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FP_23_S3 > SMA > Flashcards

SMA Flashcards

1
Q

Question

A

Answer

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2
Q

4 subtypes of SMA

A

TYPE I - severe; <6 mnths, never sit, death <2yearsTYPE II - intermediate; 7-18 months, sit but never walkTYPE III - mild; >18 mnths, stand and walk independentlyTYPE IV - very mild; 20-30s

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3
Q

Clinical features of SMA (generally)

A

NAME?

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4
Q

Cause of SMA

A 
SMN1 exon 7 deletion/gene conversion (98%) Point mutations (2%)
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5
Q

Underlying pathogenesis of SMA

A

SMN protein important in survival of anterior horn motor neurons of the spinal cord, which send signals to muscles to contract. Lack of SMN causes anterior horn cells to degenerate –> fewer, weaker signals

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6
Q

% identity between SMN1 and SMN2

A

99.9%, 5bp different

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7
Q

Copy number of SMN1 and SMN2 in normal individuals

A

0-4 per chromosome for each SMN1 and SMN2

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8
Q

Functional difference between SMN1 and SMN2

A

Synonymous C>T change in exon 7 of SMN2 (pseudogene of SMN1) > inactivates exonic splicing enhancer > leaky splicing.90% transcripts lack exon 7; truncated and degraded. SMN2 only produces 10% of the protein SMN1 does

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9
Q

How does SMN2 copy number affect phenotype

A

DOSAGE DEPENDENT DISEASE MODIFIERMultiple copies of SMN2 can increase SMN protein levels and reduce severity of phenotype HOWEVER not reliable so not used diagnostically

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10
Q

Genetics of type 1 SMA

A

Caused by homozygous deletion of at least exon 7 of SMN1.| 20% of SMN protein produced

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11
Q

Genetics of type 2 SMA

A

Comp het for del of at least exon 7 of SMA1 and gene conversion event. 30% of SMN protein produced

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12
Q

Genetics of type 3 SMA

A

Homozygous for gene conversion event| 40% SMN protein produced

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13
Q

Can genotype be used to predict phenotype

A

No - as its really difficult to determine SMN1 and SMN2 copy number due to variable copy number per allele in normal individuals. PLUS there are modifier genes

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14
Q

Principles of gene conversion

A

OCCURS IN CIS1. double strand breaks 2. 5’ and 3’ ends are moved away from each other3. broken strands align with donor sequence of high homology4. mismatch repair occurs; broken strand is remade using donor strand as template

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15
Q

Genetic testing in SMA

A

MLPA - uses probes specific to small number of differences in seq between SMN1 and SMN2

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16
Q

What proportion of NORMAL people lack SMN2

A

10%

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17
Q

What proportion of normal chromosomes have two copies of SMN1? and are the limitations of this?

A

4%| could mask a carrier of a deletion (2:0)

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18
Q

What proportion of mutations in SMA are de novo

A

2%

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19
Q

What is the UK carrier frequency of SMA?

A

Jan-50

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20
Q

What are the main clinical features of SMA?

A

Weakness and paralysis of the voluntary muscles, due to spinal cord and motor neuron degeneration. Muscular atrophy.Progressive proximal weaknessIntercostal muscle weakness, leading to breathing difficulty.Fine tremorFasciculations in the tongue make feeding difficult

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21
Q

Describe the 5 types of SMA

A

Prenatal - Arthrogryposis multiplex congenita and congenital axonal neuropathy. Death within 1 month. SMN2 copies: 1Type I: Acute infant - diagnosed <6 months old. Floppy baby, weak intercostal muscles lead to respiratory failure. 60% of SMA. Death at early age (<2yrs old). Lack of motor development, tongue fasciculation. SMN2 copies: 2Type II: Chronic infant - diagnosed 6-12months. 27% of SMA, hypotonia, 70% reach adulthood, sit unaided, no walking without support. Progressive muscle weakness. SMN2 copies 3-4Type III: Juvenile - IIIa diagnosed at <3 years; IIIb diagnosed at >3 years. 12% of SMA. Some ambulation retained. Proximal muscle weakness develops, legs more severely affected than arms. SMN2 copies: 3-4Type IV: adult - ~1% of patients, onset of muscle weakness in 2nd-3rd decade, legs more affected than arms. Normal life expectancy. SMN2 copies 4-8

22
Q

How many individuals are thought to carry two copies of SMN1 on a single chromosome

A

4%

23
Q

Describe the basic gene structure of SMN1/2.

