What is ALS?
Amyotrophic lateral sclerosis (ALS) is known as Lou Gehrig’s disease in the United States, named after the Yankee great who attended Columbia College from 1921 to 1923. ALS is a neurodegenerative disease—like Alzheimer’s and Parkinson’s disease—that primarily involves the degeneration of motor neurons in the brain and spinal cord. Motor neuron degeneration leads to progressive muscle wasting (amyotrophy), weakness, and loss of motor control in the arms, legs, and trunk and in “bulbar” muscles that control talking, chewing, and swallowing.
ALS is a fatal disease because it also affects respiratory muscles, including the diaphragm and accessory muscles of breathing. In a population of 100,000, ALS will affect approximately two people every year. In the United States, approximately 5,000 people are diagnosed with ALS annually; the average age at the time of diagnosis is between 55 and 65.
Essentially, two groups of motor neurons are affected, the so-called “upper” motor or corticospinal neuron in the motor cortex, and the “lower” motor neurons in the brain stem and spinal cord that directly activate the muscle. When the upper motor neuron in lost, we see exaggerated and abnormal reflexes, like the knee-jerk reflex.
When the lower motor neuron is sick, we see muscle wasting and weakness, associated with twitching (fasciculation) and cramping. The combination of upper and lower motor neuron signs in the absence of sensory loss is a key finding in the clinical diagnosis of ALS.
What Causes ALS?
In most cases, the cause is unknown, but in about 10 percent of patients, the disease is familial (fALS), which means that it is associated with a genetic mutation inherited from one or the other parent in a dominant manner.
Over 30 different genes have been identified in which mutation(s) cause ALS and over 60 percent of ALS cases are caused by a mutation in one of these known ALS genes. These same mutations are also found in individuals with "sporadic" ALS, who have no family history—either because the family history is unknown or incomplete, or because of an issue called "penetrance,"which relates to the likelihood that a particular mutation will cause the disease. A mutation with low penetrance may actually skip a generation. ALS-associated mutations in these same genes also occur spontaneously or de novo in individuals to cause sporadic disease.
ALS is a motor neuron disorder that can present in a variety of ways in people with sporadic or familial disease. By definition, ALS involves two populations of “motor neurons,” the so-called upper motor neuron in the motor cortex of the brain, and the lower motor neuron in the brain stem and spinal cord, which directly connects to muscle and elicits a contraction. These two principal elements of the motor system control all voluntary movements.
When the upper motor neuron degenerates, patients experience loss of motor control, stiffness or spasticity, and abnormal or exaggerated reflexes. When the lower motor neuron is lost, patients develop weakness, wasting (amyotrophy) and twitching (fasciculation) of muscle.
In ALS patients with bulbar onset, the first muscles involved are those that control speech and swallowing, and slurred speech (dysarthria) and difficulty swallowing (dysphagia) are the initial problems. In spinal onset disease, muscles that control the limbs and trunk are the first involved, and people first complain of weakness in one hand or a dropped foot that causes them to trip and fall. Most ALS patients have a mixture of upper and lower motor neuron signs. Some patients have only upper motor neuron dysfunction and are said to have primary lateral sclerosis (PLS). Others only have lower motor neuron signs and are diagnosed with progressive muscular atrophy (PMA). While some may consider these distinct disorders, we think they exist on a single disease spectrum and share critical features that characterize ALS and all related motor neuron diseases.
ALS is predominantly, but not exclusively a motor neuron disease, and patients with ALS experience non-motor symptoms including pseudobulbar affect (PBA), characterized by involuntary and uncontrollable episodes of laughing or crying that are not appropriate or proportionate to the circumstance or event, and do not necessarily reflect the way a person is feeling. Also, many patients with ALS have mild cognitive impairment involving functions controlled by frontal and temporal areas of the brain, and some patients are diagnosed with frontotemporal dementia (FTD), which is commonly associated with both familial and sporadic ALS. Symptoms of FTD can include abnormalities of personality, behavior, and language.
A diagnosis of ALS is made on a clinical basis, and there is no specific diagnostic test for this disease. The clinical diagnosis of ALS is probably correct in more than 95 percent of cases and is based on history, neurological examination, imaging, laboratory, and electrophysiological studies, all of which are useful in excluding possible mimics and causes of the signs and symptoms of ALS. Perhaps the most critical disorder in the differential diagnosis is multifocal motor neuropathy, which is dominated by lower motor neuron signs and characterized by multiple motor-conduction blocks on electrical testing. It accounts for two percent of patients seen in ALS centers. Antibodies against the GM1 ganglioside are found in 22 to 84 percent of patients with multifocal motor neuropathy. Unlike ALS, multifocal motor neuropathy responds to intravenous immune globulin (IVIG) and other treatments.
Perhaps the most important and useful test in the differential diagnosis of ALS is the electromyogram (EMG), and nerve conduction studies (NCS). The EMG is an electrodiagnostic study that records the electrical activity of muscle, both spontaneous and that which is elicited by nerve stimulation (muscle activation). This is done using small needles (electrodes) that are inserted through the skin into the muscle. The electrical activity picked up by the electrodes is displayed on a monitor, and the size and shape of the waves are recorded and analyzed. The EMG, in combination with the nerve conduction study—which measures the amount and speed of conduction of an electrical impulse through a motor or sensory nerve—can reveal the nature of the nerve and or muscle damage. Formal electrodiagnostic criteria exist for a diagnosis of motor neuron disease. And the EMG/NCS is used to determine whether the findings are at least consistent with a clinical diagnosis of ALS.
Genetics of ALS
In the large majority of cases, ALS is a sporadic disease, presenting with no obvious family history. But in about 10 percent of cases, there is a family history of ALS, suggesting a dominant pattern of inheritance. Mutations in a large and growing number of genes are known to cause motor neuron disease in ALS families, and mutations in these same genes accounts for a significant fraction (10 to 15 percent) of sporadic cases as well.
The most common known cause of ALS is a mutation in a gene called C9orf72, which accounts for nearly half of all cases of familial ALS, and about 10 percent of sporadic disease. This same mutation also causes frontotemporal dementia (FTD), which is commonly diagnosed in ALS patients, both familial and sporadic. These clinical, pathological, and genetic links between sporadic and familial ALS suggest that all forms of the disease are alike in important ways, and could respond to the same drug or therapeutic aimed at a shared target.
In more than 60 percent of familial cases, and upwards of 15 percent of sporadic ALS patients, a mutation is found in a known ALS gene, many of which have been identified in the last 10 years. It follows then that in a significant percentage of ALS families, the gene mutation has not yet been discovered. Similarly, in the majority of patients with sporadic disease, a gene mutation is either unknown, or not the cause of disease. Genomic studies at Columbia and around the world are focused on identifying the gene mutations which alone, or in combination, cause ALS in individuals and in families.