Diagnostic Information

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Diagnostic information for LGMD2B and Miyoshi Myopathy

Clinical Features: 

  • The typical age of onset is between 15-30 years of age 
  • Initial muscle weakness can occur in either:
    • proximal muscles (LGMD2B), particularly quadriceps and hamstrings
    • distal muscles (Miyoshi Myopathy), particularly gastrocnemius
  • In cases of gastrocnemius involvement, initial symptom is often inability to stand on tiptoes 1
  • Past history of steppage gait or inability to stand on tiptoes indicates distal involvement
  • Painful enlarged calves are a typical early symptom2
  • Regardless of the initial diagnosis, both distal and proximal muscles are eventually affected
  • Legs are typically affected before arms3
  • Cardiomyopathy is not generally a major feature in dysferlinopathy, but can occur in some cases4
  • Patients often remain ambulatory until > 30 years of age5.  However, the rate of progression is quite variable6
  • Posterior compartment weakness is not always present, but when it is, it is a clear differentiating factor
  • Typically presents with an autosomal recessive or sporadic pattern of inheritance
  • Wide inter- and intrafamilial variation.  Different clinical presentations and disease progression can occur in the same family and for the same genotype7,8

Laboratory Findings:

  • Muscle CT-scan and/or MRI can be used to detect distal muscle involvement
  • MRI (especially T2 weighted) can show abnormalities in presymptomatic individuals9 and in muscles without overt weakness1
  • Very high CK levels (typically > 10 times normal) are found both in symptomatic and presymptomatic patients 
  • Enzymes normally associated with liver dysfunction can also be elevated10
  • Muscle biopsies show a marked dystrophic pattern with necrosis and regeneration of muscle fibers, and in some cases inflammation11
  • Patients are sometimes misdiagnosed with polymyositis due to inflammatory appearance of biopsies6
  • Preservation of sensory and motor conduction values12
  • Absent or reduced dysferlin protein levels can be seen using anti-dysferlin antibodies on either a muscle biopsy or via western blot analysis of dysferlin from blood monocytes13NOTE:  reduced dysferlin protein levels can sometimes be a secondary effect of deficiencies of other proteins, especially Calpain-3 (LGMD 2A)14

Genetics:  

  • LGMD2B and Miyoshi Myopathy are caused by mutations in the dysferlin gene
  • Carriers are generally unaffected but can sometimes show relatively mild weakness15
  • The Dysferlin gene is found on chromosome 2p13.3-p13.1 16,17 and consists of 55 coding exons 18
  • Missense, nonsense, small deletions, small insertions, and splice site mutations have all been described.  Most mutations introduce stop codons or premature truncations of the dysferlin protein19.  See the Leiden database for a list of described mutations.  Go to http://www.dmd.nl/ and choose DYSF from the Mutation Databases pull down menu at the top of the screen.
  • Gene sequencing at the DNA or RNA level can be done from a blood sample20
  • There are no known mutational hot spots in the dysferlin gene
  • Variations in phenotype are not well explained by mutation type
  • Due to the large size of the dysferlin gene, and the absence of mutational hot spots, it is generally preferred to find evidence of deficiency at the protein level before mutation screening

Dysferlin protein:

  • The dysferlin protein has a molecular mass of 235 kDa and is made up of approximately 2080 amino acids21-22
  • Dysferlin is a transmembrane protein that is involved in membrane fusion events and is necessary for repair of the muscle sarcolemma following damage23
  • Dysferlin is expressed in skeletal  muscle, heart, white blood cells (monocytes, macrophages), and various other cell types. 

Additional information:

  • Other clinical diagnoses associated with dysferlin deficiency:
    • Distal Anterior Compartment Myopathy 8, 17
    • Other clinical phenotypes and patterns of muscle involvement can occur 6, 24
      • Proximodistal weakness at presentation
      • Pseudometabolic myopathy
      • HyperCKemia
  • Differential Diagnoses
    • Polymyositis6
    • Other forms of LGMD
  • What clinical/pathological findings most clearly point to a diagnosis of LGMD2B/Miyoshi?
    • Absent or reduced dysferlin protein levels in blood monocytes or staining of muscle biopsy
    • Very high CK levels (typically > 10X normal)
    • Distal involvement is highly suggestive
    • Recessive or sporadic pattern of inheritance

References:

1.      Brummer, D. et al., Long-term MRI and clinical follow-up of symptomatic and presymptomatic carriers of dysferlin gene mutations. Acta Myol. 2005 Jul;24(1):6-16.