A

SMN1 and SMN2 (pseudogene). Arranged in tandem.SMN1 is functional, SMN2 is largely unfunctional and lacks exon 7 in most transcripts. Increased copies of SMN2 can compensate for loss of SMN1 in some cases.SMN1 - >90% of transcripts are full length; SMN2 90% of transcripts are missing exon 7, due to the c.840C>T silent variant present in an ESE.

24
Q

How many bases so SMN1 and SMN2 differ by? What are the common variants that allow the two genes to be distinguished?

A

5.c.840C>T and c.859G>C in SMN2

25
Q

What is the SMN protein?

A

A ubiquitously expressed protein present in abundance in the motor neurons and spinal cord.It functions to chaperone the assembly of the snRNAs used for splicing. Lack of the protein thought to disrupt mRNA processing in neuromuscular junctions.

26
Q

What is the common mutation found in 95-98% of all SMA individuals?

A

A deletion encompassing at least exon 7 of SMN1 - deletion can occur by homozygous deletion, or by gene conversion to SMN2 exon 7 (contains the c.840G>C resulting in exon skipping)

27
Q

What is the mutational spectrum of SMA?

A

95-98% deletion of exon 72-5% deletion + SNP<1% homozygous SNP - majority located in exons 3 and 6. Some can be deep intronic

28
Q

What is the rate of new mutation?

A

2% de novo.

29
Q

Describe the genotype/phenotype correlations found in SMA

A

Type I: homozygous deletion of exon 7Type II: SMN1 > SMN2 gene conversion plus a hemizygous gene deletion of the other allele.Type III: 2 gene conversion event.

30
Q

How can SMN2 copy number compensate, in part, for lack of SMN1?

A

Disease is caused by low levels of protein, rather than complete lack of protein.SMA I: 9% normal active proteinSMA II: 14%SMA III: 18%Full length SMN levels of 23% are needed for normal function.The presence of 3+ SMN2 copies can make the phenotype milder.The c.859G>C variant creates an new ESE in exon 7 of SMN2, to enhance exon 7 inclusion.

31
Q

List some modifier genes involved in the phenotypic severity of SMA

A

NAIPSERF1Plastin 3ZPR1PTEN

32
Q

Describe the diagnostic workflow for SMA mutation detection

A

Copy number analysis using specific probes for SMN2 c.840G>C and SMN1 WT sequences. (QPCR, RT-PCR, MLPA)Sequencing using LR-PCR or cDNA analysis to ID point mutations on the second allele.

33
Q

What project is ongoing and looks to introduce an NIPD test for SMA?

A

NIPSIGEN.

34
Q

Why is interpreting SMA carrier tests tricky?

A

6% of parents of a simplex case will have normal SMN1 dosage:1. 4% have two copies of SMN1 on a single chromosome.2. 2% of patients have a de novo deletion of exon 7 - only 1 parent is a carrier.

35
Q

What therapies are currently being trialled to treat SMA?

A
  1. increase expression of SMN proteins by correcting SMN2 splicing using antisense oligos - ISIS-SMNrx is currently in phase 3 clinical trials - enhances inclusion of exon 7.2. Gene conversion from SMN2 to SMN13. Use stem cell therapy to compensate for lack of SMN protein - AveXis is currently in phase 1 clinical trials.
36
Q

what is the SMA carrier frequency in uk?

A

Jan-50

37
Q

what is the main clinical symptom of SMA?

A

NAME?

38
Q

describe the different SMA types? what is the most likely cause?

