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, MD, PhD
Department of Neurology
Tohoku University School of Medicine
Sendai, Japan

Initial Posting: ; Last Update: April 22, 2010.


Disease characteristics.

Dysferlinopathy includes a spectrum of muscle disease characterized by two main phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness. Miyoshi myopathy (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes are scapulo-peroneal syndrome, distal myopathy with anterior tibial onset, elevated serum CK concentration only, and congenital muscular dystrophy.


Diagnosis depends on a combination of muscle biopsy and molecular genetic testing. Muscle biopsy Western immunoblotting almost always indicates a primary dysferlinopathy. DYSF is the only gene known to be associated with dysferlinopathy.


Treatment of manifestations: Individualized management may include physical therapy, use of mechanical aids, surgical intervention for orthopedic complications, respiratory aids, and social and emotional support.

Prevention of secondary complications: Stretching exercises to prevent contractures.

Surveillance: Annual monitoring of muscle strength, joint range of motion, and respiratory function.

Genetic counseling.

Dysferlinopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

GeneReview Scope

Dysferlinopathy: Included Disorders
  • Miyoshi distal myopathy (Miyoshi myopathy)
  • Limb-girdle muscular dystrophy type 2B

For synonyms and outdated names see Nomenclature.


Clinical Diagnosis

Dysferlinopathy caused by DYSF mutations includes a spectrum of muscle disease characterized mainly by two phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness.

Miyoshi myopathy is characterized by:

  • Mid- to late-childhood or early-adult onset; mean age at onset: 19.0 years [Aoki et al 2001]
  • Early and predominant involvement of the calf muscles
  • Slow progression
  • Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L [Aoki et al 2001]
  • Primarily myogenic pattern on EMG
  • Biopsy evidence of a chronic, active myopathy without rimmed vacuoles

LGMD2B is characterized by:

  • Predominant weakness and atrophy of muscles of the pelvic and shoulder girdle
  • Onset in the proximal lower-limb musculature in the late teens or later
  • Massive elevation of serum CK concentration
  • Slow progression
  • Subclinical involvement of distal muscles, identified by careful examination or ancillary investigations such as muscle CT scan, in some individuals


Muscle biopsy

  • Histology. Muscle biopsy shows evidence of a dystrophy with random variation in fiber size and evidence of degeneration and regeneration. Type one fibers may predominate. There is often evidence of inflammation, sometimes leading to a misdiagnosis of polymyositis [Gallardo et al 2001, Fanin & Angelini 2002, Serratrice et al 2002, Prelle et al 2003].
  • Immunostaining. Antibodies to dysferlin identify a protein of approximately 230 kd and show that dysferlin is located in the muscle membrane [Anderson et al 1999, Matsuda et al 1999, Eymard et al 2000]. Most individuals with DYSF mutations show complete deficiency of the protein or sometimes patchy sarcolemmal and cytoplasmic staining on muscle biopsy. Many individuals with partial deficiency of dysferlin have been reported [Piccolo et al 2000, Matsuda et al 2001, Saito et al 2002].
  • Immunoblot. Because of variable and nonspecific patterns, immunoblot is generally considered the more reliable method for testing. If possible, both immunostaining and immunoblotting should be performed [Tagawa et al 2003].

Dysferlin expression. In individuals with dysferlinopathy, dysferlin immunoreactivity in peripheral blood monocytes cannot be detected using a commercially available monoclonal antibody [Ho et al 2002].

Molecular Genetic Testing

Gene. DYSF, which encodes the protein dysferlin, is the only gene in which mutation is known to cause dysferlinopathy.


  • Targeted mutation analysis involves testing for two mutations:
  • Sequence analysis. It is not known how the mutation detection rate for sequence analysis compares to the mutation detection rate for mutation scanning.Mutation scanning detects mutations in 80% of individuals with dysferlinopathy [Takahashi et al 2003b].

Table 1.

Summary of Molecular Genetic Testing Used in Dysferlinopathy

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
DYSFTargeted mutation analysis1624delG 4, 927delG 595%
Sequence analysis 6Sequence variantsUnknown
Mutation scanningSequence variants80% 7

See Table A. Genes and Databases for chromosome locus and protein name.


