Diagnostic Criteria

Written by Margaret Anne Rockwood | Last updated May 19th, 2026
Medically reviewed by Jennifer Morganroth, MD, MBA and Doreen Ho, MD

Physicians in primary care, internal medicine, gerontology and other first-line practices are typically ground zero for Amyotrophic Lateral Sclerosis (ALS) symptom presentation. The disease’s predominance in older adults, compounded by the multitude of mimics in aging patients, makes recognition of early symptoms and timely referrals to neurologists a challenge.

A strong grounding in the differential diagnosis of ALS offers obvious benefits for first-line physicians and their patients alike and informs patient discussions on the confirmatory testing that lies ahead.

The Gold Coast criteria for diagnosis

The Gold Coast criteria is gaining broad adoption in clinical diagnosis. It has largely replaced the previously used El Escorial/Awaji criteria, providing guidance that leads to a clinical conclusion of ‘ALS’ or ‘Not ALS’.

ALS is diagnosed when all three are present:

1. Progressive motor impairment, documented by history or repeated clinical assessment.​
2. Upper Motor Neuron (UMN) + Lower Motor Neuron (LMN) dysfunction in one or more body regions (bulbar, cervical, thoracic, lumbosacral),
   OR

LMN clinical signs in two or more body regions (when UMN signs are absent/equivocal).​

3. Exclusion of other disease processes

Definitions

• UMN dysfunction is defined by one or more of the following:
  • Increased deep tendon reflexes (incl. in weak/wasted muscles or spread to adjacent muscles)
  • Pathological reflexes (Hoffmann, Babinski, crossed adductor, snout)
  • Spasticity (velocity-dependent tone increase)
  • Slowed, poorly coordinated voluntary movement (not due to LMN weakness or parkinsonism)​

• LMN Dysfunction in a given muscle demonstrates either:

• • Clinical weakness, fasciculations and atrophy​ (supports suspicion but not full criteria without EMG)
  • EMG confirmation of both chronic neurogenic change and active denervation:​
    • Chronic: large, long-duration/high-amplitude MUPs (often polyphasic)​
    • Ongoing denervation: fibrillation potentials in the same region for diagnostic weight, positive sharp waves, or fasciculation potentials​ as evidence of ongoing denervation if coexisting with chronic changes.

• To meet the criteria, LMN involvement per body region includes:

• • Cervical/lumbosacral: two or more muscles (different roots/nerves)
  • Bulbar/thoracic: one or more muscles​

Genetic versus Sporadic ALS

ALS is traditionally classified as one of two categories:

• Genetic/Familial ALS (fALS) is historically estimated to constitute approximately 10% of cases, and is characterized by autosomal dominant inheritance and variable penetrance.

          Key Pathogenic Variants in Genetic ALS

C9orf72 (22-44% of fALS): Pathogenic variants in this gene are the most common genetic cause, and characterized by a hexanucleotide repeat expansion. This links ALS to Frontotemporal Dementia (FTD), and patients may present with cognitive/behavioral changes alongside motor weakness.

There is currently no FDA-approved targeted therapy for C9orf72, but Anti-Sense Oligonucleotide (ASO) treatment trials are underway.

SOD1 (15-20% of fALS): Pathogenic variants in this gene cause proteins to misfold and aggregate. This is the specific target for the therapy Tofersen (Qalsody).

TARDBP (TDP-43) & FUS: (5-10% of fALS). There is currently no drug target for this pathogenic variant.

Other genes found complicit in some types of ALS disease development include ALS2, SETX, SIGMAR1, SPG11 and UBQLN2. As genetic testing improves, more potential genetic origins of ALS are being implicated as drivers of ALS (as in the case of C9orf72), likely shifting the 90/10 ratio of sporadic to genetic ALS.

• Sporadic ALS (sALS), the subtype currently thought to account for approximately 90% of all cases. While these patients have no clear family history, up to 10% of “sporadic” cases may actually carry a pathogenic variant (particularly C9orf72). This finding supports a recommendation for universal genetic counseling and testing for all ALS patients.

Causes of Sporadic ALS

The estimated number of ALS cases are on the rise, with an aging population and evolving diagnostics (contributing to earlier diagnosis).

