U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Dysferlinopathy

, MD, PhD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: May 27, 2021.

Estimated reading time: 20 minutes

Summary

Clinical characteristics.

Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes: Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy type 2B (LGMD2B); and two minor phenotypes: asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT).

  • MMD (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 in this spectrum are scapuloperoneal syndrome and congenital muscular dystrophy.
  • Asymptomatic hyperCKemia is characterized by marked elevation of serum CK concentration only.
  • DMAT is characterized by early and predominant distal muscle weakness, particularly of the muscles of the anterior compartment of the legs.

Diagnosis/testing.

The diagnosis of dysferlinopathy is established in a proband with suggestive findings and biallelic pathogenic variants in DYSF identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no approved therapy for dysferlinopathy. Treatment is symptomatic only. Management should be tailored to the individual and the specific subtype. Individualized management may include physical therapy, use of mechanical aids, surgical intervention for orthopedic complications, respiratory aids, and social and emotional support.

Surveillance: Annual monitoring of muscle strength, physical function, activities of daily living, joint range of motion, balance, and respiratory function, and for evidence of cardiomyopathy for individuals with cardiac involvement.

Agents/circumstances to avoid: Weight control to avoid obesity.

Genetic counseling.

Dysferlinopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DYSF pathogenic variant, each sib of an affected individual has at conception 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 the DYSF pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

GeneReview Scope

Dysferlinopathy: Included Phenotypes
  • Miyoshi muscular dystrophy (Miyoshi myopathy)
  • Limb-girdle muscular dystrophy type 2B
  • Asymptomatic hyperCKemia
  • Distal myopathy with anterior tibial onset

For synonyms and outdated names see Nomenclature.

Diagnosis

No consensus clinical diagnostic criteria for dysferlinopathy have been published.

Suggestive Findings

Dysferlinopathy should be suspected in those with suggestive findings of major phenotypes and considered in those with suggestive findings of minor phenotypes. The diagnosis should be informed by family history.

Major Phenotypes

Dysferlinopathy should be suspected in individuals with suggestive findings of the two major phenotypes, Miyoshi muscular dystrophy and limb-girdle muscular dystrophy 2B, based on the following findings [Izumi et al 2020].

Miyoshi muscular dystrophy (MMD)

  • Mid- to late-childhood or early-adult onset; mean age at onset 19.0 years
  • Early and predominant distal muscle weakness affecting the upper and lower limbs, particularly the calf muscles (i.e., gastrocnemius and soleus muscles)
  • Slow progression
  • Elevation of serum CK concentration, often 10-100 times normal; mean CK: 8,940 IU/L
  • Primarily myogenic pattern on EMG

Limb-girdle muscular dystrophy 2B (LGMD2B)

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

Minor Phenotypes

Dysferlinopathy should be considered in individuals with suggestive findings of the following two minor phenotypes:

  • Asymptomatic hyperCKemia, characterized by marked elevation of serum CK concentration only
  • Distal myopathy with anterior tibial onset (DMAT), characterized by early and predominant distal muscle weakness affecting the lower limbs, particularly the muscles of the anterior compartment of the legs.

Family History

A family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity) should inform the consideration of dysferlinopathy in individuals with suggestive findings of the above major and minor phenotypes. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of dysferlinopathy is established in a proband with Suggestive Findings and biallelic pathogenic variants in DYSF identified by molecular genetic testing (see Table 1).

Note: Identification of biallelic DYSF variants of uncertain significance (or identification of one known DYSF pathogenic variant and one DYSF variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.

Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of a dysferlinopathy has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of DYSF is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

Note: RNA analysis of DYSF in myogenic cells may help identify deeper intronic pathogenic variants and variants affecting splicing (see Molecular Genetics, DYSF-specific laboratory technical considerations).

A muscular dystrophy multigene panel that includes DYSF and other genes of interest (see Differential Diagnosis) 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. 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. (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.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Dysferlinopathy

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
DYSF Sequence analysis 398.6% 4, 5
Gene-targeted deletion/duplication analysis 61.4% 4
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.

4.
5.

