Taiwanese Journal of Obstetrics and Gynecology
Volume 44, Issue 3 , Pages 201-208, September 2005

Current Aspects in the Molecular Genetics and Diagnostics of Spinal Muscular Atrophy

  • Shu-Chin Chien
    • ,
  • Yi-Ning Su

      Affiliations

    • Corresponding Author InformationCorrespondence to: Dr. Yi-Ning Su, Department of Medical Genetics, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan

Department of Medical Genetics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

Received 11 August 2005; received in revised form 11 August 2005; accepted 14 August 2005.

Article Outline

Summary

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene on 5q13. It leads to progressive muscle wasting and paralysis as a result of degeneration of anterior horn cells of the spinal cord. The most frequent mutation is biallelic deletion of exon 7 of the SMN1 gene. About 5-6% of SMA patients present compound heterozygosity with a point mutation on one allele and deletion on the other; the remaining cases are likely to be related to non-5q-linked defects. Introduction of a quantitative polymerase chain reaction-based test further enhances the diagnostic potential by increasing the detection rate of cases with the biallelic exon 7 deletion in SMN1 and point mutations. Due to the higher prevalence of SMA than other autosomal recessive disorders and lack of efficient medical treatment, accurate identification of SMA carriers in general populations is much more important to reduce the social and financial burden of SMA.

Key Words:  carrier , molecular diagnosis , SMN , spinal muscular atrophy

No full text is available. To read the body of this article, please view the PDF online.

 

