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SMA Case Study

SMA Case Study. Ruth Lewis SCOBEC & Birmingham Training Day 15 th October 2008. Spinal Muscular Atrophy (SMA). Autosomal recessive inheritance Progressive muscle weakness due to degeneration and loss of anterior horn cells (lower motor neurons) Patients classified clinically into groups

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SMA Case Study

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  1. SMA Case Study Ruth Lewis SCOBEC & Birmingham Training Day 15th October 2008

  2. Spinal Muscular Atrophy (SMA) • Autosomal recessive inheritance • Progressive muscle weakness due to degeneration and loss of anterior horn cells (lower motor neurons) • Patients classified clinically into groups • Prevalence approximately 1/10,000 • Carrier frequency of 1/40 – 1/60

  3. SMA region • Localised on 5q13 • Unusually complex • Includes a 500kb duplication and inversion • Duplicated region contains at least four genes including the survival motor neuron (SMN) gene • SMN exists as two homologues – SMN1 and SMN2 • SMN1 is the primary disease causing gene

  4. SMN1 and SMN2 • Highly homologous • Differences used to distinguish SMN1 and SMN2 • One of these differences disrupts an exonic splice enhancer in SMN2, resulting in a large proportion of mRNA transcripts that lack exon 7 • SMN1 produces primarily full length transcripts

  5. SMA mutations • SMN1 exons 7 and 8 are undetectable in over 95% of SMA patients • Due to either homozygous deletions or conversion of sequences of SMN1 into those of the SMN2 gene • Remaining patients are compound heterozygotes with a point mutation on one chromosome 5 and a deletion/gene conversion on the other • Absence of SMN1 results in insufficient amounts of full length transcript • Presence of SMN2 results in a small amount of full length transcript • Therefore if a patient has extra copies of SMN2, the more full length transcript will be produced and the milder the SMA phenotype

  6. Testing • Multiplex Ligation Dependent Probe Amplification (MLPA) • Kit supplied by MRC-Holland • Method to establish the copy number of the SMN1 and SMN2 genes • MLPA probes detect SMN1 exons 7 and 8, SMN2 exons 7 and 8, SMN (both 1 & 2) exons 1, 4, 6 and 8 • Each kit also contains a number of internal control probes for specific sequences on different chromosomes.

  7. Examples Two copies SMN1

  8. One copy SMN1 No copies SMN1 Examples

  9. Considerations • Approximately 4% of normal chromosomes carry two copies of the SMN1 gene.

  10. OR Additional copy SMN1 Three copies SMN1 Two copies SMN1

  11. Considerations • Approximately 4% of normal chromosomes carry two copies of the SMN1 gene. • MLPA kit not designed to detect point mutations in the SMN1 gene • High new mutation rate. In approximately 2% of SMA cases there is a de novo mutation on one allele.

  12. Case Study • Baby boy – CR • Born prematurely, normal delivery • Floppy baby • Failure to thrive • No dysmorphia • Karyotyping requested • Prader Willi, Myotonic dystrophy and SMA testing requested

  13. Test Results • XXY karyotype – Klinefelter syndrome • Homozygous deletion of SMN1 gene – SMA • Development of swallowing difficulties and apnoea • Admission of CR to hospital • Family referred to clinical genetics • Parents (Father – JR, Mother - TL) both under age 16 years, maternal and paternal grandmothers seen in genetics clinic

  14. JR TL CR SMA family 0

  15. ML PL DR SR 2 2 2 2 ? JT DL MR GR JR TL 2 2 CR 0 SMA family KE

  16. ML PL DR SR 2 2 2 2 JT DL MR GR JR TL 2 2 2 2 CR 0 SMA family KE ?

  17. ML PL DR SR 2 2 2 2 DE 1 ? JT DL MR GR JR TL AL 2 2 2 2 1 CR 0 SMA family KE

  18. JT Two copies SMN1 OR SMA family ML PL DR SR 2 2 2 2 DE KE 1 ? DL MR GR JR TL AL 2 2 2 2 1 CR 0

  19. ML PL DR SR 2 2 2 2 JS DE 3 1 ? JT DL MR GR JR TL AL CC EL 2 2 2 2 1 2 2 Two copies SMN1 OR SMA family KE CR 0 Three copies SMN1

  20. JR possible interpretations • Not a Carrier • The deletion arose de novo in CR • UPD chromosome 5 in CR • Carrier • two copies of SMN1 on the one chromosome and a deletion on the other • JR may be a carrier of the deletion in only a percentage of his cells (somatic or germ)

  21. ML PL DR SR 2 2 2 2 JS DE 3 1 JT DL MR GR JR TL AL CC EL SP 2 2 2 2 1 2 2 2 CR Two copies SMN1 OR SMA family KE ? 0

  22. Linkage Results

  23. Conclusions • Linkage analysis excluded UPD for the SMN1 chromosomal region • Cannot completely exclude the possibility that JR has two copies on one chromosome • Most likely that JR has one copy of SMN1 on each chromosome and that the deletion in CR is a de novo mutation • EL inherited the high risk haplotype from her father and the haplotype known to be associated with two copies from her mother. She is almost certainly a carrier.

  24. ML PL DR SR 2 2 2 2 JS DE 3 1 ? JT DL MR GR JR TL AL CC EL SP 2 2 2 2 1 2 2 2 CR Two copies OR 1 - 1 2 - 0 SMA family KE 0

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