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Physical Medicine and Rehabilitation for Limb-Girdle Muscular Dystrophy Workup

  • Author: Vinod Sahgal, MD; Chief Editor: Stephen Kishner, MD, MHA  more...
 
Updated: Apr 19, 2016
 

Approach Considerations

In 2014, guidelines on the diagnosis and treatment of LGMD were issued by the American Academy of Neurology and the American Association of Neuromuscular and Electrodiagnostic Medicine. They included the following recommendations[46] :

  • Genetic diagnosis of patients with suspected muscular dystrophy should be guided by a clinical approach hinging on clinical phenotype, such as muscle involvement pattern, inheritance pattern, age at onset, and associated disease manifestations, including early contractures and cardiac or respiratory involvement (level B)
  • Patients newly diagnosed with an LGMD subtype who have a high cardiac complication risk should be referred for cardiologic evaluation even if they have no cardiac symptoms (level B)
  • Pulmonary function should be periodically tested in patients with LGMD with a high respiratory failure risk (level B)
  • Patients with muscular dystrophy should be referred to a clinic that has access to specialties—such as physical therapy, occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics—aimed at treating neuromuscular disorder patients (level B)
  • With the exception of research studies aimed at determining treatment safety and efficacy, patients with LGMD should not be offered LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone (level R)
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Laboratory Studies

See the list below:

  • The single biochemical abnormality in limb-girdle muscular dystrophy (LGMD) syndrome is the elevation of the CK level. The CK elevation in the recessively inherited varieties is significantly higher than in the rest of the spectrum of LGMDs (eg, dominantly inherited, Erb dystrophy, pelvifemoral variety). However, the CK level is usually significantly lower than in patients with Duchenne or Becker dystrophy. Individuals with Duchenne or Becker dystrophy may have elevated creatine in the urine, but they do not have myoglobinuria. [47]
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Other Tests

See the list below:

  • Electromyographic abnormalities are atypical in limb-girdle muscular dystrophy (LGMD), and EMG is more useful to exclude other disorders in the differential. Nerve conduction velocities do not show abnormalities in cases of LGMD. Repetitive stimulation produces good posttetanic potentiation and no myasthenic response. Rarely, EMG of a single fiber may reveal a mild decrease in fiber density and increased jitter, but the most consistent finding is normal fiber density.
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Procedures

See the list below:

  • Muscle biopsy findings in limb-girdle muscular dystrophy are characterized by necrotic fibers with endomysial perivascular or perimysial mononuclear infiltration. (See image below.)
    Trichrome stain. Note variation in fiber size. Nec Trichrome stain. Note variation in fiber size. Necrotic fiber giant fibers and cytoplasmic inclusions.
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Histologic Findings

In limb-girdle muscular dystrophy (LGMD), hematoxylin and eosin stain and trichrome stain show a most striking predilection toward large fiber size (see image below).

Hematoxylin and eosin stain. Note the variation in Hematoxylin and eosin stain. Note the variation in fiber size. Necrotic fiber is shown with many nuclei (magnification 250X).

These large fibers show splitting (see image below) and can be 3-4 times the size of a normal fiber.

Marked endomysial fibrosis with atrophic and hyper Marked endomysial fibrosis with atrophic and hypertrophic fibers.

The splitting of fibers produces the false appearance of grouping and angulation without a large group of atrophic fibers. Frequently, ring fibers and cytoplasmic masses are also observed (see image below).

Hematoxylin and eosin stain. Note the splitting of Hematoxylin and eosin stain. Note the splitting of the fiber.

Some fibers are characterized by profuse internal nuclei (see image below).

Gomori trichrome stain. Note the variation in fibe Gomori trichrome stain. Note the variation in fiber size and subsarcolemmal vacuoles, central nuclei, and subsarcolemmal collection of trichrome-positive material.

The myoarchitecture shows evidence of necrosis and basophilia (see image below).

Light type I and dark type IIA fibers. Light type I and dark type IIA fibers.

Increases in endomysial fibrous tissue are noted, without significant evidence of cellular response.

The histochemistry of the muscle biopsy specimens generally shows a predominance of type I fibers and a reduction of type IIB fibers. Because splitting is a common feature of this disease, the split fibers are shown to belong to the same fiber type and give an appearance of fiber-type grouping (see image below).

Electron micrograph showing abnormal mitochondria, Electron micrograph showing abnormal mitochondria, a large lysosomal body, and a central nucleus.

