Clinical Pearls & Morning Reports
Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord. It begins insidiously with focal weakness but spreads relentlessly to involve most muscles, including the diaphragm. No therapy offers a substantial clinical benefit for patients with ALS. Read a new review on this topic.
Q. What is the core pathological finding in ALS?
A. The core pathological finding in ALS is motor neuron death in the motor cortex and spinal cord. Degeneration of the corticospinal axons causes thinning and scarring (sclerosis) of the lateral aspects of the spinal cord. In addition, as the brain stem and spinal motor neurons die, there is thinning of the ventral roots and denervational atrophy (amyotrophy) of the muscles of the tongue, oropharynx, and limbs.
Q. Are there many genetic variants of ALS?
A. Evolving technologies for gene mapping and DNA analysis have facilitated the identification of multiple ALS genes. SOD1 (encoding superoxide dismutase 1) was the first ALS gene to be identified, in 1993. At least 25 genes have now been reproducibly implicated in familial ALS, sporadic ALS, or both. Correlations between genetic variants and different clinical profiles in ALS, such as age at onset, disease duration, and site of onset, have been defined.
Figure 3. (10.1056/NEJMra1603471/F3) ALS Gene Discovery since 1990.
A: About 10% of ALS cases are familial, usually inherited as dominant traits. The remaining 90% of cases of ALS are sporadic (occurring without a family history). There is striking heterogeneity in the genetic causes of familial ALS, but familial ALS and sporadic ALS have similarities in their pathological features, as well as in their clinical features, suggesting a convergence of the cellular and molecular events that lead to motor neuron degeneration. These points of convergence define targets for therapy. A working view of the present panel of ALS genes is that they cluster in three categories, involving protein homeostasis, RNA homeostasis and trafficking, and cytoskeletal dynamics. Downstream of each category are diverse forms of cellular abnormalities, including the deposition of intranuclear and cytosolic protein and RNA aggregates, disturbances of protein degradative mechanisms, mitochondrial dysfunction, endoplasmic reticulum stress, defective nucleocytoplasmic trafficking, altered neuronal excitability, and altered axonal transport. In most cases, these events activate and recruit nonneuronal cells (astrocytes, microglia, and oligodendroglia), which exert both salutary and negative influences on motor neuron viability. The diverse downstream abnormalities may differentially affect subcellular compartments (dendrites, soma, axons, and neuromuscular junctions). One implication of this model is that successful therapy for ALS will require simultaneous interventions in multiple downstream pathways.
A: Heritability studies show that a substantial fraction of cases of sporadic ALS cannot be attributed to genetic or biologic factors; these cases are ascribed to environmental or undefined factors. Attempts to identify occupations or common exposures that might increase the risk of ALS have been inconclusive. Environmental studies are challenging because the number of possible exposures is large, and a critical, disease-related exposure may have happened many years before the onset of the disease. Notwithstanding the barriers to identifying environmental risk factors, some factors have been associated with ALS in multiple studies. The exposure with the strongest support is military service. In addition, smoking has been implicated as a dose-dependent risk factor for ALS. Exposure to heavy metals may be important; blood lead levels and cerebrospinal fluid manganese levels are higher in patients with ALS than in controls. There is increasing evidence that trauma precedes some individual cases of ALS.