Motor neuron diseases (MNDs) are a debilitating subset of diseases causing progressive neuronal destruction and eventual loss of muscular function, resulting in high morbidity and mortality rates. Some MNDs are inherited, however, causes of most MNDs are not known and may be catalyzed due to a wide range of risk factors. MNDs are often challenging to accurately diagnose and distinguish between, given overlapping clinical expressions and overall rarity, especially in early phases or atypical variants. Accurate and early diagnosis are crucial since they will help with appropriate and effective clinical management, especially in early stages of disease, and could even attenuate disease progression and improve patient quality of life.
Of all MNDs, amyotrophic lateral sclerosis (ALS) is the most common, comprising about 80% of cases. The classification of ALS has raised much contention within the scientific community. With there being a more comprehensive understanding of ALS recently, there is an ongoing debate as to whether ALS is a disease or a syndrome. A disease is a harmful medical condition with a specific set of associated signs and symptoms. Whereas, a syndrome is a collection of abnormalities that are associated with a particular medical condition where the cause is unknown. This article aims to discuss the leading arguments about the classification of ALS and how a better and tailored diagnosis can help improve patients’ lives.
Initially, ALS was considered a ‘pure motor neuron disease’ by Jean‐Martin Charcot, a French neurologist known for diagnosing the first cases of ALS. Charcot observed the correlations between clinical and anatomical data and ultimately classified several neurological diseases, including ALS. However, other characteristics of ALS, such as the causality, patient variation, and difficulty of diagnosis, suggest that it may be more suitable to characterize ALS as a syndrome. Problematically, it is uncertain what causes syndromes. A handful of factors have been proposed to be associated with ALS; the only established risk factors to date are aging, gender (males), and of course, a family history of ALS. Other suspected risks include environmental factors, as well as patient-related risk factors such as body max index (BMI) and lifestyle choices, including smoking, intake of antioxidants, and physical fitness. Approximately 90% of ALS cases are sporadic, with an unknown cause. A mere 10% of all ALS cases are familial and are caused by genetic mutations. However, due to the rarity of this orphan disease and the low sample size, it is still difficult to determine which genes are responsible for familial cases of ALS.
Additionally, ALS patients have large variability in clinical expression related to the site of onset, length of survival, and the influence of the condition on upper and lower motor neuron function. Furthermore, diagnosis of ALS is extremely difficult; there is no single test that allows physicians to diagnose patients with ALS. In order to address this challenge, physicians often use an arsenal of diagnostic tests, such as neurofunctional imaging and functional and behavioral tests, to better specify their clinical analysis. Diagnosis requires extensive clinical examination and multiple diagnostic assessments, and is usually confirmed by eliminating other possible neurodegenerative diseases such as Multiple Sclerosis (MS) and Parkinson’s Disease (PS). Thus, the ambiguous nature of ALS has caused some to argue that it is a syndrome, not a disease.
The question of disease vs syndrome highlights the incredible complexity of ALS and requires an extensive amount of research until it is fully elucidated, by deeply understanding the molecular mechanisms and pathogenic pathways that underlie the development of ALS. Additionally, we need to further develop and identify the ALS biomarker ‘signature’, that will allow to facilitate the identification of disease-specific biomarkers, and to develop innovative tools for early and accurate diagnosis and disease monitoring.
Importantly, we need to change our perspective and realize that there is no one single target or magic bullet to halt the neurodegenerative process. The key to an effective treatment is concealed in our ability to have a preliminary, accurate and tailored diagnosis.
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