Ultrastructure examination shows nonspecific changes consisting of Z-band spreading, mitochondrial abnormalities with inclusions as central nuclei, and disruption of the A and I bands (see image below).

Electron micrograph showing mitochondria with para Electron micrograph showing mitochondria with paracrystalline inclusions and lamellar bodies

In a morphometric analysis of muscle fibers in LGMD, Fanin and colleagues found not only differences in fiber size between the various forms of the disease but also variations in fiber atrophy between males and females. Evaluating 101 muscles from patients with LGMD, the investigators found significant fiber atrophy in LGMD types 2A and 2B but pronounced fiber hypertrophy in LGMD type 1C. They also found that in males with LGMD types 2A and 2B, muscle fiber atrophy was significantly greater than in male control subjects. In females with LGMD, however, fiber size was similar to that in female controls. Fanin et al stated that although it is possible that LGMD affects males more severely than females, the reasons behind this are unclear.[48]

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Contributor Information and Disclosures
Author

Vinod Sahgal, MD 

Vinod Sahgal, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Physical Medicine and Rehabilitation, American Congress of Rehabilitation Medicine, American Medical Association, American Spinal Injury Association

Disclosure: Nothing to disclose.

Coauthor(s)

Steven Reger, PhD 

Steven Reger, PhD is a member of the following medical societies: Association for Academic Psychiatry, New York Academy of Sciences

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kat Kolaski, MD Assistant Professor, Departments of Orthopedic Surgery and Pediatrics, Wake Forest University School of Medicine

Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kishner, MD, MHA Professor of Clinical Medicine, Physical Medicine and Rehabilitation Residency Program Director, Louisiana State University School of Medicine in New Orleans

Stephen Kishner, MD, MHA is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Elizabeth A Moberg-Wolff, MD Medical Director, Pediatric Rehabilitation Medicine Associates

Elizabeth A Moberg-Wolff, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference wish to thank Suneet Sahgal, MD, Staff Physician, Department of Physical Medicine and Rehabilitation, Northwestern University Medical School, for his previous contribution to this article.

References
  1. Leyden E. Klinik der Ruckenmarks-Krankheiten. Vol 2. Berlin:. Hirschwalk. 1876:531.

  2. Möbius PJ. Ueber die hereditaren nervenkrankheiten. Volkmanns Samml Klin Notiz. 1879. 171:1505.

  3. Erb W. Ueber die "Juvenile Form" der progressiven Muskelatrophie ihre Beziehungen zur sogenannten Pseudohypertrophie der Muskeln. Dtsh Archiv Klin Med. 1884. 34:467.

  4. Erb W. Dystrophia muscularis progressiva. Klinische und pathologisch anatomische Studien. Dtsch Nervenh. 1891. 1:13.

  5. Batten FE. The myopathies or muscular dystrophies. Q J Med. 1910. 3:313.

  6. Landouzy L, Dejerine J. De La myopathic atrophique - progressive (myopathic heriditaire debutant dansleufavec, Par la free saus alteration du systeme nerveux). Services Alad Sci. 1884. 53:98.

  7. Gower ER. A lecture on myopathy and a distal form. Br Med J. 1902. 2:89.

  8. Spiller WG. Myopathy of the distal type and its relation to the neuroforamin of muscular atrophy (Charcot Marie Tooth Type). J Neur Med Dis. 1907. 34-14.

  9. Walton JN, Nattrass FJ. On the classification, natural history and treatment of the myopathies. Brain. 1954. 77(2):169-231. [Medline].

  10. Fanin M, Tasca E, Nascimbeni AC, et al. Sarcolemmal neuronal nitric oxide synthase defect in limb-girdle muscular dystrophy: an adverse modulating factor in the disease course?. J Neuropathol Exp Neurol. 2009 Mar 12. [Medline].

  11. Garnham C, Hanna R, Chou J, Low K, Gourlay K, Campbell R, et al. Limb-girdle muscular dystrophy type 2A can result from accelerated autoproteolytic inactivation of calpain 3. Biochemistry. 2009 Feb 18. [Medline].

  12. McMillan HJ, Carter MT, Jacob PJ, et al. Homozygous contiguous gene deletion of 13q12 causing LGMD2C and ARSACS in the same patient. Muscle Nerve. 2009 Mar. 39(3):396-9. [Medline].

  13. Vuillaumier-Barrot S, Quijano-Roy S, Bouchet-Seraphin C, et al. Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype. Neuromuscul Disord. 2009 Mar. 19(3):182-8. [Medline].