Research on the causes of sporadic ALS has centered on environmental factors or combined genetic-environmental contributors. Associations have been identified with certain biological agents or chemical exposures, lifestyle choices and traumatic events:

• Military service: U.S. military veterans show an elevated risk of ALS (roughly 1.6x to 2x the general population). This was observed in Gulf War veterans, prompting research into specific neurotoxic exposures.
• Smoking: This may be an environmental risk factor with a consistent dose-response relationship, particularly in post-menopausal women.
• Physical trauma & stress: Some evidence suggests that high-impact physical activity (e.g., professional soccer, American football) has been correlated with increased risk, leading to the hypothesis that mechanical stress on motor neurons may accelerate degeneration in susceptible individuals.
• Toxins & pollution: Exposure to heavy metals (lead), pesticides, and cyanobacterial neurotoxins (e.g. β-Methylamino-L-alanine – BMAA), which has been identified in small geographic clusters, may be linked to ALS development. Recent data also links air pollution and diesel exhaust to ALS risk associated with systemic inflammation.

In the Clinic: Genetic or Sporadic?

Historically, testing was reserved for people with a family history of ALS. However, current evidence-based consensus guidelines recommend a “universal offer” to all patients meeting the Gold Coast criteria.

The clinical diagnosis process is the same for all suspected cases of ALS, but the neurologist’s classification and subsequent management will differ.

• Probable genetic ALS: this describes a patient who has a positive family history (two or more first- or second-degree relatives) OR is identified as having a known pathogenic variant in an ALS-linked gene.
• Probable sporadic ALS: this label characterizes patients who meet the Gold Coast criteria for ALS symptoms, but have no known family history and no identifiable pathogenic variant on standard panels.

In addition to the “Big Four” (C9orf72, SOD1, FUS, and TARDBP), modern evidence-based guidelines (including 2025/2026 updates from the ALS Association and ClinGen) emphasize several other genes that are “strongly” or “definitively” associated with the disease.

The provider should offer genetic testing immediately upon a confirmed or strongly suspected diagnosis of ALS. The order should be for a multi-gene panel. If a pathogenic variant is found, the provider classifies the patient as having “Genetic ALS,” even if they have no family history. This can change the prognosis and can provide a clear molecular target for therapy in some pathogenic variants.

Genetic counseling is offered both pre-test and post-test to help address the psychological impact and the risk to family members.

Exclusion of Other Diseases (Mimics)

The Gold Coast criteria require “investigations to exclude other disease processes,” which directs that a neurologist conduct a standardized workup with these modalities:

• Electromyography (EMG) / Nerve Conduction Studies (NCS): Essential to rule out multifocal motor neuropathy (MMN), myasthenia gravis or chronic inflammatory demyelinating polyneuropathy (CIDP).
• Neuroimaging (MRI): Used to rule out brain tumors or structural causes like cervical myelopathy (which mimics UMN/LMN signs).
• Laboratory tests:
  • Metabolic: Thyroid function tests, vitamin B12 level, and serum copper to exclude potentially treatable mimics.
  • Inflammatory/Infectious: Serum protein electrophoresis with immunofixation (SPEP/UPEP) to evaluate for paraproteinemias
  • Targeted testing for infections such as Lyme disease or HIV when clinically indicated and, in selected cases, testing for antiganglioside antibodies (typically associated with immune-mediated neuropathies rather than ALS)
  • Cerebrospinal Fluid (CSF) analysis: Sometimes performed to exclude inflammatory conditions if the presentation is atypical.

Upon negative findings of mimics, a diagnosis of ALS may be clinically confirmed if symptoms, tests (including those for exclusion) support it. The clinician should then initiate a multidisciplinary care plan, discuss prognosis, and provide a ‘universal offer’ for genetic counseling and testing to identify potential molecular targets for treatment.

References

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2. Epidemiology of ALS: Incidence, prevalence, and clusters. Target ALS. (2022).
3. Military service and amyotrophic lateral sclerosis in a population-representative cohort. Weisskopf, M.G. et al. (2015).
4. ALS and environmental factors. Bozzoni, V., et al. (2016). Functional Neurology.
5. Estimated familial amyotrophic lateral sclerosis proportion: A literature review and meta-analysis. Barberio, J., et al. (2023). Neurol Genet.
6. The evolving landscape of ALS genetics. Al-Chalabi, A., et al. (2024). Nature Reviews Neurology.
7. Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia. Douglas, A. G. L., et al. (2024). BMJ Neurology Open.
8. Evidence-based consensus guidelines for ALS genetic testing and counseling. Roggenbuck, J., et al. (2023). Annals of Clinical and Translational Neurology.
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10. Diagnosing ALS: The Gold Coast criteria and the role of EMG. Turner, M. R. (2022). European Journal of Neurology.
11. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: Multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review). Miller, R. G., Brooks, B. R., Swain-Eng, R. J., et al. (2009). Neurology, 73(15), 1227-1233.
12. Recent advances in the diagnosis and management of Amyotrophic lateral sclerosis. Goutman, S. A., et al. (2022). The Lancet.
13. QALSODY (tofersen) injection [Prescribing Information]. U.S. Food and Drug Administration. (2023).