Includes pathogenic variants deep within DYSF intron 50i [Dominov et al 2019]. See also Molecular Genetics, DYSF-specific laboratory technical considerations.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes (Miyoshi muscular dystrophy [MMD] and limb-girdle muscular dystrophy type 2B [LGMD2B]) and two minor phenotypes (asymptomatic hyperCKemia and distal myopathy with anterior tibial onset [DMAT]) [Ueyama et al 2002]. The major and minor phenotypes 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 muscular dystrophy. Young adults have muscle weakness and atrophy most marked in the distal part 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 type 2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles that begins in adolescence or young adulthood, with slow progression. The spectrum of muscle involvement can also on occasion manifest as the scapuloperoneal syndrome with initial weakness of the shoulder girdle muscles combined with distal weakness of the legs or congenital muscular dystrophy with early onset – as observed, for example, in two sibs with hypotonia beginning between birth and age two months who had delayed motor development and serum CK concentrations that were normal or slightly elevated before age three years [Paradas et al 2009].

Asymptomatic hyperCKemia. 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).

Distal myopathy with anterior tibial onset is characterized by leg weakness that involves the muscles of the anterior compartment of the leg, causing foot drop [Illa et al 2001].

Table 2.

Dysferlinopathy: Comparison of Phenotypes by Select Features

FeatureMMDLGMD2B Asymptomatic hyperCKemia DMAT
Percent 49.8% 139.2% 16.2% 10.5% 1
Mean age at onset (range) 22.1 yrs 1
(10-48)
28.2 yrs 1
(10-63)
Asymptomatic20 yrs 1
(20-20)
Average age when use of a cane is required (yrs after onset) 35.5 yrs 2
(16 yrs)
39.3 yrs 2
(13.6 yrs)
AsymptomaticUnknown
Age when wheelchair bound (yrs after onset) 42.8 yrs 2
(22.8 yrs)
45.1 yrs 2
(21.4 yrs)
AsymptomaticUnknown
Median CK level 4,440 13,481 17,156 11,000 1
Cardiac complications 3.6% 3AsymptomaticUnknown
Respiratory complications 22.8% 3AsymptomaticUnknown

DMAT = distal myopathy with anterior tibial onset; LGMD2B = limb-girdle muscular dystrophy type 2B; MMD = Miyoshi muscular dystrophy

1.
2.
3.

Harris et al [2016]. Note that the authors did not distinguish between phenotypes.

Histology. Muscle biopsy shows evidence of a dystrophy with random variation in fiber size and evidence of degeneration and regeneration. Type I fibers may predominate. There is often evidence of inflammation, sometimes leading to a misdiagnosis of polymyositis.

Genotype-Phenotype Correlations

Studies have reported genotype-phenotype correlates with the following two pathogenic variants [Takahashi et al 2003a, Takahashi et al 2013, Izumi et al 2020]:

  • c.2997G>T was associated with a milder form of Miyoshi muscular dystrophy and LGMD2B
  • c.3373delG was associated with Miyoshi muscular dystrophy.

Nomenclature

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 muscular dystrophy 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 muscular dystrophy and LGMD2B.

Prevalence

The prevalence is not known. In the initial (1967) description of Miyoshi muscular dystrophy, four affected individuals in two families were from Japan.

Subsequently, Tagawa et al [2003] examined 107 unrelated Japanese individuals, including 53 with unclassified LGMD, 28 with Miyoshi muscular dystrophy, and 26 with other neuromuscular disorders. Using expression of dysferlin protein by immunohistochemistry (IHC) and mini-multiplex western blotting, they found deficiency of dysferlin protein by both methods in 19% of individuals with LGMD and 75% of individuals with Miyoshi muscular dystrophy.

In Libyan Jews, the prevalence of dysferlinopathy is at least 1:1,300, with a carrier rate of approximately 10% for the variant c.4872delG [Argov et al 2000].

A founder variant, c.2779delG, has been identified in Jews of the Caucasus [Leshinsky-Silver et al 2007].

A founder variant, c.5713C>T, has been identified in individuals from Spain [Vilchez et al 2005].

Differential Diagnosis

Limb-girdle muscular dystrophies. Dysferlinopathy needs to be distinguished from other autosomal recessive limb-girdle muscular dystrophies (see OMIM Phenotypic Series: LGMD, autosomal recessive). 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.