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

  15. Nigro V, Aurino S, Piluso G. Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. Curr Opin Neurol. 2011 Oct. 24(5):429-36. [Medline].

  16. Hauser MA, Horrigan SK, Salmikangas P, et al. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet. 2000 Sep 1. 9(14):2141-7. [Medline]. [Full Text].

  17. Hauser MA, Conde CB, Kowaljow V, et al. Myotilin mutation found in second pedigree with LGMD1A. Am J Hum Genet. 2002 Dec. 71(6):1428-32. [Medline]. [Full Text].

  18. Salmikangas P, van der Ven PF, Lalowski M, et al. Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum Mol Genet. 2003 Jan 15. 12(2):189-203. [Medline]. [Full Text].

  19. Muchir A, Bonne G, van der Kooi AJ, et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet. 2000 May 22. 9(9):1453-9. [Medline]. [Full Text].

  20. Merlini L, Carbone I, Capanni C, Sabatelli P, Tortorelli S, Sotgia F, et al. Familial isolated hyperCKaemia associated with a new mutation in the caveolin-3 (CAV-3) gene. J Neurol Neurosurg Psychiatry. 2002 Jul. 73(1):65-7. [Medline]. [Full Text].

  21. Messina DN, Speer MC, Pericak-Vance MA, McNally EM. Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Am J Hum Genet. 1997 Oct. 61(4):909-17. [Medline]. [Full Text].

  22. Speer MC, Vance JM, Grubber JM, Lennon Graham F, Stajich JM, Viles KD, et al. Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7. Am J Hum Genet. 1999 Feb. 64(2):556-62. [Medline]. [Full Text].

  23. Mascarenhas DA, Spodick DH, Chad DA, et al. Cardiomyopathy of limb-girdle muscular dystrophy. J Am Coll Cardiol. 1994 Nov 1. 24(5):1328-33. [Medline].

  24. Gigliotti F, Pizzi A, Duranti R, Gorini M, Iandelli I, Scano G. Control of breathing in patients with limb girdle dystrophy: a controlled study. Thorax. 1995 Sep. 50(9):962-8. [Medline]. [Full Text].

  25. Guyon JR, Kudryashova E, Potts A, et al. Calpain 3 cleaves filamin C and regulates its ability to interact with gamma- and delta-sarcoglycans. Muscle Nerve. 2003 Oct. 28(4):472-83. [Medline].

  26. Richard I, Broux O, Allamand V, et al. Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell. 1995 Apr 7. 81(1):27-40. [Medline].

  27. Bansal D, Miyake K, Vogel SS, et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature. 2003 May 8. 423(6936):168-72. [Medline].

  28. Liu J, Aoki M, Illa I, et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet. 1998 Sep. 20(1):31-6. [Medline].

  29. Matsuda C, Hayashi YK, Ogawa M, et al. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum Mol Genet. 2001 Aug 15. 10(17):1761-6. [Medline]. [Full Text].

  30. Rosales XQ, Moser SJ, Tran T, McCarthy B, Dunn N, Habib P, et al. Cardiovascular magnetic resonance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I. J Cardiovasc Magn Reson. 2011 Aug 4. 13:39. [Medline]. [Full Text].

  31. Nigro V, de Sá Moreira E, Piluso G, et al. Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the delta-sarcoglycan gene. Nat Genet. 1996 Oct. 14(2):195-8. [Medline].

  32. Noguchi S, McNally EM, Ben Othmane K, et al. Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy. Science. 1995 Nov 3. 270(5237):819-22. [Medline].

  33. Roberds SL, Leturcq F, Allamand V, et al. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell. 1994 Aug 26. 78(4):625-33. [Medline].

  34. Moreira ES, Wiltshire TJ, Faulkner G, et al. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet. 2000 Feb. 24(2):163-6. [Medline].

  35. Frosk P, Weiler T, Nylen E, Sudha T, Greenberg CR, Morgan K, et al. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am J Hum Genet. 2002 Mar. 70(3):663-72. [Medline]. [Full Text].

  36. Brockington M, Yuva Y, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet. 2001 Dec 1. 10(25):2851-9. [Medline].

  37. Krag TO, Hauerslev S, Sveen ML, Schwartz M, Vissing J. Level of muscle regeneration in limb-girdle muscular dystrophy type 2I relates to genotype and clinical severity. Skelet Muscle. 2011 Oct 5. 1(1):31. [Medline]. [Full Text].

  38. Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet. 2002 Sep. 71(3):492-500. [Medline]. [Full Text].

