Clinical Presentation and more Pathophysiology
Identify common signs and symptoms seen in SMA type 1
Hypotonia and weakness (progressive, symmetric, proximal, greater in legs than arms)
Others: diminished/absent DTR, respiratory and feeding complications (weak cry and cough; poor feeding; tongue fasciculations; lack of head control; facial weakness)
Describe the role of genetics in SMA type I
autosomal recessive
homozygous deletion of the "survival motor neuron 1" gene (SMN1)
SMN1 encodes for survival motor neuron (SMN), a protein that inhibits neuronal apoptosis. Loss-of-function of both copies causes neurons to have an increased susceptibility to programmed cell death (leads to loss of anterior horn cells causing the severe muscle weakness and atrophy
How many classes of SMA are there? List and rank the classes from mild-> severe.
4, Type 4-> Type1A
What is Nusinersen? Which SMN protein does it impact?
Purpose of gene therapy is to increase the production of SMN protein in MNs and thereby improve motor function and survival.
Nusinersen - antisense oligonucleotide binds to SMN2 pre-mRNA and prevents exon 7 from being "skipped". allows SMN2 mRNA to get expressed, making more functional SMN proteins
Complete the sentence: SMA is a ___ splicing error. Name the exon lost and the chromosome location.
RNA; 7th on 5th chromosome (94% of cases)
Identify the types of SMA and criteria for naming them. Which phenotypes are more severe?
5 types ( 4 Classes) determined by timing of onset of symptoms
Differentiate upper and lower motor neuron disease and their characteristics
lower - when motor neuron dies, motor unit stops working --> muscle weakness (hypotonia) --> muscle atrophy. abnormal nerve conduction
Upper - increased muscle tone and spasticity. Normal nerve conduction
Why did our patient have a weak cry?
due to weakness in abdominal muscles
Describe Nusinersen in regards to effectiveness and cost
Clinical progression is arrested or even reversed.
Extremely high cost and the necessity of intrathecal administration of nusinersen are problematical, but this drug is a superb example of modern therapeutics driven by detailed molecular genetic information.
SMA causes an apoptosis of what type of motor neurons (Hint: Think about our lecture from this week)
a-LMN (particularly the anterior horn cells in the spinal cord)
Explain what SMA syndrome does to a neuro exam.
Diminished or absent DTR
Identify organ systems affected by SMA
MSK
Resp - change in chest wall; atrophied muscles w/ spared diaphragm
GI - difficulty swallowing, risk malnutrition
Neuro - diminished/absent DTR
Complete the sentence: SMN proteins block ____ which are proteins involved in apoptosis.
Caspases
What is the successful recombinant virus vector based gene therapy used to treat SMA called?
GIMME THE DRUG NAME (one time shot)
Onasemnogene Abeparvovec
What is paradoxical breathing and a bell shaped torso? And why did it occur with our patient?
paradoxical breathing (inward movement of the abdomen upon inhalation), bell-shaped torso (toso looks like a bell DUH)
due to intercostal weakness but spared diaphragm, respiratory distress (or other prolonged shortness of breath)
DAILY DOUBLE!
Complete the sentence: SMA is the #1 cause of ____ death.
What age do they usually die by?
infant; 2
Describe the histological findings of muscular biopsy in patient with SMA type I
Atrophied muscle cells with some minor compensatory muscle cells being bigger than usual.
Explain the difference between Type 1A vs Type 1B Syndrome for infants? In your answer please use terms such as “congenital” and “infantile”? Which type did our patient present with?
Congenital (1A) most severe symptoms begin in the womb w/ decreased fetal movement. Infantile (1B) appears normal at birth but after a few weeks displays decreased muscle tone and progressive weakness, worse proximally than distally and more obvious in the legs. Our pt had 1B
What is the MOA of adenoassociated virus vector gene therapy?
an agent based on adenovirus 9 based vector that carries a normal copy of SMN1 to the lower motor neurons of the spinal cord
What is the major distinction between SMN 1 and SMN 2 in terms of their effeciency? Which one determines the severity of SMA and why?
SMN 2 gene will have to pick up the slack for the production of the SMN protein. The more SMN2 genes we have the more functional SMN proteins we will have to offset the loss of SMN1
Summarize what SMA is, must also describe which population (race of ppl) it targets the most?
SMA is a group of genetic disorders characterized by progressive degeneration of spinal cord and brainstem motor neurons resulting in hypotonia, atrophy of skeletal muscles, and generalized weakness.
Second most common lethal autosomal recessive condition in white populations (second to CF). It usually presents in infancy with extreme muscle weakness and atrophy due to severe loss of anterior horn cells.
A defect in the assembly of what causes problems with the formation of the SMN complex?
SnRNPs (small nuclear ribonucleoprotein) due to the inability to splice out the introns
SMN2 gene is almost identical to the SMN1 gene. What is the difference that is located at exon 7? What does this cause?
c.840C>T (840th nucleotide C is changed to T); cause to produce only some functional SMN protein where the rest is rapidly degraded
DAILY DOUBLE!!!
What is the name of the first orally available drug to treat SMA (Came out 2020)? Double points if you can explain the MOA of this new drug.
orally-administered drug risdiplam (Evrysdi) to treat patients age two months of age and older with SMA. risdiplam, modifies the splicing of SMN2 messenger RNA to include exon 7 which results in an increase in the concentration of the functional SMN protein.
Within 4 weeks of taking Evrysdi, SMN protein levels in the blood more than doubled for all SMA types, throughout 12 months of the trials.
Describe the nerve conduction study. What would the results be for a pt with SMA?
Measures how well the nerves carry electrical signals. Provides info on velocity (myelination) and amplitude of axonal fibers
For SMA, sensory would be normal.
Motor would show delayed conduction velocity and decreased compound AP