Multigene panels are increasingly used to identify pathogenic variants and confirm a diagnosis of a specific form of LGMD.

Dystrophinopathies. The dystrophinopathies cover a spectrum of X-linked muscle disease (associated with pathogenic variants in DMD) ranging from mild to severe that includes Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy. DMD usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. BMD is characterized by later-onset skeletal muscle weakness.

Distal myopathies. See Table 3.

Table 3.

Distal Myopathies

GeneDisordersMOIMean Age at Onset (Yrs)Initial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle Biopsy
GNE GNE myopathy (Nonaka distal myopathy)AR20-40Anterior compartment in legsNormal or ; typically ≤4x normalRimmed vacuoles
LDB3 (ZASP)Myofibrillar myopathy 4 (OMIM 609452)AD>40Anterior compartment in legsNormal or slightly Vacuolar & myofibrillar myopathy
MATR3 Amyotrophic lateral sclerosis 21 (formerly MPD2) (See ALS Overview.)AD35-60Asymmetric lower leg & hands; dysphonia1-8x normalRimmed vacuoles
MYH7 Laing distal myopathy AD<5Ankle & great toe extensorsUsually normal; rarely 8x normalType I fiber atrophy in tibial anterior muscles; disproportion in proximal muscles
MYOT Myofibrillar myopathy 3 (OMIM 609200)AD>40Posterior > anterior in legsSlightly Vacuolar & myofibrillar myopathy
TIA1 Welander distal myopathy (OMIM 604454)AD
AR
>40Intrinsic muscles of hand & extensor pollicus longusNormalRimmed vacuoles
TTN Udd distal myopathy – tibial muscular dystrophy AD>30Anterior compartment in legsNormal or slightly ± Rimmed vacuoles

Distal myopathies of unknown genetic cause:

  • Distal myopathy with pes cavus and areflexia (OMIM 601846) is associated with onset between ages 15 and 50 years; the anterior and posterior lower legs are involved initially, serum creatine kinase concentration is elevated to two to six times normal, and muscle biopsy is dystrophic with rimmed vacuoles. This disorder is also associated with dysphonia and dysphagia.
  • New Finnish distal myopathy (MPD3; OMIM 610099) is associated with mean onset after age 30 years; the hands or anterior lower legs are involved initially, serum creatine kinase concentration ranges from normal to approximately three times normal, and muscle biopsy is dystrophic with rimmed vacuole and eosinophilic inclusions.

Management

No clinical practice guidelines for dysferlinopathy have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with dysferlinopathy, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Dysferlinopathy

System/ConcernEvaluationComment
Musculoskeletal Neuromuscular, physical medicine & rehab / PT/OT evalTo evaluate extent of disease as determined by:
  • Muscle strength & function in arms, hands, legs (esp calves), & feet
  • Balance
  • Function
  • Fine motor skills
  • Impact on activities of daily living
  • Need for ongoing PT & OT
  • Need for AFOs & assistive ambulatory devices
  • Need for adaptive devices
  • Need for handicapped parking
Respiratory PFTs incl supine & sitting spirometry, MIP, MEPTo evaluate for effects of muscle weakness on respiratory function, esp in nonambulatory persons
Cardiac Baseline echocardiogramTo evaluate for evidence of cardiac involvement (cardiomegaly, cardiomyopathy, arrhythmia)
Genetic
counseling
By a genetics professional 1To review results of genetic testing & to inform patients & families re nature, MOI & implications of dysferlinopathy in order to facilitate medical & personal decision making
Family support/
resources
Assess:
  • Use of community or online resources, incl patient advocacy organizations;
  • Need for social work involvement for caregiver support.

AFOs = ankle-foot orthoses; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MOI = mode of inheritance; OT = occupational therapy; PFTs = pulmonary function tests; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

There is no approved therapy for dysferlinopathy. Treatment is symptomatic only.

Management should be tailored to the individual and the specific subtype. A general approach to appropriate management can prolong survival and improve quality of life.

Table 5.

