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Initial Posting: ; Last Update: March 5, 2015.

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Clinical 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 scapuloperoneal 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, which encodes the protein dysferlin, is the only gene in which pathogenic variants are known to cause 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; and for evidence of cardiomyopathy for subtypes with cardiac involvement.

Agents/circumstances to avoid: Weight control to avoid obesity; avoidance of steroid treatment.

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 pathogenic variants in the family are known.

GeneReview Scope

Dysferlinopathy: Included Phenotypes 1
  • Miyoshi distal myopathy (Miyoshi myopathy)
  • Limb-girdle muscular dystrophy type 2B

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


Dysferlinopathy caused by DYSF pathogenic variants 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 the following:

  • 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 the following:

  • 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 pathogenic variants 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, Ankala et al 2014].

Molecular Genetic Testing

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

Table 1.

Molecular Genetic Testing Used in Dysferlinopathy

Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method
DYSFTargeted analysis for pathogenic variants 2, 3, 495%
Sequence analysis 5Unknown

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Note: Pathogenic variants included in a panel may vary by laboratory.


Detects 1624delG pathogenic variant in Libyan Jews


Detects 927delG pathogenic variant in Jews of the Caucasus [Leshinsky-Silver et al 2007]


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing Strategy

To confirm/establish the diagnosis in a proband. Because there are number of conditions that lead to muscle weakness with an elevated CK level, 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]. Further molecular genetic testing can then be pursued.

One genetic testing strategy is molecular genetic testing of DYSF, the only gene in which pathogenic variants are known to cause dysferlinopathy.

An alternative genetic testing strategy is use of a multigene panel that includes DYSF and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Characteristics

Clinical Description

Several different clinical presentations have been observed [Ueyama et al 2002] and can occur within families having the same pathogenic variants [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.

Scapuloperoneal 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 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 pathogenic variant was associated with a milder form of Miyoshi myopathy and the 3510G>A pathogenic variant was associated with a more severe form [Takahashi et al 2003a, Takahashi et al 2013].


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 pathogenic variants cause both Miyoshi myopathy and LGMD2B.


The prevalence is not known. In the initial (1967) description of Miyoshi myopathy, 50 out of 72 families were from 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 1,300, with a carrier rate of approximately 10% [Argov et al 2000].

A founder variant (Arg1905Ter) has been reported in Spain [Vilchez et al 2005].

Differential Diagnosis

Dysferlinopathy needs to be distinguished from other autosomal recessive limb-girdle muscular dystrophies.

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 (OMIM 608099 and 604286), calpainopathy, and dysferlinopathy. In some cases, demonstration of complete or partial deficiencies for any particular protein can then be followed by molecular genetic studies of the corresponding gene.

The caveolinopathies are a group of muscle diseases caused by pathogenic variants in CAV3, which encodes caveolin-3 (OMIM 601253), 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;
  • 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 (OMIM 604454)>40 yearsDistal upper limbs (finger & wrist extensors)Normal or slightly increasedRimmed vacuoles(2p13)
Udd distal myopathy>35Anterior compartment in legs± Rimmed vacuolesTTN
Zaspopathy (Markesbery-Griggs late-onset distal myopathy) (OMIM 609452)>40Vacuolar & myofibrillar myopathyLDB3
Distal myotilinopathy (OMIM 609200)>40Posterior > anterior in legsSlightly increasedVacuolar & myofibrillar myopathyMYOT
Laing early-onset distal myopathy (MPD1)<20Anterior compartment in legs & 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 & hands; dysphonia1-8 timesRimmed vacuoles(5q)
Distal myopathy with pes cavus and areflexia15-50Anterior & 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 myopathy15-20Anterior compartment in legs<10 timesRimmed vacuolesGNE

Locus given only if the gene is not known


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Consultation with a clinical geneticist and/or genetic counselor

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

Control weight to avoid obesity; avoid use of steroids [Walter et al 2013].

Evaluation of Relatives at Risk

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

Therapies Under Investigation

A double-blinded, placebo-controlled clinical trial of deflazacort in individuals with genetically confirmed dysferlinopathy has been completed [Walter et al 2013]. After six months of treatment, muscle strength did not improve; rather, there was a trend towards worsening muscle strength for affected individuals on deflazacort treatment. Muscle strength improved after the study drug was discontinued. Side effects included a broad spectrum typically seen in those taking steroids. Therefore, deflazacort treatment is not effective as a therapy for individuals with dysferlinopathies; additionally, the authors concluded that steroid treatment in general should be avoided in this condition [Walter et al 2013].

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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 individual are obligate heterozygotes and therefore carry one DYSF pathogenic variant.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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 of a DYSF pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with dysferlinopathy are obligate heterozygotes (carriers) for a pathogenic variant in DYSF.

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

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the DYSF pathogenic variants in the family.

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 and Preimplantation Genetic Diagnosis

Once the DYSF pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.


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 (MDA) - USA
    161 North Clark
    Suite 3550
    Chicago IL 60601
    Phone: 800-572-1717
  • Muscular Dystrophy UK
    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 NameGeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
LGMD2BDYSF2p13​.2DysferlinDYSF homepage - Leiden Muscular Dystrophy pagesDYSFDYSF

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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 pathogenic variant was identified in alternative exons [Krahn et al 2009]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Argov et al [2000] identified the 1624delG pathogenic variant in 12 Libyan Jewish families with LGMD2B. Among Japanese individuals with Miyoshi myopathy, four pathogenic variants (1939C>G, 3370G>T, 3746delG, and 4870delT) account for 60% of all pathogenic variants [Takahashi et al 2003a]. The possible existence of a founder effect for the 2785C>T pathogenic variant in the Italian population was reported [Cagliani et al 2003]. Many pathogenic variants have been observed in individuals of various ethnic origins. These pathogenic variants 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 as yet 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 colocalizes 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. While no correlations between pathogenic variant type and phenotype have been found, the 3510G>A pathogenic variant 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.


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Chapter Notes

Revision History

  • 5 March 2015 (me) Comprehensive update posted live
  • 22 April 2010 (me) Comprehensive update posted live
  • 19 April 2006 (me) Comprehensive update posted live
  • 5 February 2004 (me) Review posted live
  • 24 September 2003 (ma) Original submission
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