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Congenital muscular dystrophy with laminin α2 chain deficiency: Identification of a new intermediate phenotype and correlation of clinical findings to muscle immunohistochemistry

  • Neuropediatrics
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Abstract

The laminins comprise of a family of heterotrimeric proteins of the extracellular matrix. The cross-shaped proteins consist of a heavy α-chain and two light chains, called β and γ. Each group of chains, classified on their sequence identity and domain organization, include different isoforms. A deficiency of the α2 chain of laminin-2, previously termed merosin or M component, was shown to be responsible for one form of congenital muscular dystrophy (CMD). We investigated muscle biopsies of 20 patients with the clinical diagnosis of CMD and histological evidence of muscular dystrophy for the expression of different laminin chains. Patients with evidence of pachygyria/lissencephaly of the CNS were excluded from this series. The immunohistochemical analysis was correlated to clinical findings and MRI data of the brain. Of 20 patients, 11 (55%) revealed complete or near-complete deficiency of the α2 chain in their skeletal muscle specimens. So far none of these patients became ambulant. Of 20 patients 2 showed partial but clear-cut α2 chain-deficiency. These two patients became ambulant at 18 months and 3 years. All 13 patients with complete or partial α2 chain-deficiency demonstrated cerebral white matter changes on MRI. In contrast, 6/7 CMD patients with normal α2 chain expression became ambulant and none of the 6/7 tested showed evidence of cerebral abnormal T2 sequence signal of the myelin on MRI.

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Abbreviations

CK :

creatine kinase

CMD :

congenital muscular dystrophy

FCMD :

Fukuyama congenital muscular dystrophy

MEB :

muscle eye brain disease

WWS :

Walker-Warburg syndrome

References

  1. Arahata K, Hayashi YK, Koga R et al. (1993) Laminin in animal models for muscular dystrophy: defect of laminin M in skeletal and cardiac muscles and peripheral nerve of the homozygous dystrophic dy/dy mice. Proc Jpn Acad 69:259–264

    Google Scholar 

  2. Brown JC, Timpl R (1994) The laminins. Matrix Biol 14: 275–281

    Google Scholar 

  3. Campbell KP, Ervasti JM (1993) A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol 122:809–823

    Google Scholar 

  4. Dubowitz V (1994) Workshop report on 22nd ENMC sponsored meeting on congential muscular dystrophy held in Baarn, The Netherlands, May 14–16 1993. Neuromusc Disord 4: 75–81

    Google Scholar 

  5. Ehrig K, Leivo I, Agraves WS, Ruoslahti E, Engvall E (1990) Merosin, a tissue-specific basement membrane protein, is a laminin-like protein. Proc Natl Acad Sci USA 87: 3264–3268

    Google Scholar 

  6. Engvall E (1993) Laminin variants: why, where and when? Kidney Int 43: 2–6

    Google Scholar 

  7. Engvall E, Leivo I (1988) Merosin, a protein specific for basement membranes of Schwann cells, striated muscle, and trophoblast is expressed late in nerve and muscle development. Proc Natl Acad Sci USA 85: 1544–1548

    Google Scholar 

  8. Engvall E, Earwicker D, Day A, Muir D, Manthorpe M, Paulsson M (1992) Merosin promotes cell attachement and neurite outgrowth and is a component of the neurite-promoting factor of RN22 Schwannoma cells. Exp Cell Res 198: 115–123

    Google Scholar 

  9. Fardeau M, Dubowitz V (1995) Proceedings of the 27th ENMC sponsored workshop on congenital muscular dystrophy 22–24 April 1994, The Netherlands. Neuromusc Disord 5: 253–258

    Google Scholar 

  10. Goodman SL, Deutzmann R, Mark K von der (1987) Two distinct cell-binding domains in laminin can independently promote nonneuronal cell adhesion and spreading. J Cell Biol 105: 589–598

    Google Scholar 

  11. Hayashi YK, Engvall E, Arikawa-Hirasawa E et al. (1993) Abnormal localization of laminin subunits in muscular dystrophies. J Neurol Sci 119: 53–64

    Google Scholar 

  12. Hayashi YK, Koga R, Tsukahara T et al. (1995) Deficiency of laminin α2-chain mRNA in muscle in a patient with merosin-negative congenital muscular dystrophy. Muscle Nerve 18: 1027–1030

    Google Scholar 

  13. Helbling-Leclerc A, Zhang X, Topaloglu H et al. (1995) Mutations in the laminin α2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 11: 216–218