Treatment of Manifestations in Individuals with Dysferlinopathy

Manifestation/
Concern
TreatmentConsiderations/Other
Musculoskeletal PT, rehabilitation medicineAmbulatory assistive devices, balanced physical activity 1, stretching exercises to promote mobility & prevent contractures; regular exercise as tolerated
Orthopedic surgeryAs needed for complications incl foot deformity & scoliosis
Activities of
daily living
PT
  • Transfers (e.g., from bed to wheelchair, wheelchair to car)
  • Medical alert system for those unable to stand after a fall
OT
  • Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming
  • To assist w/household modifications to meet special needs
Respiratory Respiratory functionPer treating pulmonologist; a concern mostly in nonambulatory persons
Family support/
resources
Social & emotional support & stimulationTo maximize sense of social involvement & productivity & ↓ sense of social isolation common in these disorders

OT = occupational therapy; PT = physical therapy

1.

All affected persons should consult their physician before beginning an exercise program.

Surveillance

Routine follow up with the multidisciplinary team (annually or more frequently as determined by managing physician) is recommended. See Table 6.

Table 6.

Recommended Multidisciplinary Team Surveillance for Individuals with Dysferlinopathy

System/ConcernEvaluationFrequency
Neuromuscular Evaluate disease progression & coordinate care.At least annually
Rehabilitation
medicine
Eval & monitoring of:
  • Muscle strength testing using a quantitative scale (e.g., MMT, hand-held dynamometry, QMA 1) to evaluate progressive muscle involvement
  • Physical function (e.g., 6-min walk test, AMAT 2)
  • Activities of daily living
At least annually
PT Eval & mgmt for balance & need for AFOs, cane, walker, wheelchair. & powerchairAt least annually, or more frequently based on needs
OT Eval & mgmt of fine motor skills & hand function, such as Jebsen Hand Function Test 3At least annually
Respiratory PFTs incl supine & sitting spirometry, MIP, MEP on affected persons at advanced stages of diseaseAs needed, if symptomatic or abnormal PFTs
Cardiac Follow up not needed unless symptomatic or findings on initial eval were abnormal
Family support/
resources
Assess social & emotional support & stimulation.At least annually

AFOs = ankle-foot orthoses; AMAT = Adult Myopathy Assessment Tool; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MMT = manual muscle testing; OT = occupational therapy; PFTs = pulmonary function tests; PT = physical therapy; QMA = Quantitative Muscle Assessment

1.
2.
3.

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

Comparison of the effect of prednisolone with vamorolone on dysferlin-deficient myofiber repair showed that vamorolone stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse myofibers [Sreetama et al 2018].

Exon skipping is a therapeutic approach that is feasible for various genetic disorders [Rodrigues & Yokota 2018]. Dominov et al [2019] designed antisense oligonucleotides (AONs) to bypass the effect of the affected individual’s pathogenic variant on RNA splicing. AON-mediated exon skipping corrected the aberrant pseudoexon splicing events in vitro, which increased normal mRNA production and significantly restored dysferlin protein expression [Dominov et al 2019].

Ono et al [2020] recently demonstrated that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin, and AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers [Ono et al 2020].

Search ClinicalTrials.gov 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. 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, 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 (i.e., presumed to be carriers of one DYSF pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a DYSF pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for a DYSF pathogenic variant, each sib of an affected individual has at conception 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.
  • Intrafamilial clinical variability may be observed between sibs who inherit biallelic DYSF pathogenic variants; for example, Miyoshi muscular dystrophy, limb-girdle muscular dystrophy type 2B, and distal myopathy with anterior tibial onset have been reported in the same family [Saito et al 2007].
  • 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. Each sib of the proband's parents is at a 50% risk of being a carrier of a DYSF pathogenic variant.

Carrier 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 and discussion of the availability of prenatal and preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

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
    Email: ehwang@jain-foundation.org
  • Muscular Dystrophy Association (MDA) - USA
    Phone: 800-572-1717
    Email: ResourceCenter@mdausa.org
  • Muscular Dystrophy UK
    United Kingdom
    Phone: 0800 652 6352

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
DYSF 2p13​.2 Dysferlin DYSF homepage - Leiden Muscular Dystrophy pages DYSF DYSF

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)

253601MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2; LGMDR2
254130MIYOSHI MUSCULAR DYSTROPHY 1; MMD1
603009DYSFERLIN; DYSF

Molecular Pathogenesis

Dysferlin is expressed in the plasma membrane of skeletal muscles and is involved in calcium-mediated membrane fusion events and plasma membrane repair [Bansal et al 2003, Lennon et al 2003].

