Spinal muscular atrophy, or SMA, is a genetic disorder where nerve cells in the spinal cord
die prematurely, and this causes the muscles that would normally be controlled by those
nerves to atrophy, or wither away, which causes weakness.
When the brain wants a muscle to contract, it sends a signal through an upper motor neuron,
which takes the impulse from the brain to the spinal cord, and then through a lower
motor neuron, which goes from the spinal cord to the neuromuscular junction, which is where
the lower motor neuron touches the muscle cell.
The lower motor neurons which cause voluntary contraction of skeletal muscle are called
alpha motor neurons, and these alpha motor neurons are the ones that die in SMA.
Their cell bodies are located in the anterior horn, or front part, of the spinal cord, and
their axons project from the spinal cord all the way to the muscles they innervate.
A group of these neurons is called a motor nerve.
If a lower motor neuron dies or if the entire nerve is injured, the motor unit, which includes
the neuron and the muscle fibers it innervates, stops working.
Depending on how many muscle fibers stop contracting, there can be overall muscle weakness or in
an extreme situation, a flaccid, or low-tone paralysis.
This denervated muscle also atrophies over time, a classic example of "use it or lose
it".
This contrasts with the increased muscle tone and spasticity that develops after an upper
motor neuron is damaged.
When a lot of these muscle fibers are affected, fasciculations can happen which are, spontaneous,
involuntary muscle contractions.
Alpha motor neurons also carry the signal for muscle contraction in deep tendon reflexes,
like the knee-jerk reflex, and they diminish or disappear when alpha motor neurons are
damaged.
Now, it turns out that there are a few types and subtypes of SMA.
Type 1a, congenital SMA, is the most severe of all and it starts even before birth, when
mothers may notice decreased fetal movements.
SMA type Ib, also called infantile SMA or Werdnig-Hoffman disease, is the classic form
where babies often appear normal at birth and then in the first few weeks of life develop
hypotonia or low muscle tone.
These infants have progressive weakness, which is worse proximally than distally, and is
initially more obvious in the legs, making it hard for them to do things like sit up.
They can also have weakness in the muscles involved in sucking, chewing, and swallowing
and as a result, they can have difficulty taking milk, eating foods, or even safely
swallowing their own secretions which can lead to aspiration.
The weakness can also affect the chest wall muscles and diaphragm leading to breathing
difficulty and eventually respiratory failure.
For these reasons, most of these babies survive only a few years.
SMA types II, III, and IV are each successively milder and have a later age of onset.
In addition to muscle weakness, feeding problems, and breathing difficulties, chronic symptoms
of SMA include scoliosis due to poor muscle support of the spine and extremely thin limbs
due to muscle wasting.
The different types of SMA all result from the same a homozygous deletion of the "survival
motor neuron" gene or SMN1 gene on chromosome 5, and this is inherited in an autosomal recessive
pattern.
The SMN protein from the SMN1 gene is expressed in all cells and is required to live.
For one, the SMN protein is a component of the spliceosome, a molecular machine that
cuts the introns out of pre-messenger RNAs.
SMN also blocks caspases, which are proteins involved in apoptosis, or programmed cell
death, so lacking SMN may also enhance apoptosis.
SMN protein's also particularly important for alpha motor neurons, but the exact mechanism
relating the protein to the function of those cells is still unclear.
Now, the genetics help explain the continuum of severity that we see across SMA, and it
has to do with the SMN2 gene, which is a pseudogene that sits next to SMN1 on chromosome 5.
Pseudogenes are mutated copies of genes that arose during evolution, and are less functional
or non-functional versions of their counterparts.
SMN2 is more than 99% identical to SMN1, but it has one important change in exon 7, called
c.840C>T. And this means that while the 840th nucleotide is a C in SMN1, it's a T in SMN2.
And this tiny mutation results in exon 7 being spliced out of the majority of the SMN2 mRNA.
Not having exon 7 means this SMN2 gene churns out SMN proteins that mostly get rapidly degraded,
with only a couple full-length, functional SMN proteins, relative to SMN1 which churns
out only functional SMN proteins.
Furthermore, often people might have multiple duplications of the SMN genes, which might
result in several copies of SMN2 and this SMN2 copy number actually varies quite a bit
in a population.
Now, all this is important because patients with SMA, have no functioning copies of SMN1,
and since SMN2 still makes a small amount of functional SMN protein, the number of copies
of SMN2 determines the severity of spinal muscular atrophy.
More copies means more SMN protein and a milder SMA phenotype.
So, as an example, a patient with two SMN2 genes might have infantile SMA, whereas a
patient with four SMN2 genes might have a milder subtype.
Treatment for SMA has historically been supportive, like giving infants nutrition through a feeding
tube as well as respiratory support to help with muscle stiffness and strengthen respiratory
muscles.
A relatively new therapy for SMA is called nusinersen.
Nusinersen is an antisense oligonucleotide, that binds to the SMN2 pre-mRNA and prevents
exon 7 from being removed, which allows the SMN2 mRNA to get expressed, ultimately making
a more normal amount of SMN protein.
All right, as a quick recap, spinal muscular atrophy is an autosomal recessive disorder
where a deletion of the SMN1 gene causes alpha-motor neurons in the spinal cord to die, resulting
muscle weakness and atrophy and in the more severe cases, respiratory failure and death.
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