See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a mutation that is present in the indicated gene


In Libyan Jews


In Jews of the Caucasus


Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Takahashi et al [2003b]

Testing Strategy

To confirm/establish the diagnosis in a proband

  • For individuals of Libyan Jewish ancestry or Jews of the Caucasus with immunohistochemical evidence of dysferlin deficiency on muscle biopsy, targeted mutation analysis can be used for confirmation of the diagnosis and genetic counseling purposes.
  • For individuals of other ethnic backgrounds, sequence analysis can be used. However, sequence analysis of all 55 exons of DYSF for mutations using genomic DNA derived from leukocytes is a lengthy, costly, and inefficient procedure that will miss mutations in the promoter or non-coding regions of the gene. Therefore, when the clinical index of suspicion of Miyoshi myopathy or LGMD2B is high, a reasonable approach is to test a muscle biopsy for dysferlin using Western immunoblotting. Absence of dysferlin protein almost always indicates a primary dysferlinopathy; however, it is important to note that reduced levels of dysferlin may be secondary to other primary muscular dystrophies [Aoki et al 2001].

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Several different clinical presentations have been observed [Ueyama et al 2002] and can occur within families having the same mutations [Liu et al 1998, Weiler et al 1999, Illarioshkin et al 2000, Nakagawa et al 2001, Ueyama et al 2001]. The weakness and atrophy may be asymmetric with any of these presentations.

Miyoshi myopathy. Young adults have muscle weakness and atrophy most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Early on, affected individuals are not able to stand on tiptoe, but retain the ability to stand on the heels. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles, at which time climbing stairs, standing, and walking become difficult. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. The weakness may eventually include the shoulder girdle muscles [Mahjneh et al 2001].

Limb-girdle muscular dystrophy syndrome. Early weakness and atrophy of the pelvic and shoulder girdle muscles begins in adolescence or young adulthood, with slow progression.

Scapulo-peroneal syndrome. Occasionally, affected individuals present with initial weakness of the shoulder girdle muscles combined with distal weakness of the legs.

Distal myopathy with anterior tibial onset. Occasionally, leg weakness may involve the anterior compartment and cause foot drop [Illa et al 2001].

Elevated serum CK concentration only. Some individuals have only a marked elevation of serum CK concentration. This is usually considered a presymptomatic presentation of myopathy in an individual who eventually develops muscle weakness and atrophy. Sometimes the calf muscles are enlarged; this presentation may be confused with a dystrophinopathy (i.e., Duchenne or Becker muscular dystrophy).

Congenital muscular dystrophy. Two sibs with hypotonia beginning between birth and age two months had delayed motor development and serum CK concentrations that were normal or slightly elevated before age three years [Paradas et al 2009].

Of 41 Japanese individuals with genotypically proven dysferlinopathy, 20 had Miyoshi myopathy and 21 had LGMD2B (Table 2) [Takahashi et al 2003b]. On occasion, both phenotypes can be observed in affected sibs [Liu et al 1998].

Table 2.

Comparison of Miyoshi Myopathy and LGMD2B

Miyoshi MyopathyLGMD2B
Mean age at onset
21.8 ± 7.4 yrs
(14-37 yrs)
26.2 ± 9.2 yrs
(14-41 yrs)
Average age of using a cane
(yrs after onset)
35.5 yrs
(16 yrs)
39.3 yrs
(13.6 yrs)
Age at which wheelchair-bound
(yrs after onset)
42.8 yrs
(22.8 yrs)
45.1 yrs
(21.4 yrs)

Genotype-Phenotype Correlations

One study reported that the 3370G>T mutation was associated with a milder form of Miyoshi myopathy and the 3510G>A mutation was associated with a more severe form [Takahashi et al 2003a].


Dysferlinopathy was originally called LGMD2B because at the time that it was mapped to 2p13 it was the second form (2) of autosomal recessive (B) limb-girdle muscular dystrophy (LGMD) to be mapped. The gene for Miyoshi myopathy and the gene for LGMD2B were mapped to the same genetic interval at chromosome 2p13. Two groups independently identified a novel human skeletal muscle gene, DYSF, at this locus and documented that DYSF mutations cause both Miyoshi myopathy and LGMD2B.


The prevalence is not known. In the initial description of Miyoshi myopathy 50 out of 72 families were from Japan. However, in Japan, Tagawa et al [2003] examined a total of 107 unrelated Japanese individuals, including 53 with unclassified LGMD, 28 with Miyoshi myopathy, and 26 with other neuromuscular disorders. Expression of dysferlin protein was observed using immunohistochemistry (IHC) and mini-multiplex Western blotting (MMW). They found a deficiency of dysferlin protein by using both IHC and MMW in 19% of individuals with LGMD and 75% of individuals with Miyoshi myopathy.

