Limb-Girdle muscular dystrophy in Brazilian children: clinical, histological and molecular characterization

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Published Dec 7, 2023
DOI: https://doi.org/10.18103/mra.v11i11.4761

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Marco Antônio Veloso de Albuquerque, MD, PhD
Department of Neurology, University of São Paulo, São Paulo/São Paulo, Brazil. Current address: Department of Neurology, University of São Paulo, São Paulo.
Kok Fernando, MD, PhD
Department of Neurology, University of São Paulo, São Paulo/São Paulo, Brazil. Current address: Department of Neurology, University of São Paulo, São Paulo.
Umbertina Conti Reed, MD, PhD
Department of Neurology, University of São Paulo, São Paulo/São Paulo, Brazil. Current address: Department of Neurology, University of São Paulo, São Paulo.

Abstract

Background: Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic muscular dystrophies, involving autosomal recessive (LGMD R) and dominant (LGMD D) subtypes. The recessive forms are far more common than dominant, particularly in children. The clinical course in this group is characterized by progressive proximal weakness, initially in pelvic and after in shoulder-girdle musculature, varying from very mild to severe degree. Significant overlap of clinical phenotypes, with clinical and genetic heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form LGMD.


Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in children with LGMD who attend a big public neuromuscular centre in our country to determine the frequency of different forms.


Results: Thirty-nine patients were enrolled in this study and 34 were classified as LGMD. The female to male ratio was 3:1. The mean age at onset of the disease was 6 years (2-13 years). The first sign of the disease were related to a proximal muscular involvement in lower limb, including: frequent falls (22 patients), difficulty  in climbing stairs (12 patients) and difficulty to rise from the floor (2 patients). In three patients, the first sign was walking on tiptoe. All patients showed normal milestones and were able to walk before 18 months of age. CK level was elevated in all cases. Of the 34 cases defined LGMD, the frequency found were: 15(44%) Sarcoglycanopathies (LGMD Sarcoglycan-related); Five (15%), Calpainopathy (LGMD Calpain3-related); Five (15%) Dysferlinopathy (LGMD Dysferlin-related) and two (6%) LGMD FKRP-related. In 7/34 patients (21%) it was not possible to define the specific subtype, despite the techniques used. Calf hypertrophy, winging of the scapula and scoliosis were the most characteristic signs in Sarcoglycanopathies. In FKRP-related forms, calf hypertrophy was also observed. Atrophy of posterior compartment of thighs is frequent in children with Dysferlinopathy and could suggest the diagnosis. In Calpainopathy winging of the scapulae and contractures in Achilles tendons were the more important findings. Muscle biopsy showed a dystrophic pattern in all cases, more intense in Sarcoglycanopathies and LGMD FKRP-related.


Conclusions: Our study on LGMD in children demonstrates that Sarcoglycanopathy is the most frequent form of LGMD, particularly in most severe forms. Because of clinical findings overlapping and unspecific pattern in muscle biopsy, for a correctly identify of the subtype, mutation screening through a myopathies panel or exome sequencing is essential.


Descriptors: 1.Muscular dystrophy; 2. Muscular dystrophy Limb-Girdle/classification; 3. Muscular dystrophy Limb-Girdle/genetic; 4.Muscular dystrophy Limb-Girdle/pathology; 5. Child; 6. Biopsy.

Keywords: LGMD, children, Brazilian, muscle biopsy

Article Details

How to Cite
ALBUQUERQUE, Marco Antônio Veloso de; FERNANDO, Kok; REED, Umbertina Conti. Limb-Girdle muscular dystrophy in Brazilian children: clinical, histological and molecular characterization. Medical Research Archives, [S.l.], v. 11, n. 11, dec. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4761>. Date accessed: 16 may 2024. doi: https://doi.org/10.18103/mra.v11i11.4761.
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Vol 11 No 11 (2023): November Issue, Vol.11, Issue 11
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Research Articles

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References

1. Dubowitz V. What is muscular dystrophy? Forty years of progressive ignorance. J R Coll Physicians Lond. 2000 Sep-Oct;34(5):464-8.

2. Dubowitz V. Muscle biopsy--technical and diagnostic aspects. Ann Clin Res. 1974 Apr; 6(2):69-79.

3. Vainzof M, Zatz M. Protein defects in neuromuscular diseases. Braz J Med Biol Res. 2003 May; 36(5):543-55.

4. Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. Neuromuscul Disord. 2005 Mar; 15(3):207-17.

5. Kirschner J, Bonnemann CG. The congenital and limb-girdle muscular dystrophies: sharpening the focus, blurring the boundaries. Arch Neurol. 2004 Feb; 61(2):189-99.

6. Bushby KM. Diagnostic criteria for the limb-girdle muscular dystrophies: report of the ENMC Consortium on Limb-Girdle Dystrophies. Neuromuscul Disord. 1995 Jan; 5(1):71-4.