A
  • type 1 = most common form <6 months- floppy babydeath at early age- poor head control and unable to sit- swallowing and feeding difficulties- homozygous deletiontype 2 = <1 year- low muscle tone- may be able to sit, never able to walk- 70% reach adulthood- gene conversion in one allele and hemi deletion in other- type 3 = >1 until adulthood- can stand and walkprobability of being ambulatory decreases with age- gene conversion in both allelestype 4 = adult onsetnormal life expectancy<1% of patientsaytypical - non chromosome 5 relatedfloppiness, multiple fractures, high CK
39
Q

if a baby presents as floppy, what is the testing triad?

A

SMA, myotonic dystrophy and PWSnew TD = R70 (separate referral from hypotonic infants which go for R69 DM1, PWS and microarray so now the consultant has to specify SMA)

40
Q

what causes SMA?

A

homozygous or compound het deletions and mutations of SMN1- 98% homozygous deletion of SMN1 exon 7 (deletions or gene conversions)- 2% compound het for a deletion and mutation- <1% have homozygous pathogenic mutation in SMN1mutations may be deep intronic. 2% of deletions are de novo (unequal crossing over)Incidence of SMA remains high due to high new mutation rate- germline and somatic mosaicism have been described

41
Q

why is the SMA gene difficult to test

A
  • has SMN2 (centromeric) pseudogene- complex region of high instability with repetitive sequences, retrotransposable elements, deletions and inverted duplications- 4% of population have two copies of SMN1 on one chromosome (can have up to 5 copies)- SMN1 and 2 differ by 5 base pairs- critical difference is a synonymous variant in SMN2 exon 7 which alters ESE and 90% of transcripts lack exon 7 in SMN2 and produce truncated product and so is degraded- SMN2 still produces some full length SMN protein (10%) but not sufficient to compensate for lack of SMN1- homozygous SMN1 del patients have at least one copy of SMN2 as SMN null mice is embryonic lethal- higher copies of SMN2 leads to milder phenotypes
42
Q

what is the SMN protein a component of?

A

spliceosome

43
Q

how do you test for SMA?

A

-98% are deletions so MLPA or real-time PCR for SMN1 exon 7 & 8 deletion - MLPA uses probes specific to the SNV differences between SMN1 and SMN2- multiplex real time PCR uses TaqMan probes specific to exon 7 SMN1 and a control probe- 2% sequence variant - NGS, allele specific long range PCR and RT-PCR/cDNA sequencing are used for specific analysis of SMN1

44
Q

why might a parent of a child with SMA have normal SMN1 dosage? how can this be confirmed?

A
  • 4% of population have two copies of SMN1 on one chromosome - linkage analysis- de novo deletion - 2% of patients, can do bayes calculation for normal dosage parent.
45
Q

what therapies are available for SMA?what are issues with these treatments?

A

drugs work by stabilising the SMN protein or modulating SMN2 expression- Increasing protein: Zolgensma - virus vector delivers SMN1 transgene to affected motor neuronsmodulate SMN2:Nusinersen/Spinraza is an antisense oligo to promote inclusion of exon 7 in SMN2 transcripts by blocking intron 7 splice site to increase SMN protein levels. highly stable and not toxic. Risdiplam - oral (not injected)promotes inclusion of exon 7 in SMN2Issues - usually diagnosedin advanced stages where motor degeneration has occured. screened for?current pilot study to include SMA in UK newborn screening - March 2022

46
Q

How many types of SMA are there?

A

6 - Prenatal, type 1, Type 2, Type 3, Type 4 and atypical SMA

47
Q

Describe 3 characteristic features of SMA

A

Progressive proximal symmetrical limb and trunk muscle weakness,Intercostal muscle weakness,Fine tremorFacial weaknessCarrier freq 1:40-60 depending population

48
Q

What is the most common type of SMA? Describe clin features

A

Type 1 - profound hypotonia, symmetrical flaccid paralysis, progressive, death at early age

49
Q

Give me some molecular facts about SMA

A

SMN1 and pseudogene SMN24% population have 2 copies of SMN1 on one chrm (range 0-5)95-98% SMA homozygous for deletion of at least exon 72-5% are compound heterozygotes for del and pathogenic inactivating mutation

50
Q

How do we interpret SMA carrier testing?

A

Bayes calculation

FP_23_S3 (6 decks)

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