurring without an identified familial genetic etiology. Dedicated online databases provide information on the geographic prevalence of TARDBP pathogenic variants (GeneReviews: TARDBP-Related ALS-FTD).

ALS diagnosis is clinical, based on evidence of progressive upper and lower motor neuron degeneration across multiple body regions. Electromyography and nerve conduction studies document denervation and assess the distribution of motor neuron involvement. Neuroimaging is employed to exclude structural and other conditions in the differential. GeneReviews notes that no consensus clinical diagnostic criteria specifically for TARDBP-related ALS-FTD have been published; the GeneReviews chapter defines the entity as the spectrum of phenotypes caused by pathogenic variants in TARDBP, which encodes the TDP-43 protein (GeneReviews: TARDBP-Related ALS-FTD). Genetic testing plays a central role in familial cases, with SOD1, C9ORF72, FUS, and TARDBP representing the principal gene targets documented in this packet. Differential diagnosis considerations include other motor neuron disorders.

Three distinct FDA-approved pharmacological agents for ALS are documented in this packet. Riluzole, available under the brand names Rilutek and Tiglutik, was the first drug approved for ALS (1995) and represents an established approved option. Edaravone (Radicava; intravenous formulation, 2017) and its oral suspension formulation (Radicava ORS, 2022) constitute a second approved pharmacological class. Tofersen (Qalsody, 2023) is an antisense oligonucleotide targeting SOD1, approved for ALS associated with a SOD1 mutation. GeneReviews notes that as of the chapter data, no approved antisense oligonucleotide therapies exist specifically for TARDBP-related ALS-FTD, in contrast to the availability of tofersen for SOD1-related disease (GeneReviews: TARDBP-Related ALS-FTD). GeneReviews further documents multidisciplinary supportive care — encompassing neurology, physiotherapy, and occupational therapy — as central to management, aimed at improving quality of life, maximizing function, and reducing complications; no cure for TARDBP-ALS-FTD is documented (GeneReviews: TARDBP-Related ALS-FTD). Multiple investigational compounds have received orphan drug designation for ALS; designation indicates regulatory recognition of unmet need and does not constitute approved treatment status.

ALS is a progressive neurodegenerative condition. GeneReviews characterizes management of TARDBP-related ALS-FTD as supportive, with surveillance protocols described for monitoring existing manifestations, individual response to care, and the emergence of new features (GeneReviews: TARDBP-Related ALS-FTD). No cure is documented in GeneReviews for this subtype. Intra- and interfamilial variability in age of onset and clinical course is documented for TARDBP pathogenic variants. No specific survival statistics or quantified functional outcome benchmarks are provided in this packet. The progressive nature of the condition is reflected in the GeneReviews management framework, which describes increasing reliance on supportive care across the disease course.

ALS is the subject of numerous active clinical trials documented in ClinicalTrials.gov, spanning drug therapy, biologic agents, medical devices, and gene therapy approaches. Active studies include a Phase 3 trial evaluating pridopidine for efficacy and safety in ALS, alongside earlier-phase investigations. Gene therapy research is represented among both trial registrations and published scientific literature, which encompasses over 1,200 classified articles according to the research landscape data in this packet. Basic science and preclinical research represent the dominant publication type, alongside a substantial body of reviews, biomarker studies, and clinical trial reports. Patient assistance resources documented in this packet include copay support through the HealthWell Foundation's Amyotrophic Lateral Sclerosis Fund and travel and lodging assistance through the National Organization for Rare Disorders, both listed as currently accepting enrollment.