7. Bonnemann CG, Finkel RS. Sarcolemmal proteins and the spectrum of limb-girdle muscular dystrophies. Semin Pediatr Neurol. 2002 Jun; 9(2):81-99.

8. Muntoni F. Cardiomyopathy in muscular dystrophies. Curr Opin Neurol. 2003 Oct; 16(5):577-83.

9. Angelini C. Limb-girdle muscular dystrophies: heterogeneity of clinical phenotypes and pathogenetic mechanisms. Acta Myol. 2004 Dec; 23(3):130-6.

10. Darras BT, Jones HR. Diagnosis of pediatric neuromuscular disorders in the era of DNA analysis. Pediatr Neurol. 2000 Oct; 23(4):289-300.

11. Straub V, Bushby K. The childhood limb-girdle muscular dystrophies. Semin Pediatr Neurol. 2006 Jun; 13(2):104-14.

12. Bushby KM, Beckmann JS. The limb-girdle muscular dystrophies--proposal for a new nomenclature. Neuromuscul Disord. 1995 Jul; 5(4):337-43.

13. Straub V, Murphy A, Udd B; LGMD workshop study group. 229th ENMC international workshop: Limb girdle muscular dystrophies - Nomenclature and reformed classification Naarden, the Netherlands, 17-19 March 2017. Neuromuscul Disord. 2018 Aug; 28(8):702-710. doi: 10.1016/j.nmd.2018. 05.007. Epub 2018 May 24. PMID: 30055862.

14. Rosales XQ, Tsao CY. Childhood onset of limb-girdle muscular dystrophy. Pediatr Neurol. 2012 Jan; 46(1):13-23.

15. Passos-Bueno MR, Vainzof M, Moreira ES, Zatz M. Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G. Am J Med Genet. 1999 Feb 19; 82(5):392-8.

16. Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001 Dec; 69(6):1198-209.

17. Brockington M, Blake DJ, Brown SC, Muntoni F. The gene for a novel glycosyltransferase is mutated in congenital muscular dystrophy MDC1C and limb girdle muscular dystrophy 2I. Neuromuscul Disord. 2002 Mar; 12(3):233-4.

18. Walter MC, Petersen JA, Stucka R, Fischer D, Schroder R, Vorgerd M, et al. FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients. J Med Genet. 2004 Apr; 41(4):e50.

19. Kang PB, Feener CA, Estrella E, Thorne M, White AJ, Darras BT, et al. LGMD2I in a North American population. BMC Musculoskelet Disord. 2007; 8:115.

20. Sveen ML, Schwartz M, Vissing J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol. 2006 May; 59(5):808-15.

21. Bolduc V, Marlow G, Boycott KM, Saleki K, Inoue H, Kroon J, et al. Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am J Hum Genet. 2010 Feb 12; 86(2):213-21.

22. Hicks D, Sarkozy A, Muelas N, Koehler K, Huebner A, Hudson G, et al. A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy. Brain. 2011 Jan; 134(Pt 1):171-82.

23. Moore SA, Shilling CJ, Westra S, Wall C, Wicklund MP, Stolle C, et al. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol. 2006 Oct; 65(10):995-1003.

24. Vainzof M, Passos-Bueno MR, Pavanello RC, Marie SK, Oliveira AS, Zatz M. Sarcoglycanopathies are responsible for 68% of severe autosomal recessive limb-girdle muscular dystrophy in the Brazilian population. J Neurol Sci. 1999 Mar 15; 164(1):44-9.

25. Ginjaar HB, van der Kooi AJ, Ceelie H, Kneppers AL, van Meegen M, Barth PG, et al. Sarcoglycanopathies in Dutch patients with autosomal recessive limb girdle muscular dystrophy. J Neurol. 2000 Jul;247(7):524-9.

26. Duggan DJ, Fanin M, Pegoraro E, Angelini C, Hoffman EP. alpha-Sarcoglycan (adhalin) deficiency: complete deficiency patients are 5% of childhood-onset dystrophin-normal muscular dystrophy and most partial deficiency patients do not have gene mutations. J Neurol Sci. 1996 Sep 1; 140(1-2):30-9.

27. Ferreira AF, Carvalho MS, Resende MB, Wakamatsu A, Reed UC, Marie SK. Phenotypic and immunohistochemical characterization of sarcoglycanopathies. Clinics (Sao Paulo). 2011; 66(10):1713-9.

28. Gouveia TL, Paim JF, Pavanello RC, Zatz M, Vainzof M. Sarcoglycanopathies: a multiplex molecular analysis for the most common mutations. Diagn Mol Pathol. 2006 Jun; 15(2):95-100.

