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Spinal Muscular Atrophy (SMA) is a term applied to a number of different disorders, all having in common a genetic cause and the manifestation of weakness due to loss of the motor neurons of the spinal cord and brainstem. One form of SMA, caused by mutation in the SMN gene, is by far the most common, hence in proper context the label “Spinal muscular atrophy” of “SMA” refers to this specific form.
In all of its forms, the primary feature of SMA is muscle weakness, accompanied by atrophy of muscle. This is the result of denervation, or loss of the signal to contract, that is transmitted from the spinal cord. This is normally transmitted from motor neurons in the spinal cord to muscle via the motor neuron’s axon, but either the motor neuron with its axon, or the axon itself, is lost in all forms of SMA. This is the reason for the label: “spinal muscular atrophy” means muscle atrophy caused by a problem in the spinal cord. This is in contrast to many other neuromuscular disorders, such as muscular dystrophy, where the primary problem is within the muscle itself.
The features of SMA are strongly related to its severity and age of onset. SMA caused by mutation of the SMN gene has a wide range, from infancy to adult, fatal to trivial, with different affected individuals manifesting every shade of impairment between these two extremes. Many of the symptoms of SMA relate to secondary complications of muscle weakness, and as such can be at least partially remediated by prospective therapy.
Infantile SMA is the most severe form. Some of the symptoms include:
In general, across the range of SMA the earlier the symptoms appear, the more severe the weakness and shorter the life span, but there are exceptions. In the most severe form of SMN-related SMA, the onset can be over a short period of just weeks, whereas in the milder forms weakness can develop over the course of years. There is, as yet, no specific therapy to slow the course of motor neuron dysfunction. The major management issue in Type 1 SMA is the prevention and early treatment of respiratory infections; pneumonia and other causes of respiratory insufficiency are the cause of death in the majority of the cases. The course of SMA, at all levels of the disorder, is unusual in that the progression of weakness decreases over time. Thus many individuals settle into a “plateau” phase, sometime after onset, where little or no change is detectable for long periods of time. Despite the lack of a specific therapy for the underlying condition, much can be done to prevent or minimize many of the complications of weakness, and by this means affect the course. Without any specific therapy, the average life expectancy for all infants with Type 1 SMA is about 8 to 9 months. In years past children with SMA type 2 were said to survive “until school age”, but now with more aggressive management of complications the average life span is unknown — individuals are living longer and the average can’t yet be known. Certainly individuals with type 3 SMA can have a regular life span. Intellectual and sexual functions are unaffected by SMA.
In order to be diagnosed with Spinal Muscular Atrophy, symptoms need to be present. In most cases a diagnosis can be made by the SMN gene test, which determines whether there is at least one copy of the SMN1 gene by looking for its unique sequences (that distinguish it from the almost identical SMN2) in exons 7 and 8. In some cases, when the SMN gene test is not possible or does not show any abnormality, other tests such as an EMG electromyography (EMG) or muscle biopsy may be indicated.
In humans and chimps, the region of chromosome 5 that contains the SMN (survival motor neuron) gene has a large duplication. A large sequence that contains several genes occurs twice — i.e. once in each of the adjacent segments. A second change that is found only in humans is that the two copies of the gene — known as SMN1 and SMN2 — differ by only a few base pairs. The important change in the SMN2 gene, for the purposes of SMA, is a silent mutation that occurs at the splice junction of intron 6 to exon 7. This affects splicing of the SMN2 pre-RNA, resulting in about 90% of the transcripts being inappropriately spliced into a form that excludes exon 7. This shorter mRNA transcript codes for a shorter SMN protein, which is rapidly degraded. About 10% of the mRNA transcript from SMN2 is spliced into the full length transcript that codes for the fully functional SMN protein.
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