Spinal muscular atrophy – causes, symptoms, diagnosis, treatment, pathology
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 cordto 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 allthe 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 entirenerve 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-toneparalysis.
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 severeof all and it starts even before birth, when mothers may notice decreased fetal movements. SMA type Ib, also called infantile SMA orWerdnig-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 a 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 difficultytaking milk, eating foods, or even safely swallowing their own secretions which canlead to aspiration. The weakness can also affect the chest wallmuscles and diaphragm leading to breathing difficulty and eventually respiratory failure. For these reasons, most of these babies surviveonly a few years. SMA types II, III, and IV are each successivelymilder 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 musclesupport of the spine and extremely thin limbs due to muscle wasting.
The different types of SMA all result fromthe same a homozygous deletion of the “survival motor neuron” gene or SMN1 gene on chromosome5, and this is inherited in an autosomal recessive pattern. The SMN protein from the SMN1 gene is expressedin all cells and is required to live. For one, the SMN protein is a component ofthe spliceosome, a molecular machine that cuts the introns out of pre-messenger RNAs. SMN also blocks caspases, which are proteinsinvolved in apoptosis, or programmed cell death, so lacking SMN may also enhance apoptosis. SMN protein’s also particularly importantfor alpha motor neurons, but the exact mechanism relating the protein to the function of thosecells is still unclear. Now, the genetics help explain the continuumof severity that we see across SMA, and it has to do with the SMN2 gene, which is a pseudogenethat sits next to SMN1 on chromosome 5. Pseudogenes are mutated copies of genes thatarose during evolution, and are less functional or non-functional versions of their counterparts. SMN2 is more than 99% identical to SMN1, butit has one important change in exon 7, called c.840C>T.
And this means that while the 840thnucleotide 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, functionalSMN 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 thisSMN2 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 milderSMA phenotype. So, as an example, a patient with two SMN2genes 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 businesses. Nusinersen is an antisense oligonucleotide,that binds to the SMN2 pre-mRNA and prevents exon 7 from being removed, which allows theSMN2 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 deletion of the SMN1 gene causes alpha-motorneurons in the spinal cord to die, resulting muscle weakness and atrophy and in the more severe cases, respiratory failure and death. Thanks for watching, you can help supportus by donating on Patreon, or subscribing to our channel, or telling your friends about us on social media.