| Amyotrophic lateral sclerosis, also called ALS, Lou
Gehrig disease, Charcot disease or, in The diagram shows solid lines extending down from the brain which represent the upper motor neurons. The broken lines that meet them in either the brain stem or spinal cord and extend out to the muscle represent the lower motor neurons. And again, according to the Escorial criteria for diagnosing ALS, both types of neurons must be affected in several regions of the body for a person to be diagnosed with ALS. |
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There are two to three new ALS cases per 100,000 people diagnosed each year worldwide. In the US approximately 15 new cases are diagnosed each day and roughly 35,000 people are living with ALS at a given time. While most patients are between 50 and 70 years old, ALS can occur at any age. Men are affected slightly more frequently than women, in a ration of 1.5/1.
Causes of ALS can be looked at in several ways.
Epidemiology: Studies have identified a few geographic areas that at certain times have had greater than the expected numbers of cases, a phenomenon called a cluster. This was documented in the past in the western Pacific islands (Guam) and parts of Japan and Australia. Clusters have been reported within the US as well, including a recent reported excess at Kelly Air Force Base in Texas. However, further careful investigations have not supported the reports.
Genetic Influences: Roughly 90% of the time ALS occurs as single case within a family. This is termed sporadic ALS (SALS). The causes of SALS are still unknown. Our hypothesis is that a group of genetic changes may be inherited together as predisposing factors, or factors which increase a person’s risk or vulnerability for developing ALS. Their presence forms a threshold, over which a person may be “pushed” when certain environmental factors are present, causing the person to develop symptoms of ALS. While both the predisposing genetic factors and environmental factors are largely unknown at this time, we and others have associated changes in the paraoxanase cluster of genes (PON) with SALS. The paraoxanases include an enzyme that detoxify several common pesticides. This may be the first step in understanding how SALS can develop.
Inherited or familial ALS (FALS) accounts for about 10 percent of all ALS cases. FALS usually is inherited in a dominant manner, with multiple cases appearing in multiple generations. In 1993 Dr. Siddique led an international team that reported the first gene FALS gene, superxoide dismutase or SOD1, a gene that causes about 20% of dominantly inherited cases. He also led a consortium that recently identified mutations in the fused-in-sarcoma gene (FUS) in about 3% of remaining FALS families. Mutations in gene coding for the TAR binding protein (TDP 43 or TAR 43) are now implicated in a very small portion of FALS cases as well. Very rarely, ALS occurs as a recessive disorder, generally with its onset in childhood. We identified the ALSIN gene as the cause of a portion of these cases. Mutations in ALSIN may also cause juvenile PLS.
Chemical disturbances within the nervous system: Scientists are also interested in whether naturally-occurring, but toxic chemicals could cause ALS. For example, glutamate is a chemical normally present in the brain, where it is required for cells to carry messages from one to another. Usually, once that task is done, glutamate is removed by another chemical called a transporter. ALS patients have higher than normal amounts of glutamate in their nervous systems. That led to the hypothesis that the transporter is not effective in removing excess glutamate and that excess over-stimulates motor neurons until they die. This is the basis for drug treatment with Rilutek (riluzole) and the current clinical trial of ceftriaxone.
Several single cause theories:
Viruses and abnormalities of the immune system have generated considerable interest. It is hypothesized that a virus or foreign substance may cause the body’s immune system to attack its nervous system, called an autoimmune process. Immune system abnormalities and autoimmune diseases are reported more frequently in ALS patients and their relatives. However, specific and consistent abnormalities have been difficult to identify and related treatment trials have not resulted in improvement of symptoms.
A large number of ALS patients may have abnormal antibodies. However, it is not clear which of these antibodies produce disease and which may merely be associated with it.
A viral "triggering" agent for ALS has also been proposed, something that would produce disease in a manner similar to polio, in which the poliomyelitis virus may produce an acute infection of the motor neurons, resulting in motor paralysis. One theory is that ALS results from a persistent viral infection, producing progressive motor disability. It is known that polio survivors may have a second phase of progressive muscular atrophy years after the acute phase of their illness, although the mechanism for this is not understood. These post-polio patients do not appear to have greater risk for ALS.
Multiple neurotrophic factors, or chemicals that affect the growth and maintenance of neurons, have been examined for their roles in ALS. One theory suggests that a deficiency of growth factors results in reduced survival and eventual degeneration of motor neurons. Nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), brain deprived neurotrophic factor (BDNF), glial-deprived neurotrophic factor (GDNF) and insulin-like growth factor (IGF-1) all promote motor neuron survival in tissue culture and animal models of motor neuron disease. However, multiple clinical trials have demonstrated that neurotrophic factors are not effective in treating ALS.
Other theories: Many other potential etiologies have been proposed. The only factors consistently identified are heavy metal exposure, particularly lead, and a family history of ALS, Parkinson disease and dementia. There are limited reported associations with increased dietary fat, cigarette smoking, electrical injury, and combat service in the Gulf region. Both enteroviruses and retroviruses have been implicated as well.