29. Dincer P, Leturcq F, Richard I, Piccolo F, Yalnizoglu D, de Toma C, et al. A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey. Ann Neurol. 1997 Aug; 42(2):222-9.

30. Richard I, Brenguier L, Dincer P, Roudaut C, Bady B, Burgunder JM, et al. Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins. Am J Hum Genet. 1997 May; 60(5):1128-38.

31. de Paula F, Vainzof M, Passos-Bueno MR, de Cassia MPR, Matioli SR, L VBA, et al. Clinical variability in calpainopathy: what makes the difference? Eur J Hum Genet. 2002 Dec; 10(12):825-32.

32. Saenz A, Leturcq F, Cobo AM, Poza JJ, Ferrer X, Otaegui D, et al. LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain. 2005 Apr; 128(Pt 4):732-42.

33. Piluso G, Politano L, Aurino S, Fanin M, Ricci E, Ventriglia VM, et al. Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. J Med Genet. 2005 Sep; 42(9):686-93.

34. Krahn M, Bernard R, Pecheux C, Hammouda el H, Eymard B, Lopez de Munain A, et al. Screening of the CAPN3 gene in patients with possible LGMD2A. Clin Genet. 2006 May; 69(5):444-9.

35. Fanin M, Pegoraro E, Matsuda-Asada C, Brown RH, Jr., Angelini C. Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy. Neurology. 2001 Mar 13; 56(5):660-5.

36. Schessl J, Walter MC, Schreiber G, Schara U, Muller CR, Lochmuller H, et al. Phenotypic variability in siblings with calpainopathy (LGMD2A). Acta Myol. 2008 Oct; 27:54-8.

37. Krahn M, Lopez de Munain A, Streichenberger N, Bernard R, Pecheux C, Testard H, et al. CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann Neurol. 2006 Jun;59(6):905-11.

38. Luo SS, Xi JY, Lu JH, Zhao CB, Zhu WH, Lin J, et al. Clinical and pathological features in 15 Chinese patients with calpainopathy. Muscle Nerve. 2011 Mar; 43(3):402-9.

39. Guglieri M, Magri F, D'Angelo MG, Prelle A, Morandi L, Rodolico C, et al. Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. Hum Mutat. 2008 Feb; 29(2):258-66.

40. Klinge L, Aboumousa A, Eagle M, Hudson J, Sarkozy A, Vita G, et al. New aspects on patients affected by dysferlin deficient muscular dystrophy. J Neurol Neurosurg Psychiatry. 2010 Sep;81(9):946-53.

41. Rosales XQ, Gastier-Foster JM, Lewis S, Vinod M, Thrush DL, Astbury C, et al. Novel diagnostic features of dysferlinopathies. Muscle Nerve. 2010 Jul; 42(1):14-21.

42. Urtizberea JA, Bassez G, Leturcq F, Nguyen K, Krahn M, Levy N. Dysferlinopathies. Neurol India. 2008 Jul-Sep;56(3):289-97.

43. Kang PB, Feener CA, Estrella E, Thorne M, White AJ, Darras BT, et al. LGMD2I in a North American population. BMC Musculoskelet Disord. 2007; 8:115.

44. Sveen ML, Schwartz M, Vissing J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol. 2006 May; 59(5):808-15.

45. Hong D, Zhang W, Wang W, Wang Z, Yuan Y. Asian patients with limb girdle muscular dystrophy 2I (LGMD2I). J Clin Neurosci. 2011 Apr; 18(4):494-9.

46. Okazaki T, Matsuura K, Kasagi N, Adachi K, Kai M, Okubo M, Nishino I, Nanba E, Maegaki Y. Duchenne muscular dystrophy-like phenotype in an LGMD2I patient with novel FKRP gene variants. Hum Genome Var. 2020 Apr 20;7:12.

47. de Paula F, Vieira N, Starling A, Yamamoto LU, Lima B, de Cassia Pavanello R, et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet. 2003 Dec; 11(12):923-30.

48. Ki CS, Hong JS, Jeong GY, Ahn KJ, Choi KM, Kim DK, et al. Identification of lamin A/C (LMNA) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B. J Hum Genet. 2002; 47(5):225-8.

49. Astejada MN, Goto K, Nagano A, Ura S, Noguchi S, Nonaka I, et al. Emerinopathy and laminopathy clinical, pathological and molecular features of muscular dystrophy with nuclear envelopathy in Japan. Acta Myol. 2007 Dec; 26(3):159-64.

50. Quijano-Roy S, Mbieleu B, Bonnemann CG, Jeannet PY, Colomer J, Clarke NF, et al. De novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann Neurol. 2008 Aug;64(2):177-86.

51. Bushby K. Diagnosis and management of the limb girdle muscular dystrophies. Pract Neurol. 2009 Dec; 9(6):314-23.