Mechanism of disease causation. Loss-of-function variants result in very low levels of dysferlin expression in skeletal muscle membranes.

DYSF-specific laboratory technical considerations

Table 7.

Notable DYSF Pathogenic Variants

Reference SequencesDNA Nucleotide Change (Alias 1)Predicted Protein Change (Alias 1)Comment [Reference]
NM_003494​.4
NP_003485​.1
c.2779delGp.Ala927LeufsTer21Founder variant in Jews of the Caucasus [Leshinsky-Silver et al 2007]
c.2997G>Tp.Trp999CysCommon variant assoc w/milder form [Izumi et al 2020]
c.3373delGp.Glu1125LysfsTer9Common variant assoc w/MMD [Izumi et al 2020]
c.4872delG
(1624delG)
p.Glu1624AspfsTer10Founder variant in Libyan Jewish population [Argov et al 2000]
c.5713C>T
(6086C>T)
p.Arg1905TerFounder variant in Spain [Vilchez et al 2005]
NG_008694​.1 c.5668-824C>Tp.Lys1889_Asp1890insTer47Common variant that results in inclusion of pseudoexon 50.1 [Dominov et al 2019]

MMD = Miyoshi muscular dystrophy

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Chapter Notes

Revision History

  • 27 May 2021 (bp) Comprehensive update posted live
  • 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

