Amyotrophic Lateral Sclerosis: Update for the Primary Care Clinician
Motor neuron from the spinal cord containing an inclusion from ALS.
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Amyotrophic lateral sclerosis (ALS), which is often referred to as Lou Gehrig's disease, is a progressive neurodegenerative disorder that is characterized by a loss of upper and lower motor neurons. Muscle weakness and atrophy develop gradually over many years. Often, the diagnosis is delayed because of the vague symptomatology, and primary care clinicians may be the first healthcare providers whom patients consult.
Primary care clinicians should refer patients with suspected neurodegenerative symptoms to a neurologist, preferably one who specializes in movement disorders. Primary care clinicians may also be involved in palliative care and symptom management as the disease process progresses. Frequently, primary care clinicians are also a source of education and support for the caregivers of patients with ALS.
It is difficult to estimate the incidence and prevalence of ALS because it is not a reportable disease. According to the Mehta et al, the estimated incidence of ALS across all ages is approximately 4 to 5 persons per 100,000.1 ALS is diagnosed each year in the United States in an estimated 5000 persons, with an estimated prevalence of 12,000 to 15,000 cases. ALS is more prevalent in men than in women, with a typical age at diagnosis of 55 to 75 years.1,2
The etiology of ALS is unknown, but some risk factors have been proposed, including genetic predisposition, toxic effects of heavy metal, viral infection, environmental and occupational exposures, cigarette smoking, repeated physical trauma, military service, and participation in strenuous physical activity, such as professional athletics.3-5 Investigations into etiology have revealed a pathologic overlap between frontotemporal degeneration (FTD) and ALS; these two diseases have similar features.6,7
Two classifications of ALS have been described: familial (inherited) and sporadic. Approximately 10% of all cases of ALS are thought to be familial and due to genetic mutations.8 Numerous genetic mutations have been associated with ALS. A mutation in the superoxide dismutase gene 1 (SOD1) accounts for approximately 20% of familial cases of ALS. Superoxide dismutase is a critical enzyme involved in protecting mitochondria from oxidative stress.8 In addition, a repeated nucleotide abnormality at the 9p21 genetic locus, termed the C9orf72 mutation, has been detected in 60% of familial cases of ALS and 10% of sporadic cases.9 At the molecular level, the pathology of ALS is highly complex, and dysfunction has been found in numerous cellular components. However, the “trigger” of these cellular changes is unknown. A pathologic process of excessive glutamate excitation of motor neurons, leading to degeneration and dysfunction, is found in ALS.10 Mitochondrial abnormalities in the spinal cord, such as swelling and vacuolization, are a pathologic hallmark of ALS.11 The presence of proteinaceous aggregates in the spinal cord in ALS suggests malfunction of protein degradation and clearance.12 Diminished levels of vascular endothelial growth factor (VEGF) and angiogenin (ANG), which are involved in the maintenance of neural networks and vasculature, have also been implicated in ALS.13 A neurotoxin, β-methylamino-L-alanine, is related to ALS in some populations, including military personnel who have served in the Middle East.14 Malfunction of RNA transcription and splicing is a common causal factor in both familial and sporadic ALS, in which the accumulation and misassembly of neurofilaments disrupt neuronal axon integrity—another hallmark of ALS pathology.15