In Libyan Jews, the prevalence is at least one per 1300, with a carrier rate of approximately 10% [Argov et al 2000].

A founder mutation (Arg1905X) has been reported in Spain [Vilchez et al 2005].

Differential Diagnosis

Dysferlinopathy needs to be distinguished from other autosomal recessive limb-girdle muscular dystrophies (see Limb-Girdle Muscular Dystrophy Overview).

Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. Most individuals with LGMD show relative sparing of the heart and bulbar muscles, although exceptions occur, depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes.

The limb-girdle muscular dystrophies typically show degeneration/regeneration of muscle (dystrophic biopsy), which is usually associated with elevated serum creatine kinase concentration. Biochemical testing (i.e., protein testing by immunostaining) performed on a muscle biopsy can establish the diagnosis of the LGMD subtypes sarcoglycanopathy, calpainopathy, and dysferlinopathy. In some cases, demonstration of complete or partial deficiencies for any particular protein can then be followed by mutation studies of the corresponding gene.

The caveolinopathies are a group of muscle diseases caused by mutations in CAV3, which encodes caveolin-3, a muscle-specific membrane protein and the principal component of caveolae membrane in muscle cells in vivo. The caveolinopathies, which are inherited in an autosomal dominant manner, can be classified into five phenotypes:

  • Limb-girdle muscular dystrophy 1C (LGMD1C) characterized by onset usually in the first decade, mild-to-moderate proximal muscle weakness, calf hypertrophy, positive Gower sign, and variable muscle cramps after exercise;
  • Isolated hyperCKemia (i.e., elevated serum concentration of creatine kinase (CK) in the absence of signs of muscle disease) (HCK);
  • Rippling muscle disease (RMD), characterized by signs of increased muscle irritability, such as percussion-induced rapid contraction (PIRC), percussion-induced muscle mounding (PIMM), and/or electrically silent muscle contractions (rippling muscle);
  • Distal myopathy (DM), observed in one individual only; and
  • Hypertrophic cardiomyopathy (HCM), without skeletal muscle manifestations.

The differential diagnosis also includes the dystrophinopathies (Duchenne/Becker muscular dystrophy), polymyositis, and distal myopathies [Udd & Griggs 2001].

Other distal myopathies have been identified with clinical and genetic patterns as follows (see Table 3).

Table 3.

Distal Myopathies

Disease NameMean Age at OnsetInitial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyGene (Locus) 1
Autosomal Dominant
Welander distal myopathy>40 yearsDistal upper limbs (finger and wrist extensors)Normal or slightly increasedRimmed vacuoles(2p13)
Udd distal myopathy>35Anterior compartment in legs± Rimmed vacuolesTTN
Griggs late-onset distal myopathy
>40Vacuolar and myofibrillar myopathyLDB3
Distal myotilinopathy>40Posterior >
anterior in legs
Slightly increasedVacuolar and myofibrillarMYOT
Laing early- onset distal myopathy (MPD1)<20Anterior compartment in legs and neck flexorsModerately increasedType 1 fiber atrophy in tibial anterior muscles; disproportion in proximal musclesMYH7
Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg and hands; dysphonia1-8 timesRimmed vacuoles(5q)
Distal myopathy with pes cavus and areflexia15-50Anterior and posterior lower leg; dysphonia and dysphagia2-6 timesDystrophic, rimmed vacuoles(19p13)
New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg1-4 timesDystrophic; rimmed vacuoles; eosinophilic inclusions(8p22-q11 and 12q13-q22)
Autosomal Recessive
Nonaka early-adult-
onset distal myopathy
15-20Anterior compartment in legs<10 timesRimmed vacuolesGNE
Miyoshi early-adult-
onset myopathy
Posterior compartment in legs>10 timesMyopathic changesDYSF

Udd & Griggs 2001

1. Locus given only if the gene is not known


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with dysferlinopathy, the following evaluations are recommended:

  • Assessment of strength and function in the arms, hands, legs, and feet; especially calf muscle
  • If needed, measurement of serum CK concentration

Treatment of Manifestations

No definitive treatments exist for the limb-girdle muscular dystrophies.

Management should be tailored to each individual and each specific subtype. A general approach to appropriate management can prolong survival and improve quality of life. This general approach is based on the typical progression and complications of individuals with LGMD as described by McDonald et al [1995] and Bushby [1999].

  • Physical therapy and stretching exercises to promote mobility and prevent contractures
  • Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility
  • Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis
  • Use of respiratory aids when indicated
  • Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders

Prevention of Secondary Complications

Stretching exercises to prevent contractures are indicated.