References

Literature Cited

  • Argov Z, Sadeh M, Mazor K, Soffer D, Kahana E, Eisenberg I, Mitrani-Rosenbaum S, Richard I, Beckmann J, Keers S, Bashir R, Bushby K, Rosenmann H. Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features. Brain. 2000;123:1229–37. [PubMed: 10825360]
  • Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R, McNeil PL, Campbell KP. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature. 2003;423:168–72. [PubMed: 12736685]
  • Dominov JA, Uyan Ö, McKenna-Yasek D, Nallamilli BRR, Kergourlay V, Bartoli M, Levy N, Hudson J, Evangelista T, Lochmuller H, Krahn M, Rufibach L, Hegde M, Brown RH Jr. Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation. Ann Clin Transl Neurol. 2019;6:642–54. [PMC free article: PMC6469257] [PubMed: 31019989]
  • Harris E, Bladen CL, Mayhew A, James M, Bettinson K, Moore U, Smith FE, Rufibach L, Cnaan A, Bharucha-Goebel DX, Blamire AM, Bravver E, Carlier PG, Day JW, Díaz-Manera J, Eagle M, Grieben U, Harms M, Jones KJ, Lochmüller H, Mendell JR, Mori-Yoshimura M, Paradas C, Pegoraro E, Pestronk A, Salort-Campana E, Schreiber-Katz O, Semplicini C, Spuler S, Stojkovic T, Straub V, Takeda S, Tesi Rocha C, Walter MC, Bushby K, et al. The clinical outcome study for dysferlinopathy: an international multicenter study. Neurol Genet. 2016;2:e89. [PMC free article: PMC4994875] [PubMed: 27602406]
  • Harris-Love MO, Joe G, Davenport TE, Koziol D, Abbett Rose K, Shrader JA, Vasconcelos OM, McElroy B, Dalakas MC. Reliability of the Adult Myopathy Assessment Tool in individuals with myositis. Arthritis Care Res (Hoboken). 2015;67:563–70. [PMC free article: PMC4450351] [PubMed: 25201624]
  • Illa I, Serrano-Munuera C, Gallardo E, Lasa A, Rojas-Garcia R, Palmer J, Gallano P, Baiget M, Matsuda C, Brown RH. Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype. Ann Neurol. 2001;49:130–4. [PubMed: 11198284]
  • Illarioshkin SN, Ivanova-Smolenskaya IA, Greenberg CR, Nylen E, Sukhorukov VS, Poleshchuk VV, Markova ED, Wrogemann K. Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Neurology. 2000;55:1931–3. [PubMed: 11134403]
  • Izumi R, Takahashi T, Suzuki N, Niihori T, Ono H, Nakamura N, Katada S, Kato M, Warita H, Tateyama M, Aoki M. The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype–phenotype relationship and a hotspot on the inner DysF domain. Hum Mutat. 2020;41:1540–54. [PubMed: 32400077]
  • Jebsen RH, Taylor N, Trieschmann RB, Trotter MJ, Howard LA. An objective and standardized test of hand function. Arch Phys Med Rehabil. 1969;50:311–9. [PubMed: 5788487]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Lennon NJ, Kho A, Bacskai BJ, Perlmutter SL, Hyman BT, Brown RH Jr. Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J Biol Chem. 2003;278:50466–73. [PubMed: 14506282]
  • Leshinsky-Silver E, Argov Z, Rozenboim L, Cohen S, Tzofi Z, Cohen Y, Wirguin Y, Dabby R, Lev D, Sadeh M. Dysferlinopathy in the Jews of the Caucasus: a frequent mutation in the dysferlin gene. Neuromuscul Disord. 2007;17:950–4. [PubMed: 17825554]
  • Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, Serrano C, Urtizberea JA, Hentati F, Hamida MB, Bohlega S, Culper EJ, Amato AA, Bossie K, Oeltjen J, Bejaoui K, McKenna-Yasek D, Hosler BA, Schurr E, Arahata K, de Jong PJ, Brown RH Jr. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet. 1998;20:31–6. [PubMed: 9731526]
  • Mahjneh I, Marconi G, Bushby K, Anderson LV, Tolvanen-Mahjneh H, Somer H. Dysferlinopathy (LGMD2B): a 23-year follow-up study of 10 patients homozygous for the same frameshifting dysferlin mutations. Neuromuscul Disord. 2001;11:20–6. [PubMed: 11166162]
  • Matsuda C, Hayashi YK, Ogawa M, Aoki M, Murayama K, Nishino I, Nonaka I, Arahata K, Brown RH Jr. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum Mol Genet. 2001;10:1761–6. [PubMed: 11532985]
  • Nakagawa M, Matsuzaki T, Suehara M, Kanzato N, Takashima H, Higuchi I, Matsumura T, Goto K, Arahata K, Osame M. Phenotypic variation in a large Japanese family with Miyoshi myopathy with nonsense mutation in exon 19 of dysferlin gene. J Neurol Sci. 2001;184:15–9. [PubMed: 11231027]
  • Ono H, Suzuki N, Kanno S, Kawahara G, Izumi R, Takahansi T, Kitajima Y, Osana S, Nakamura N, Akiyama T, Ikeda K, Shijo T, Mitsuzawa S, Nagatomi R, Araki N, Yasui A, Warita H, Hayashi YK, Miyake K, Aoki M. AMPK complex activation promotes sarcolemmal repair in dysferlinopathy. Mol Ther. 2020;28:1133–53. [PMC free article: PMC7132631] [PubMed: 32087766]