  39. Schneiderman LJ, Sampson WI, Schoene WC, et al. Genetic studies of a family with two unusual autosomal dominant conditions: muscular dystrophy and Pelger-Huet anomaly. Clinical, pathologic and linkage considerations. Am J Med. 1969 Mar. 46(3):380-93. [Medline].

  40. Bacon PA, Smith B. Familial muscular dystrophy of late onset. J Neurol Neurosurg Psychiatry. 1971 Feb. 34(1):93-7. [Medline]. [Full Text].

  41. De Coster W, De Reuck J, Thiery E. A late autosomal dominant form of limb-girdle muscular dystrophy. A clinical, genetic, and morphological study. Eur Neurol. 1974. 12(3):159-72. [Medline].

  42. SHY GM, McEACHERN D. The clinical features and response to cortisone of menopausal muscular dystrophy. J Neurol Neurosurg Psychiatry. 1951 May. 14(2):101-7. [Medline]. [Full Text].

  43. Denny-Brown D. Myopathic weakness of quadriceps. Proc R Soc Med. 1939. 32:867.

  44. van Wijngaarden GK, Hagen CJ, Bethlem J, Meijer AE. Myopathy of the quadriceps muscles. J Neurol Sci. 1968 Sep-Oct. 7(2):201-6. [Medline].

  45. Espir ML, Matthews WB. Hereditary quadriceps myopathy. J Neurol Neurosurg Psychiatry. 1973 Dec. 36(6):1041-5. [Medline]. [Full Text].

  46. Narayanaswami P, Weiss M, Selcen D, et al. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2014 Oct 14. 83 (16):1453-63. [Medline]. [Full Text].

  47. Cossée M, Lagier-Tourenne C, Seguela C, et al. Use of SNP array analysis to identify a novel TRIM32 mutation in limb-girdle muscular dystrophy type 2H. Neuromuscul Disord. 2009 Mar 18. [Medline].

  48. Fanin M, Nascimbeni AC, Angelini C. Gender difference in limb-girdle muscular dystrophy: a muscle fiber morphometric study in 101 patients. Clin Neuropathol. 2014 May-Jun. 33(3):179-85. [Medline].

  49. Siciliano G, Simoncini C, Giannotti S, Zampa V, Angelini C, Ricci G. Muscle exercise in limb girdle muscular dystrophies: pitfall and advantages. Acta Myol. 2015 May. 34 (1):3-8. [Medline]. [Full Text].

  50. Jensen BR, Berthelsen MP, Husu E, Christensen SB, Prahm KP, Vissing J. Body weight-supported training in Becker and limb girdle 2I muscular dystrophy. Muscle Nerve. 2016 Jan 16. [Medline].

  51. Yeldan I, Gurses HN, Yuksel H. Comparison study of chest physiotherapy home training programmes on respiratory functions in patients with muscular dystrophy. Clin Rehabil. 2008 Aug. 22(8):741-8. [Medline].

  52. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975 Feb 13. 292(7):344-7. [Medline].

  53. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975 Feb 20. 292(8):403-7. [Medline].

  54. Boulogne D. Recherches sur la paralysie, musculaire psudohypertrophyic, on Paralysé myosclerozyic. Selections translated in Brody IA, ed. Neurologic Classic 1973. Arch Gen Med. 1868. 11:5, 179, 305, 421, 552.

  55. Bramwell E. Observations on myopathy. Proc R Soc Med. 1922. 16:1.

 
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Hematoxylin and eosin stain. Note the variation in fiber size. Necrotic fiber is shown with many nuclei (magnification 250X).
Marked endomysial fibrosis with atrophic and hypertrophic fibers.
Hematoxylin and eosin stain. Note the splitting of the fiber.
Gomori trichrome stain. Note the variation in fiber size and subsarcolemmal vacuoles, central nuclei, and subsarcolemmal collection of trichrome-positive material.
Light type I and dark type IIA fibers.
Electron micrograph showing abnormal mitochondria, a large lysosomal body, and a central nucleus.
Electron micrograph showing mitochondria with paracrystalline inclusions and lamellar bodies
Electron micrograph showing streaming of band Z and splitting of the muscle fiber. A central nucleus is surrounded by a collection of small mitochondria.
Trichrome stain. Note variation in fiber size. Necrotic fiber giant fibers and cytoplasmic inclusions.
Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, in dysferlin, and in caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan, can result in limb-girdle muscular dystrophy.
 
 
 
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