Back to Article Outline

References 

  1. Cusin V , Clermont O , Gerard B , Chantereau D , Elion J . Prevalence of SMN1 deletion and duplication in carrier and normal populations: implication for genetic counselling . J Med Genet . 2003;40:e39
  2. Feldkotter M , Schwarzer V , Wirth R , Wienker TF , Wirth B . Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and Carriers are asymptomatic and couples who are both carriers run a 25% risk of having an affected child with each pregnancy. In the current medical system, we can only identify couples at risk when they have already borne a child with SMA. A powerful and efficient carrier-prediction of severity of spinal muscular atrophy . Am J Hum Genet . 2002;70:358–368
  3. Ogino S , Wilson RB . Genetic testing and risk assessment for spinal muscular atrophy (SMA) . Hum Genet . 2002;111:477–500
  4. Pearn J . Classification of spinal muscular atrophies . Lancet . 1980;i:919–922
  5. Melki J . Spinal muscular atrophy . Curr Opin Neurol . 1997;10:381–385
  6. Munsat TL , Davies KE . International SMA consortium meeting. (26–28 June 1992, Bonn, Germany) . Neuromuscul Disord . 1992;2:423–428
  7. Zerres K , Rudnik-Schoneborn S . Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications . Arch Neurol . 1995;52:518–523
  8. Scheffer H , Cobben JM , Matthijs G , Wirth B . Best practice guidelines for molecular analysis in spinal muscular atrophy . Eur J Hum Genet . 2001;9:484–491
  9. Wirth B . An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA) . Hum Mutat . 2000;15:228–237
  10. Lefebvre S , Burglen L , Reboullet S , et al.   Identification and characterization of a spinal muscular atrophy-determining gene . Cell . 1995;80:155–165
  11. Burglen L , Lefebvre S , Clermont O , et al.   Structure and organization of the human survival motor neurone (SMN) gene . Genomics . 1996;32:479–482
  12. Lorson CL , Hahnen E , Androphy EJ , Wirth B . A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy . Proc Natl Acad Sci USA . 1999;96:6307–6311
  13. Lorson CL , Androphy EJ . The domain encoded by exon 2 of the survival motor neuron protein mediates nucleic acid binding . Hum Mol Genet . 1998;7:1269–1275
  14. Chang JG , Hsieh-Li HM , Jong YJ , Wang NM , Tsai CH , Li H . Treatment of spinal muscular atrophy by sodium butyrate . Proc Natl Acad Sci USA . 2001;98:9808–9813
  15. Cartegni L , Krainer AR . Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1 . Nat Genet . 2002;30:377–384
  16. Chan V , Yip B , Yam I , et al.   Carrier incidence for spinal muscular atrophy in southern Chinese . J Neurol . 2004;251:1089–1093
  17. Wirth B , Herz M , Wetter A , et al.   Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling . Am J Hum Genet . 1999;64:1340–1356
  18. Cusco I , Lopez E , Soler-Botija C , Jesus Barcelo M , Baiget M , Tizzano EF . A genetic and phenotypic analysis in Spanish spinal muscular atrophy patients with c.399_402del AGAG, the most frequently found subtle mutation in the SMN1 gene . Hum Mutat . 2003;22:136–143
  19. Talbot K , Ponting CP , Theodosiou AM , et al.   Missense mutation clustering in the survival motor neuron gene: a role for a conserved tyrosine and glycine rich region of the protein in RNA metabolism? . Hum Mol Genet . 1997;6:497–500
  20. Clermont O , Burlet P , Burglen L , et al.   Use of genetic and physical mapping to locate the spinal muscular atrophy locus between two new highly polymorphic DNA markers . Am J Hum Genet . 1994;54:687–694
  21. Chen KL , Wang YL , Rennert H , et al.   Duplications and de novo deletions of the SMNt gene demonstrated by fluorescence-based carrier testing for spinal muscular atrophy . Am J Med Genet . 1999;85:463–469
  22. Zeesman S , Whelan DT , Carson N , et al.   Parents of children with spinal muscular atrophy are not obligate carriers: carrier testing is important for reproductive decision-making . Am J Med Genet . 2002;107:247–249
  23. Mailman MD , Heinz JW , Papp AC , et al.   Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2 . Genet Med . 2002;4:20–26
  24. Ogino S , Wilson RB . SMN dosage analysis and risk assessment for spinal muscular atrophy . Am J Hum Genet . 2002;70:1596–1598 author reply 1598–9
  25. Schrank B , Gotz R , Gunnersen JM , et al.   Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos . Proc Natl Acad Sci USA . 1997;94:9920–9925
  26. Viollet L , Bertrandy S , Bueno Brunialti AL , et al.   cDNA isolation, expression, and chromosomal localization of the mouse survival motor neuron gene (Smn) . Genomics . 1997;40:185–188
  27. Hsieh-Li HM , Chang JG , Jong YJ , et al.   A mouse model for spinal muscular atrophy . Nat Genet . 2000;24:66–70
  28. Monani UR , Sendtner M , Coovert DD , et al.   The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy . Hum Mol Genet . 2000;9:333–339
  29. Cifuentes-Diaz C , Frugier T , Tiziano FD , et al.   Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy . J Cell Biol . 2001;152:1107–1114
  30. Frugier T , Tiziano FD , Cifuentes-Diaz C , et al.   Nuclear targeting defect of SMN lacking the C-terminus in a mouse model of spinal muscular atrophy . Hum Mol Genet . 2000;9:849–858
  31. Byers RK , Banker BQ . Infantile muscular atrophy . Arch Neurol . 1961;5:140–164
  32. Nicole S , Diaz CC , Frugier T , Melki J . Spinal muscular atrophy: recent advances and future prospects . Muscle Nerve . 2002;26:4–13
  33. van der Steege G , Grootscholten PM , van der Vlies P , et al.   PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy . Lancet . 1995;345:985–986
  34. Anhuf D , Eggermann T , Rudnik-Schoneborn S , Zerres K . Determination of SMN1 and SMN2 copy number using TaqMan technology . Hum Mutat . 2003;22:74–78
  35. Gerard B , Ginet N , Matthijs G , et al.   Genotype determination at the survival motor neuron locus in a normal population and SMA carriers using competitive PCR and primer extension . Hum Mutat . 2000;16:253–263
  36. McAndrew PE , Parsons DW , Simard LR , et al.   Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number . Am J Hum Genet . 1997;60:1411–1422
  37. Scheffer H , Cobben JM , Mensink RG , Stulp RP , van der Steege G , Buys CH . SMA carrier testing-validation of hemizygous SMN exon 7 deletion test for the identification of proximal spinal muscular atrophy carriers and patients with a single allele deletion . Eur J Hum Genet . 2000;8:79–86
  38. Su YN , Hung CC , Li H , et al.   Quantitative analysis of SMN1 and SMN2 genes based on DHPLC: a highly efficient and reliable carrier-screening test . Hum Mutat . 2005;25:460–467
  39. Wirth B , Schmidt T , Hahnen E , et al.   De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling . Am J Hum Genet . 1997;61:1102–1111
  40. Campbell L , Daniels RJ , Dubowitz V , Davies KE . Maternal mosaicism for a second mutational event in a type I spinal muscular atrophy family . Am J Hum Genet . 1998;63:37–44
  41. Parano E , Pavone L , Falsaperla R , Trifiletti R , Wang C . Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy . Ann Neurol . 1996;40:247–251
  42. Muqit MM , Moss J , Sewry C , Lane RJ . Phenotypic variability in siblings with type III spinal muscular atrophy . J Neurol Neurosurg Psychiatry . 2004;75:1762–1764

PII: S1028-4559(09)60142-X

doi:10.1016/S1028-4559(09)60142-X

Taiwanese Journal of Obstetrics and Gynecology
Volume 44, Issue 3 , Pages 201-208, September 2005

Article Tools