2.      Diers, A. et al., Painful enlargement of the calf muscles in limb girdle muscular dystrophy type 2B (LGMD2B) with a novel compound heterozygous mutation in DYSF. Neuromuscul Disord. 2007 Feb;17(2):157-62.

3.      Mahjneh, I. et al., Dysferlinopathy (LGMD2B): a 23-year follow-up study of 10 patients homozygous for the same frameshifting dysferlin mutations. Neuromuscul Disord. 2001 Jan;11(1):20-6.

4.      Wenzel, K. et al., Dysfunction of dysferlin-deficient hearts. J Mol Med. 2007 Nov;85(11):1203-14.

5.      Aoki, M. and T. Takahashi, Mutational and clinical features of Japanese patients with dysferlinopathy (Miyoshi myopathy and limb girdle muscular dystrophy type 2B). Rinsho Shinkeigaku. 2005 Nov;45(11):938-42. Japanese

6.      Nguyen, K. et al., Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes. Arch Neurol. 2007 Aug;64(8):1176-82.

7.      Weiler, T. et al., Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s). Hum Mol Genet. 1999 May;8(5):871-7.

8.      Saito, H. et al., Distal anterior compartment myopathy with early ankle contractures. Muscle Nerve. 2007 Oct;36(4):525-7.

9.      Okahashi, S. et al., Asymptomatic sporadic dysferlinopathy presenting with elevation of serum creatine kinase. Typical distribution of muscle involvement shown by MRI but not by CT. Intern Med. 2008; 47(4):305-7.

10.   Brüss, M. et al., Dysferlinopathy as an extrahepatic cause for the elevation of serum transaminases. Med Klin (Munich). 2004 Jun 15;99(6):326-9. German.

11.   Nagaraju, K.  et al., Dysferlin Deficiency Enhances Monocyte Phagocytosis: A Model for the Inflammatory Onset of Limb-Girdle Muscular Dystrophy 2B. Am J Pathol. 2008 Mar;172(3):774-785.

12.   Miyoshi, K., et al., Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy. Seventeen cases in eight families including an autopsied case. Brain. 1986 Feb;109  (Pt 1):31-54.

13.   Ho, M. et al., A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Ann Neurol. 2002 Jan;51(1):129-33.

14.   Hermanova, M. et al., Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients. Muscle Nerve. 2006 Mar;33(3):424-32.

15.   Illa, I. et al., Symptomatic dysferlin gene mutation carriers: characterization of two cases. Neurology. 2007 Apr 17;68(16):1284-9.

16.   Bashir, R. et al., A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet. 1998 Sep;20(1):37-42.

17.   Liu, J. 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.

18.   Aoki, M. et al., Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy. Neurology. 2001 Jul 24;57(2):271-8.

19.   Wenzel, K. et al., Novel sequence variants in dysferlin-deficient muscular dystrophy leading to mRNA decay and possible C2-domain misfolding. Hum Mutat. 2006 Jun;27(6):599-600.

20.   de Luna, N. et al., Dysferlin expression in monocytes: a source of mRNA for mutation analysis. Neuromuscul Disord. 2007 Jan;17(1):69-76.

21.   Anderson, LV et al., Dysferlin is a plasma membrane protein and is expressed early in human development. Hum Mol Genet. 1999 May;8(5):855-61.

22.   Matsuda, C. et al., Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy. Neurology. 1999 Sep 22;53(5):1119-22.

23.   Bansal, D. et al., Defective membrane repair in dysferlin-deficient muscular dystrophy., Nature. 2003 May 8;423(6936):168-72.

24.   Seror, P. et al., Complete fatty degeneration of lumbar erector spine muscles caused by a primary dysferlinopathy. Muscle Nerve. 2008 Mar;37(3):410-4.