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There are both sporadic (no family history) and genetic (inherited) forms of disease described below.
Classical ALS is a distinct syndrome characterized by a combination of UMN and LMN problems and occurs in about two thirds of people with ALS.
Progressive Bulbar Palsy (PBP) – was originally described by Duchenne in 1860. In approximately 25 percent of people with ALS, the initial symptoms begin in muscles innervated by the lower brainstem that control articulation, chewing and swallowing. Sometimes the disease remains in this form for years, but usually it progresses to generalized muscle weakness, that is, to ALS. When the disease is strictly limited to the bulbar muscles clinically and electrodiagnostically, it is PBP, not classical ALS.
Whether the above forms of sporadic ALS represent a spectrum of the same disease or whether they are in fact distinct is not yet known.
In some instances, ALS runs in the family, i.e. it is genetic. This happens in 10% or less of all people with ALS although it is likely that your genetic makeup may play a role in your susceptibility to disease. A nice overview of genetics in lay language can be found on the MDA website.
Briefly, all of our genetic information is carried on chromosomes that are strands of a chemical called DNA (deoxy ribonucleic acid). DNA contains a sequence of information in the form of building blocks called nucleotides. These DNA strands are located in the nucleus of every cell in the body and are organized in pairs. There are 22 pairs of chromosomes called autosomes and an additional pair of sex chromosomes that determine whether you are a male or female. For each pair of chromosomes, you have inherited one chromosome from your mother and one from your father.
The DNA of chromosomes is organized in a sequence of nucleotides that code for genes. Genes are organized like beads on a necklace, and each gene contains information that tells the cell how to make a particular protein. The chromosome also contains regions that control the production of the protein and respond to events in the cell.
In order to make a protein, information from the DNA is first “transcribed” or converted into RNA (Ribonucleic Acid) as a message that will leave the nucleus and travel into the cell. We call this messenger RNA (mRNA). This message provides the information to the cell about how to make the protein. Every three nucleotides in the message RNA tells the cell one amino acid (these are the building blocks of any protein) in the protein. The sequence of nucleotides in the RNA determines the sequence of amino acids in the protein and provides the code for what sequence of amino acids to string together to create the specified protein. The mRNA is used as a template by the cell to make the protein - i.e. translate the information. In genetic illnesses, there are abnormalities in the genetic code of DNA (called mutations) that result in problems with protein production. In some cases no protein is made, in others an abnormal protein that is rapidly degraded is made, in others an abnormal protein that malfunctions can be made, and finally there may be problems in the regulation of normal protein production.
Genetic problems can be inherited in several ways. A disease may be dominant or recessive. If it is dominant, then only one of the two copies of the gene is abnormal, yet it results in disease. In recessive diseases, there needs to be a problem in each of the two genes that are inherited from your parents. Each parent would be a carrier and not have the disease while the child who has inherited a damaged gene from each parent would show the disease. Most X-linked mutations affect males (who only have one X chromosome, paired with a Y chromosome) but rarely affect females (who have two X chromosomes, one of which usually doesn't have the mutation). However, X-linked mutations can sometimes affect females.
Familial ALS cases comprise 5 to 10 percent of all cases of ALS. Familial ALS (FALS) is inherited as an autosomal dominant trait. Almost 20 % of people with FALS have damage (called a mutation) in the gene that codes for the protein Cu/Zn superoxide dismutase (SOD 1) located on chromosome 21. There are no differences between familial and sporadic ALS on neurological exam except for occasional sensory loss in people with FALS. Other genes that, when damaged, can lead to ALS, have been identified on chromosomes 2, 9, 15, 18 and the X chromosome. We expect to find more genes as well as genes that can modify disease through research and genetic studies in families and siblings of people with both sporadic and familial ALS.
In addition to directly inheriting a gene that causes ALS, there are also susceptibility genes. In this case, a particular gene structure is inherited that seems to alter the risk of developing ALS but is not directly causal. Some genes that, when constructed in a certain variation, can modify susceptibility to ALS have already been identified. These include the gene for vascular endothelial growth factor- VEGF, the gene for iron processing-HFe, and a gene responsible to help metabolize organophosphate insecticides-POMC. Recently there have been more modifying genes that have been implicated although additional work is ongoing to identify them.
Western Pacific ALS
Western Pacific ALS occurs primarily on the island of Guam, the Kii Peninsula of Japan, and New Guinea. The people on Guam have the same clinical characteristics seen in sporadic ALS and also can have a dementia and Parkinsons like illness. The illness on Guam is the first to be tied to a toxin, the cycad nut. This nut contains a compound that is toxic to nerve cells called BMAA and is similar to glutamate. The nut is eaten by the fruit bat which was a delicacy among the Chamorro population of Guam. This allowed a very high concentration of the toxin to be eaten and it has been postulated but not proven, that this caused the disease. The fruit bat was eaten to extinction and now fruit bats for consumption are imported, the disease has all but disappeared!
Rare cases of adolescent motor neuron disease that are clinically indistinguishable from ALS have been reported. Onset is between ages twelve and sixteen. Although ALS can occur at young ages, these cases are probably different from sporadic ALS.
This is a rare disorder seem in young men. In this variant there is localized atrophy of one arm associated with increased reflexes implicating the presence of upper and lower motor neuron damage. However, the disorder is a problem at the junction between the cervical spine and the skull where there is pressure on the cervical spinal cord. In order to detect it, MRI of the neck needs to be performed in different positions including neck flexion and extension.
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