The following surveillance is appropriate:

  • Annual monitoring of muscle strength, joint range of motion, and respiratory function
  • Monitoring for evidence of cardiomyopathy in those subtypes with known occurrence of cardiac involvement

Agents/Circumstances to Avoid

Weight control to avoid obesity is indicated.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Dysferlinopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with dysferlinopathy are obligate heterozygotes (carriers) for a disease-causing mutation in the DYSF gene.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible if the disease-causing mutations in a family are known.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutations have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Jain Foundation Inc.
    The Jain Foundation is a non-profit foundation whose mission is to diagnose and cure limb girdle muscular dystrophies caused by dysferlin protein deficiency (LGMD2B/Miyoshi Myopathy).
    2310 130th Avenue Northeast
    Suite B101
    Bellevue WA 98005
    Phone: 425-882-1440
  • Muscular Dystrophy Association - USA (MDA)
    222 S. Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
  • Muscular Dystrophy Campaign
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Dysferlinopathy: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
LGMD2BDYSF2p13​.2DysferlinDYSF homepage - Leiden Muscular Dystrophy pagesDYSF

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Dysferlinopathy (View All in OMIM)


Gene structure. DYS has 55 exons and 6,243 base-pair nucleotides in an open reading frame predicted to encode a protein of 2,080 amino acids. Recently, novel dysferlin transcripts were characterized by identifying alternative exons 1 of DYSF-v1 (GenBank DQ267935), exon 5a (GenBank DQ976379), and exon 40a (GenBank EF015906), although no disease-causing mutation was identified in alternative exons [Krahn et al 2009]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Argov et al [2000] identified the 1624delG mutation in 12 Libyan Jewish families with LGMD2B. Among Japanese individuals with Miyoshi myopathy, four mutations (1939C>G, 3370G>T, 3746delG, and 4870delT) account for 60% of all mutations [Takahashi et al 2003a]. The possible existence of a founder effect for the 2785C>T mutation in the Italian population was reported [Cagliani et al 2003]. Many mutations have been observed in individuals of various ethnic origins. These mutations were widely spread throughout the coding sequence of the gene without any mutational "hot spot" [Cagliani et al 2005, Nguyen et al 2005]. [Krahn et al 2009]

Normal gene product. Antibodies to dysferlin identify a protein of approximately 230 kd and show that dysferlin is located in the muscle membrane [Anderson et al 1999, Matsuda et al 1999]. Although the function of dysferlin is still unknown, dysferlin includes C2 domains thought to be important for calcium-mediated membrane fusion, and dysferlin was reported to have an essential role in the calcium-dependent membrane repair of skeletal muscle fibers [Bansal et al 2003, Bansal & Campbell 2004].

Matsuda et al [2001] reported a possible interaction between dysferlin and caveolin-3 to subserve signaling functions of caveolae. Lennon et al [2003] reported an interaction between dysferlin and phospholipid- and calcium-binding annexins and suggested a role for annexins A1 and A2 in vesicle fusion during dysferlin-mediated membrane repair. Matsuda et al [2005] reported that affixin (beta-parvin), a novel, integrin-linked kinase-binding protein, is a dysferlin-binding protein that co-localizes with dysferlin at the sarcolemma of normal human skeletal muscle. The immunoreactivity of affixin was reduced in sarcolemma of Miyoshi myopathy and LGMD2B muscles, although the total amount of affixin protein was normal.

Abnormal gene product. Although there were no correlations between the type of mutation and the phenotype, the 3510G>A mutation associated with the severe form of Miyoshi myopathy is located around a region of relative hydrophilia. Takahashi et al [2003a] speculate that this hydrophilic region may be important for the function of the protein.

Disruption of the muscle membrane repair machinery is responsible for dysferlin-deficient muscle degeneration in dysferlin-null mice [Bansal et al 2003, Bansal & Campbell 2004]. Cenacchi et al [2005] reported that histopathologic, immunohistochemical, and ultrastructural analyses show muscle with dysferlinopathy to be characterized by a very active inflammatory/degenerative process, possibly associated with an inefficient repair and regenerative system.


Literature Cited

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Chapter Notes

Revision History

  • 22 April 2010 (me) Comprehensive update posted live
  • 19 April 2006 (me) Comprehensive update posted to live Web site
  • 5 February 2004 (me) Review posted to live Web site
  • 24 September 2003 (ma) Original submission
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