20.03.04 AR disorders - i.e. SMA Flashcards

1
Q

Estimated incidence of SMA

A

1 in 6- 10,000

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2
Q

Carrier frequency of SMA

A

1 in 50 in UK

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3
Q

Is it a common cause of infant death

A

Yes, second most common AR disorder after CF.

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4
Q

What is the pathology of SMA

A
  • spinal cord and anterior horn motor neuron degeneration.

- The result of synaptic defects in motor neuromuscular junctions (NMJs)

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5
Q

Clinical phenotype

A
  • Progressive proximal limb and trunk muscle weakness
  • Breathing difficulties (intercostal muscle weakness)
  • paralysis of voluntary muscles
  • Tremor in fingers
  • Tongue fasiculations, poor suck and swallow.
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6
Q

What is prenatal SMA

A
  • Severe weakness of prenatal onset
  • Arthrogryposis multiplex congenita. Congenital joint contractures, absence of movement (except face and extraocular), death from respiratory arrest before 1 month of age.
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7
Q

What is type I SMA

A
  • 60% of all SMA.
  • Diagnosed before 6 months age.
  • Floppy baby= profound hypotonia, tongue fasiculations, lack of motor development
  • Progressive weakness in infancy and death at an early age (often due to aspiration pneumonia)
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8
Q

What is type II SMA

A
  • Intermediate subtype. 27% of SMA cases
  • Onset between 6-12 months
  • Low muscle tone, absent tendon reflexes. Can sit unaided but never able to walk
  • Reduced life expectancy (70% reach adulthood)
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9
Q

What is type III SMA

A
  • 12% of SMA patients
  • Onset of muscle weakness ~ after 10 months (IIIa) or 3 years (IIIb)
  • Can stand and are ambulatory (probability decreases with age)
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10
Q

What is type IV SMA

A
  • 1% of SMA patients
  • Onset of muscle weakness in 2nd or 3rd decade of life
  • Can stand and walk alone
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11
Q

What is atypical SMA

A
  • SMA with congenital bone fractures.

- Floppiness, multiple fractures of long bones, CNS involvement and elevated CK levels

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12
Q

Differential diagnosis for floppy babies

A
  • SMA
  • DM1
  • PWS
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13
Q

Which genes are associated with SMA

A
  • SMN1 and 2

- 5q12.2-13.3

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14
Q

SMA is caused by what

A

-Hom or het deletions/ mutations in SMN1

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15
Q

How are SMN1 and 2 arranged

A
  • SMN1 is telomeric

- SMN2 is centromeric

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16
Q

How many base pairs are different between SMN1 and 2

A

5bp

17
Q

Is SMN1 and 2 amino acid sequence identical

A

Yes

18
Q

Which synonymous variant alters the splicing efficiency of exon 7 of SMN2

A

c.840C>T

19
Q

Why does c.840C>T reducing splicing of exon 7 in SMN2

A
  • c.840C > T is translationally silent but disrupts an exonic splice enhancer (ESE) and creates a new exonic splice silencer (ESS)
  • Causes exon skipping. Non-functional protein which is rapidly degraded
20
Q

What proportion of transcripts are full length for SMN1 and 2

A
  • SMN1= 90% of transcripts are full length

- SMN2= 90% of transcripts lack exon 7

21
Q

What does SMN protein do in motor neurons

A
  • Complexes with Gemin and acts as a chaperone to assist the assembly of small ribonuclear proteins (snRNPs) in motor neurons.
  • Component of the spliceosome
22
Q

Is SMN protein essential for life

A
  • Yes.
  • Also SMA patients with hom SMN1 deletions have at least 1 copy of SMN2
  • Mouse knock outs are embryonic lethal with no SMN protein
23
Q

What two hypotheses are there for SMA disease mechanism

A
  • Loss of SMN impairs mRNA production and neurons are deficient in necessary proteins for growth and function
  • SMN has a motor neuron specific function.
24
Q

What percentage of SMA patients have a hom deletion of at least exon 7

A

95-98%

25
Q

How can exon 7 of SMN1 be lost

A
  • Deletion

- Conversion to exon 7 of SMN2 (unidirectional and non-reciprocal)

26
Q

What proportion of SMA patients are hom for inactivating point mutations

A

<1%

27
Q

Why is the incidence of SMA high even though it is lethal

A

-High mutation rate

28
Q

Has mosaicism been reported in SMA

A

Yes

29
Q

Is there a genotype phenotype correlation

A

Yes

  • SMA I= hom deletion of SMN1
  • SMA II= SMN1 to SMN2 gene conversion and a deletion
  • SMAIII= gene conversion on both alleles
30
Q

Can SMN2 compensate for SMN1 loss

A
  • Not fully but when SMN2 copy number increases, the small amounts of full length transcript can result in milder SMA II or III.
  • Correlation is not absolute or strong enough to have prognostic value, so not reported
31
Q

What genetic tests are offered in the diagnostic setting

A
  • Exon 7 and 8 dosage of SMN1
  • Often by MLPA, Real time PCR or qPCR
  • Probes are specific to the differences between SMN1 and 2
32
Q

What other testing is available to patients with clinical symptoms but only a het deletion

A

-Sequence analysis to look for 2nd undetected variant

33
Q

Why is carrier testing complex

A
  • 6% of parents will have normal SMN1 dosage
    1) 4% will have both copies on a single chromosome
    2) De novo deletion in 2% cases (i.e. only 1 parent is a carrier)
  • Linkage analysis would clarify
34
Q

Strategies for SMN therapies

A

increase the expression of SMN protein

35
Q

Examples of SMN therapies in development

A

1) Antisense oligonucleotides (ASOs) to correct SMN2 splicing. e.g. Spinraza. Benefits: no toxicity and highly stable
2) gene conversion from SMN2 to SMN2
3) Stem cell or gene threrapy to compensate for the lack of SMN protein. AAV9 virus engineered to carry WT SMN. e.g. Zolgensma. However, has some side effects.

36
Q

When is treatment most effective

A
  • Early
  • Motor neurons are non-dividing so once lost they cannot be replaced. Patients with advanced states of degeneration won’t benefit from treatment