Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the selective loss of motor neurons in the brain and spinal cord, leading to muscle weakness, atrophy, and ultimately paralysis. The disease primarily affects both upper motor neurons (originating in the motor cortex) and lower motor neurons (located in the brainstem and spinal cord), resulting in a combination of spasticity and muscle wasting. Pathogenetically, ALS involves a complex interplay of genetic, molecular, and environmental factors, including mutations in genes such as SOD1, TARDBP, FUS, and C9orf72, excitotoxicity due to glutamate accumulation, oxidative stress, mitochondrial dysfunction, impaired axonal transport, and neuroinflammation. The progressive degeneration of motor neurons impairs voluntary muscle control, affecting speech, swallowing, limb movement, and respiration. Health impacts are profound, as ALS leads to increasing physical disability, loss of independence, and ultimately death, most commonly due to respiratory failure. The disease has a relentless course, with the majority of patients succumbing within 3 to 5 years of symptom onset, although some may survive longer.
Sporadic ALS is the most common form, accounting for approximately 90–95% of all cases. It occurs in individuals with no apparent family history of the disease. The etiology is multifactorial, involving a combination of genetic susceptibility and environmental exposures, but the precise causative factors often remain unidentified. The clinical presentation is highly variable, but typically includes progressive weakness, muscle atrophy, and fasciculations. The age of onset is usually between 55 and 65 years, and the disease course is relentlessly progressive.
Familial ALS constitutes about 5–10% of ALS cases and is defined by the presence of a family history of the disease, often with an autosomal dominant inheritance pattern. Several gene mutations have been implicated, including SOD1, C9orf72, TARDBP, and FUS, among others. Familial ALS tends to have an earlier age of onset and may display specific phenotypic features depending on the underlying genetic mutation. Disease progression and prognosis can vary, but overall are similar to sporadic ALS.
Bulbar-onset ALS is characterized by initial symptoms related to dysfunction of the cranial nerves, such as dysarthria, dysphagia, and difficulty chewing or swallowing. This subtype typically presents in older adults and is associated with a more rapid progression and poorer prognosis compared to limb-onset forms. Bulbar involvement can lead to early respiratory compromise and increased risk of aspiration.
Limb-onset ALS is the most frequent clinical presentation, marked by initial weakness, stiffness, or atrophy in the arms or legs. Patients may notice difficulty with fine motor tasks, walking, or frequent tripping. Disease progression typically leads to involvement of other muscle groups, including bulbar and respiratory muscles, over time.
ALS has a global incidence of approximately 1.5 to 2.7 cases per 100,000 person-years and a prevalence of 4 to 6 cases per 100,000 population. The disease affects men slightly more frequently than women, with a male-to-female ratio of about 1.2 to 1.5:1. The median age at onset is between 55 and 65 years, although cases have been reported in both younger and older individuals. The lifetime risk of developing ALS is estimated at 1 in 350 for men and 1 in 400 for women. Geographical variation exists, with higher incidence rates reported in Europe and North America compared to Asia and Africa. Familial forms account for 5–10% of cases, with the remainder being sporadic. Survival varies, with a median duration from symptom onset to death of 3 to 5 years, although approximately 10% of patients may survive for 10 years or longer.
The diagnosis of ALS is primarily clinical, based on the presence of progressive motor weakness involving both upper and lower motor neuron signs in multiple body regions, in the absence of alternative explanations. The revised El Escorial criteria and the Awaji criteria are widely used, requiring evidence of lower motor neuron degeneration by clinical, electrophysiological, or neuropathological examination, upper motor neuron degeneration by clinical examination, and progressive spread of symptoms or signs within a region or to other regions. Electromyography (EMG) is essential for detecting denervation and fasciculations, while nerve conduction studies help exclude other neuropathies. Magnetic resonance imaging (MRI) of the brain and spinal cord is performed to rule out structural lesions or mimics such as cervical myelopathy or multifocal motor neuropathy. Laboratory tests, including serum and cerebrospinal fluid analysis, may be used to exclude metabolic, infectious, or autoimmune causes. Genetic testing is considered in cases with a family history or early-onset disease. The diagnosis is supported by the exclusion of other diseases and the demonstration of a progressive pattern of motor neuron involvement.
Riluzole is an orally administered medication that acts as a glutamate release inhibitor and is approved to prolong survival and delay the need for ventilatory support in patients with ALS. Edaravone is administered intravenously and functions as a free radical scavenger, providing neuroprotective effects by reducing oxidative stress, and is indicated to slow the progression of physical decline in ALS. Tofersen is an antisense oligonucleotide specifically designed to target and reduce the synthesis of mutant SOD1 protein in patients with SOD1 gene mutations, offering a genetically targeted approach for this subset of ALS. Lenzumestrocel is a cell-based therapy that involves the administration of autologous bone marrow-derived mesenchymal stem cells and is utilized for its potential neuroprotective and regenerative properties in ALS management. Mecobalamin, also known as methylcobalamin or methyl vitamin B12, is a form of vitamin B12 that has been employed for its neurotrophic effects and its role in supporting neuronal survival and function in individuals with ALS.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| tofersen (Rec INN; USAN) | 2088232-70-4 | |||
| lenzumestrocel (Rec INN) | 3037017-62-9 | |||
 | edaravone (Prop INN; USAN) | 89-25-8 | C10 H10 N2 O | 174.199 |
 | riluzole (Rec INN; USAN) | 1744-22-5 | C8 H5 F3 N2 O S | 234.198 |
 | mecobalamin; methyl cobalamine; methyl vitamin B12; methylcobalamin | 13422-55-4 | C63 H91 Co N13 O14 P | 1344.382 |
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