The location of the neurons that are sick determines which symptoms a patient will have.
Signs of upper motor neuron damage include:
Spasticity. A feeling of tightness and stiffness and inability to relax the muscle occurs because a muscle is receiving a continuous message to contract. Spasticity can occur in any muscle in any part of the body.
Brisk,exaggerated or hypertonic reflexes. Normally, when a muscle and its tendon are stretched by the tap of a hammer the muscle will contract moderately and quickly return to its relaxed state. With upper motor neuron damage, the contraction may be exaggerated.
Pseudobulbar affect. Outbursts of uncontrollable laughing or crying occur in response to minimal stimulation because upper motor neurons are unable to send their normal message to stop an action. This may also be called emotional lability.
Signs of lower motor neuron damage include:
Muscle cramping. Involuntary, forceful, sustained contraction of a muscle that does not relax may occur. This contraction makes the muscle visibly and palpably hard.
Fasciculations. These small involuntary contractions and relaxations of muscles are visible under the skin as twitches or ripples. They are not painful, although they may produce a crawling sensation.
Muscle weakness and paralysis. Weakness generally starts in one place in the body and spreads. Roughly 1/3 of patients experience their first weakness in the “bulbar” muscles, or the muscles that are controlled by neurons that run through the brainstem (or bulb), causing difficulty with talking, chewing, swallowing. Approximately 2/3 of patients have “limb onset,” meaning weakness first appears in an arm or leg. A minority experience their first weakness in the muscles of breathing.
Muscle atrophy. Muscle tissue painlessly deteriorates, shrinks or wastes because it is not being stimulated normally.
Decreased or absent reflexes. Tapping of the muscle and its tendon produces decreased or no movement.
Cognitive impairment may occur along with other ALS symptoms. It can range from mild difficulties with decision making, judgment and mood to seriously disabling frontotemporal dementia (FTD). FTD occurs because the frontal and temporal lobes of the brain degenerate. Estimates of the number of ALS patients affected by cognitive impairment and FTD vary widely, ranging from less than 10% to as much as 45%. Since the impairment may be very mild it may difficult to recognize.
The area of the brain called the motor strip, located at the back of the frontal lobe where it abuts the temporal lobe, is where the top parts of upper motor neurons are located. The areas of the brain that are affected in FTD are next to these upper motor neurons.
A patient who may have ALS is usually evaluated by a neurologist, a doctor who specializes in disorders of the nervous system. There is no single test that diagnoses ALS. ALS is a “clinical” diagnosis, based on the neurologist’s interpretation of the patient’s symptoms in combination with test results. The patient must have a group of symptoms present throughout the body (see the Escorial criteria below) for which no alternate explanation can be found. A series of tests are done to confirm motor neuron involvement and exclude conditions that can have symptoms similar to ALS. Although the diagnostic work-up is extensive, the tests are generally not risky or painful. This testing is important because many of these conditions are treatable. Once the diagnosis of ALS has been established, the short and long-term care of the patient and family can be planned.
The three kinds of diagnostic tests usually performed are imaging studies, electrodiagnostic studies, and fluid/tissue analysis.
Imaging studies: X-rays, CT (Computerized Tomography) scans, MRI (Magnetic Resonance Imaging) scans and myelography are done to exclude any structural abnormality of the nervous system, such as a tumor or protruding spinal disc.
Electrodiagnositc studies: Electromyograhpy (EMG) records the electrical activity of the muscle and nerve conduction velocities (NCV) quantify the nerve's ability to transmit electrical impulses. These studies evaluate the integrity of the muscle and nerve.
Fluid analysis: Blood, urine and, occasionally, cerebrospinal fluid (CSF) are screened for metabolic, endocrine, immunologic, infectious and toxic abnormalities.
Tissue analysis: Muscle and/or nerve biopsy may be used to support the diagnosis and to exclude other neuromuscular conditions.
In general, patients with ALS will not have significant abnormalities on imaging studies and fluid analyses, but will show characteristic results on electrodiagnostic studies and muscle biopsy.
Approximately ten percent of ALS is genetic in origin and genetic testing for causative genes can be done. Click here for an extensive discussion of genetic testing in ALS.
These strict criteria were designed to standardize ALS diagnosis for clinical trials and ensure that patients who have symptoms mimicking ALS are not mis-diagnosed. They are named after the Portugese community, el Escorial, in which neuromuscular specialists met to develop them.
The criteria have defined levels of certainty regarding the presence of ALS, ranging from suspected, to probable, to definite. For example, definite ALS requires signs of both upper and lower motor neuron involvement in three regions of the body. There may be patients with suspected or probable ALS whose symptoms are disabling, even though they are not widespread enough to be called definite ALS. Admittedly, this circumstance can be extremely frustrating to patients and families, but strict adherence to the criteria is essential to prevent incorrect diagnoses.
