Spinal muscular atrophy – causes, symptoms, diagnosis, treatment, pathology

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 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. Thanks for watching, you can help support
us by donating on patreon, or subscribing to our channel, or telling your friends about
us on social media.

54 Replies to “Spinal muscular atrophy – causes, symptoms, diagnosis, treatment, pathology”

  1. The best thing in you gives you a detailed information about the disease
    and explain how the disease has become in detail and in an orderly
    manner that is fantastic
    Thanks keep going in this way

  2. please do one on brain metastasis…it is an unmet clinical need and incidence seems to be on the rise due to emergence of targeted therapeutics throughout the last years (the CNS seems to offer cancer cells a sanctuary site to seed and colonize new target sites)…

    http://www.nature.com/nrc/journal/v16/n7/full/nrc.2016.64.html

    https://www.google.de/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-8#q=brain+metastasis+review+cell

  3. iam suffering from SMA about 24 years. there is no medicine for it .
    we can take stem cells therapy for SMA. please reply me please please

  4. Hey, so does Nusinersen only helps in slowing dows/ reducing the effect of the disease or completly cures it?
    If it prevents the exon 7 from SMN2 from being removed, then the SMN2 is fully functional as SMN1 and produces no degraded and only functional proteins. So, can we say that the disease can been cured by taking the drug regularly?
    (plz reply asap)

  5. you are doing a great job. The videos that u upload are really helpful. plz plz plz do upload more. I am a medical student and these videos are really helpful. Thank u so much. plz do make more videos from neurology.

  6. Hi, I may be wrong however SMA has more than the 840CT difference between gene 1 and 2 in exon 7 correct? Reading some articles I see that there can be several changes in difference gene location.

    Please let me know if anyone has an idea. SMA is the title of my literature review

  7. I still don't understand, how is the deletion of SMN 1 (which produces SMN proteins) directly contribute to the death of alpha motors and spinal cords?

  8. Hello everyone
    I m 31 year old I m suffering from bulging disc L4,L5 n S1 due to which my right calf muscle and sole (planter) has become weak in strength and size now I can’t walk properly and my doc is just giving me pregabalin n some vitamins B12 tablets n its been almost 8 months I m suffering from this situation
    Pleaseeee anyone tell me what should I do to recover my calf muscle’s strength n size
    Please suggest any medicine or exercise

  9. Is there more to the milk thing in infants ? Do they become lactose intolerant for life or do they just struggle as newborns with the mechanics of actually feeding ?

  10. Could you maybe make a follow up to this and really go into detail about spinraza and nusinersen? My boyfriend has SMA and I just want to learn all I can about it

  11. Nusinersen doesn't bind directly to exon 7 but to a regulatory motif (ISS-N1) in the downstream intron. Other than that great video! 🙂

  12. Okay great.. But how do you know for sure if you have a milder version? And how can you get help as an adult?

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