  • Paradas C, González-Quereda L, De Luna N, Gallardo E, García-Consuegra I, Gómez H, Cabello A, Illa I, Gallano P. A new phenotype of dysferlinopathy with congenital onset. Neuromuscul Disord. 2009;19:21–5. [PubMed: 19084402]
  • Piccolo F, Moore SA, Ford GC, Campbell KP. Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb-girdle muscular dystrophies. Ann Neurol. 2000;48:902–12. [PubMed: 11117547]
  • Rodrigues M, Yokota T. An overview of recent advances and clinical applications of exon skipping and splice modulation for muscular dystrophy and various genetic diseases. Methods Mol Biol. 2018;1828:31–55. [PubMed: 30171533]
  • Saito H, Suzuki N, Ishiguro H, Hirota K, Itoyama Y, Takahashi T, Aoki M. Distal anterior compartment myopathy with early ankle contractures. Muscle Nerve. 2007;36:525–7. [PubMed: 17614318]
  • Sreetama SC, Chandra G, Van der Meulen JH, Ahmad MM, Suzuki P, Bhuvanendran S, Nagaraju K, Hoffman EP, Jaiswal JK. Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit. Mol Ther. 2018;26:2231–42. [PMC free article: PMC6127637] [PubMed: 30166241]
  • Tagawa K, Ogawa M, Kawabe K, Yamanaka G, Matsumura T, Goto K, Nonaka I, Nishino I, Hayashi YK. Protein and gene analyses of dysferlinopathy in a large group of Japanese muscular dystrophy patients. J Neurol Sci. 2003;211:23–8. [PubMed: 12767493]
  • Takahashi T, Aoki M, Suzuki N, Tateyama M, Yaginuma C, Sato H, Hayasaka M, Sugawara H, Ito M, Abe-Kondo E, Shimakura N, Ibi T, Kuru S, Wakayama T, Sobue G, Fujii N, Saito T, Matsumura T, Funakawa I, Mukai E, Kawanami T, Morita M, Yamazaki M, Hasegawa T, Shimizu J, Tsuji S, Kuzuhara S, Tanaka H, Yoshioka M, Konno H, Onodera H, Itoyama Y. Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B. J Neurol Neurosurg Psychiatry. 2013;84:433–40. [PMC free article: PMC3595148] [PubMed: 23243261]
  • Takahashi T, Aoki M, Tateyama M, Kondo E, Mizuno T, Onodera Y, Takano R, Kawai H, Kamakura K, Mochizuki H, Shizuka-Ikeda M, Nakagawa M, Yoshida Y, Akanuma J, Hoshino K, Saito H, Nishizawa M, Kato S, Saito K, Miyachi T, Yamashita H, Kawai M, Matsumura T, Kuzuhara S, Ibi T, Sahashi K, Nakai H, Kohnosu T, Nonaka I, Arahata K, Brown RH Jr, Saito H, Itoyama Y. Dysferlin mutations in Japanese Miyoshi myopathy: Relationship to phenotype. Neurology. 2003a;60:1799–804. [PubMed: 12796534]
  • Takahashi T, Aoki M, Tateyama M, Onodera Y, Kondo E, Sato H, Ito M, Yoshioka M, Konno K, Brown RH Jr, Saito H, Itoyama Y (2003b) Mutational and clinical features of Japanese patients with dysferlinopathy. Neurology 60 Suppl A:233.
  • Ueyama H, Kumamoto T, Horinouchi H, Fujimoto S, Aono H, Tsuda T. Clinical heterogeneity in dysferlinopathy. Intern Med. 2002;41:532–6. [PubMed: 12132520]
  • Ueyama H, Kumamoto T, Nagao S, Masuda T, Horinouchi H, Fujimoto S, Tsuda T. A new dysferlin gene mutation in two Japanese families with limb-girdle muscular dystrophy 2B and Miyoshi myopathy. Neuromuscul Disord. 2001;11:139–45. [PubMed: 11257469]
  • Vilchez JJ, Gallano P, Gallardo E, Lasa A, Rojas-Garcia R, Freixas A, De Luna N, Calafell F, Sevilla T, Mayordomo F, Baiget M, Illa I. Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population. Arch Neurol. 2005;62:1256–9. [PubMed: 16087766]
  • Visser J, Mans E, de Visser M, van den Berg-Vos RM, Franssen H, de Jong JM, van den Berg LH, Wokke JH, de Haan RJ. Comparison of maximal voluntary isometric contraction and hand-held dynamometry in measuring muscle strength of patients with progressive lower motor neuron syndrome. Neuromuscul Disord. 2003;13:744–50. [PubMed: 14561498]
  • Walter MC, Reilich P, Thiele S, Schessl J, Schreiber H, Reiners K, Kress W, Müller-Reible C, Vorgerd M, Urban P, Schrank B, Deschauer M, Schlotter-Weigel B, Kohnen R, Lochmüller H. Treatment of dysferlinpathy with deflazacort: a double-blind, placebo-controlled clinical trial. Orphanet J Rare Dis. 2013;8:26. [PMC free article: PMC3617000] [PubMed: 23406536]
  • Weiler T, Bashir R, Anderson LV, Davison K, Moss JA, Britton S, Nylen E, Keers S, Vafiadaki E, Greenberg CR, Bushby CR, Wrogemann K. 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;8:871–7. [PubMed: 10196377]
Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2022 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1303PMID: 20301480

Views

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...