The diagnosis of ALS requires:
The presence of
The absence ofEvidence of lower motor neuron degeneration by clinical, electrophysiological or neuropathologic examination and Evidence of upper motor neuron degeneration by clinical examination and Progressive spread of the symptoms or signs within a region or to other regions, as determined by history or examination, together with
Electrophysiological or pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration and Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.
Approximately 10% of ALS is inherited or “runs in families.” It is called familial ALS or FALS. The most important factor to consider when determining risk to other family members is family history. From that, inheritance pattern can be determined and risk to other family members estimated.
The most common inheritance pattern identified in FALS is autosomal dominant. Autosomal means the disease causing gene is located on one of the numbered chromosomes, not one of the sex chromosomes. Dominant means one copy of the mutated gene is enough to cause disease. At conception each parent randomly passes one of the parent’s two copies of a given gene to the child, regardless of the genders of the affected parent or the child. Therefore, each child of an affected parent has a 50% chance of inheriting the FALS gene and a 50 % chance of not. The child's second copy of the gene pair will not have a mutation, having come from the unaffected parent. Generally, a person with a mutation for FALS is likely to develop the disease. However, presence of a disease causing mutation does not guarantee a person will develop ALS, and the severity and scope of the onset of the disease generally cannot be predicted. The reasons for this are not yet understood.
There are a few families in which ALS is inherited in an X-linked dominant manner, meaning the causative gene is located on the X chromosome and one copy of the mutated gene can produce disease. The hallmark of these families is that affected males never pass the disease to their sons. This is because males, who have one X and one Y chromosome, get their only X chromosome from their mothers. Affected mothers may pass the disease causing copy of their Xs to children of both genders.
Rarely, ALS is inherited in a recessive manner, meaning two copies of the mutated gene, one inherited from each parent, must be present for a person to develop disease. Generally, ALS inherited in this way has an early onset in childhood and a relatively longer course.
Approximately 20% of FALS is caused by mutations in a gene located on chromosome 21 called copper-zinc superoxide dismutase 1 (SOD1). SOD1's normal job is to aid in the removal of substances called free radicals, too much of which can harm the body’s cells. We now know that mutations in SOD1 make SOD function in a new and toxic way, causing injury to motor neurons instead of preventing it. An international team, led by our program director, Teepu Siddique MD, identified SOD1's disease causing role in 1993.
Two other genes have been identified that cause a small percentage of FALS. In 2008 mutations were identified in the gene coding for TAR-DNA/RNA binding protein (TDP43 or TAR43). In 2009, Dr. Siddique led a consortium that identified mutations in the gene fused-in-sarcoma/translated in liposarcoma (FUS/TLS) in a small number of families from divergent ethnic backgrounds.
In 2001 we identified mutations in ALSIN that cause very rare recessive, juvenile onset FALS and equally rare recessive, juvenile onset primary lateral sclerosis.
Identification of a disease causing gene mutation means the genetic reason for that patient's FALS has been determined. However, for about 70-75% of families with FALS the causative gene is not known. Normal genetic testing results mean that the genetic cause of the FALS has not been identified. Normal genetic testing does not change the diagnosis or mean the disease may not be inherited by other family members. We are actively pursuing identification of other causative genes in FALS. To read more about our research click here. We are actively searching for additional causative genes. For more information on our research,click here.
Genetic testing may be done for the causative genes SOD1, TDP43, FUS/TLS and ALSIN. Testing may also be done for angiogenin and FIG4, genes whose roles in ALS are controversial. A blood sample is taken and sent to a specialized lab, where the gene of interest may be examined using a technique called DNA sequencing.
One must remember that genetic testing determines the absence or presence of a genetic mutation, but it cannot diagnose ALS. This makes sense if one remembers that any mutation identified would have been present from conception and most FALS patients do not develop ALS until adulthood.
Testing is appropriate for anyone who has symptoms of ALS and a family history of ALS, that is, another relative who also had/had the disease. Testing may also be indicated if the family history is unknown, if there is a suspicion of ALS in another family member or if a parent passed away at a young age.
A person with a family history of FALS may have a genetic test even if he or she does not have symptoms. This is called presymptomatic genetic testing. Presymptomatic testing can only be done for individuals who have a family member with ALS with a previously identified disease causing mutation in a known gene. Test results, regardless of outcome, can have a major psychological impact. Therefore, genetic and psychological counseling is required before such testing. For further information on genetic counseling and testing for ALS contact Sandra Donkervoort MS CGC.
There is currently one FDA approved drug for the treatment for ALS. Rilutek, which is the brand name for riluzole, is a chemical that suppresses release of glutamate into the nervous system, so theoretically it helps control the amount available for stimulation of neurons.
Click here for clinical trial information.
Most experts agree that ALS patients do better with a multi-disciplinary approach to their care. Our clinics offer physicians, nurses and other health professionals who work as a team to provide skilled symptom management and psychological support.
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