    Google Scholar 

  14. Hillaire D, Leclerc A, Fauré S et al. (1994) Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. Hum Mol Genet 3: 1657–1661

    Google Scholar 

  15. Matsumura K, Campbell KP (1993) Deficiency of dystrophin-associated proteins: a common mechanism leading to muscle cell necrosis in severe childhood muscular dystrophies. Neuromuse Disord 2: 109–118

    Google Scholar 

  16. Muntoni F, Sewry C, Wilson L, Angelini C, Trevisan CP, Brambati B, Dubowitz V (1995) Prenatal diagnosis in congenital muscular dystrophy. Lancet 345: 591

    Google Scholar 

  17. Paulsson, M (1993) Laminin and collagen IV variants and heterogeneity in basement membrane composition. In: Timpl R, Rohrbach DH (eds) Molecular and cellular aspects of basement membranes. Academic Press, San Diego, pp 177–187

    Google Scholar 

  18. Philpot J, Topaloglu H, Pennock J, Dubowitz V (1995) Familial concordance of brain magnetic resonance imaging changes in congenital muscular dystrophy. Neuromusc Disord 5: 227–231

    Google Scholar 

  19. Philpot J, Sewry C, Pennock J, Dubowitz (1995) Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle. Neuromusc Disord 5: 301–306

    Google Scholar 

  20. Sewry C, Philpot J, Mahony D, Wilson LA, Muntoni F, Dubowitz (1995) Expression of laminin subunits in congenital muscular dystrophy. Neuromusc Disord 5: 307–316

    Google Scholar 

  21. Sewry CA, Chevallay M, Tomé FMS (1995) Expression of laminin subunits in human fetal skeletal muscle. Histochem J 27: 497–504

    Google Scholar 

  22. Straub V, Bittner, RE, Leger, JJ, Voit, T (1992) Direct visualization of the dystrophin network on skeletal muscle fiber membrane. J Cell Biol 119: 1183–1191

    Google Scholar 

  23. Sunada Y, Bernier SM, Kozak CA, Yamada Y, Campbell KP (1994) Deficiency of merosin in dystrophic dy mice and genetic linkage of laminin M chain gene to dy locus. J Biol Chem 269: 13729–13732

    Google Scholar 

  24. Timpl R, Martin GR (1987) Laminin and other basement membrane components. Ann Rev Cell Biol 3: 57–85

    Google Scholar 

  25. Tomè FMS, Evangelista T, Leclerc A et al. (1994) Congenital muscular dystrophy with merosin deficiency. CR Acad Sci Paris 317: 351–357

    Google Scholar 

  26. Voit T, Haas K, Lèger JOC, Pons F, Lèger JJ (1991) Xp21 dystrophin and 6q2 dystrophin-related protein. Am J Pathol 139: 969–976

    Google Scholar 

  27. Voit T, Fardeau M, Tomé FMS (1994) Prenatal detection of merosin expression in human placenta. Neuropediatrics 25: 332–333

    Google Scholar 

  28. Voit T, Sewry CA, Meyer K et al. (1995) Preserved merosin M-chain (or laminin-α2) expression in skeletal muscle distinguishes Walker-Warburg Syndrome from Fukuyama Muscular Dystrophy and merosin-deficient Congenital Muscular Dystrophy. Neuropediatrics 26: 148–155

    Google Scholar 

  29. Vuolteenaho R, Nissinen M, Sainio K et al. (1994) Human laminin M chain (merosin): complete primary structure, chromosomal assignment, and expression of the M and A chain in human fetal tissues. J Cell Biol 124: 381–394

    Google Scholar 

  30. Xu H, Christmas P, Wu XR, Wewer UM, Engvall E (1994) Defective muscle basement membrane and lack of Mlaminin in the dystrophic dy/dy mouse. Proc Natl Acad Sci USA 91: 5572–5576

    Google Scholar 

  31. Xu H, Wu XR, Wewer UM, Engvall E (1994) Murine muscular dystrophy caused by a mutation in the laminin α2 (Lama2) gene. Nat Genet 8: 297–302

    Google Scholar 

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Herrmann, R., Straub, V., Meyer, K. et al. Congenital muscular dystrophy with laminin α2 chain deficiency: Identification of a new intermediate phenotype and correlation of clinical findings to muscle immunohistochemistry. Eur J Pediatr 155, 968–976 (1996). https://doi.org/10.1007/BF02282889

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  • DOI: https://doi.org/10.1007/BF02282889

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