Dysferlinopathies (LGMD R2 and Miyoshi Myopathy)

Autosomal recessive DYSF-related muscular dystrophies: dysferlin-related limb-girdle muscular dystrophy R2, Miyoshi myopathy, distal myopathy with anterior tibial onset, asymptomatic hyperCKaemia and rare forms.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Dysferlinopathy is defined by its gene rather than the initial distribution of weakness. For decades, the same molecular abnormality received different names according to the first affected muscle group: distal Miyoshi myopathy for posterior lower-leg onset, limb-girdle muscular dystrophy type 2B for pelvic onset, and distal myopathy with anterior tibial onset when foot drop appeared first. Dysferlin identification established that these presentations and isolated CK elevation share one cause, coexisting within families and even siblings with the same variants [1, 15].

The eponym honours Japanese neurologist Miyoshi. GeneReviews cites the first description in 1967, comprising four patients from two Japanese families. Miyoshi and colleagues' 1986 Brain series established the phenotype in 17 patients from eight families: young-adult onset, predominant gastrocnemius/soleus weakness and atrophy, early inability to stand on tiptoe despite preserved heel walking, spared small hand muscles, CK up to one hundred times normal early in disease and elevated presymptomatically. Autopsy in a 68-year-old documented generalised, predominantly distal muscle disease without nervous system lesions [1, 16].

Two groups simultaneously identified the 2p13 gene in 1998. From the Miyoshi locus, Liu and colleagues characterised 6.9 kb muscle cDNA, named dysferlin, identified nine variants in nine families and showed that one variant could produce Miyoshi, limb-girdle or anterior-tibial myopathy. From LGMD2B, Bashir and colleagues found two homozygous frameshift variants in nine families and recognised similarity to Caenorhabditis elegans fer-1 spermatogenesis factor. “Dysferlin” combines dystrophy with that homology. São Paulo researchers Passos-Bueno, Moreira and Zatz coauthored the latter study [15, 17].

Bansal and colleagues established the mechanism in 2003: dysferlin-deficient fibres could not seal sarcolemmal injury in calcium's presence and accumulated submembranous vesicles. Dysferlinopathy became the human model of membrane-repair dystrophy, distinct from dystrophin–glycoprotein complex loss directly compromising sarcolemmal mechanical stability [7].

Nomenclature changed in 2018. The 229th workshop of the European Neuromuscular Centre (ENMC) defined limb-girdle muscular dystrophies (LGMD) by progressive proximal weakness of genetic origin, primary skeletal muscle involvement, acquisition of independent ambulation, elevated CK, dystrophic imaging or histology, and at least two unrelated families. The proposed naming formula was “LGMD, inheritance (R or D), sequence number and protein”; LGMD2B became dysferlin-related LGMD R2. Online Mendelian Inheritance in Man (OMIM) and Orphanet retain separate entries for Miyoshi myopathy and DMAT, supporting “dysferlinopathy” as the term for the overall group [1, 2, 5].

The Jain Foundation-funded international Clinical Outcome Study for Dysferlinopathy (COS) changed interpretation of these labels. In 168 participants, cross-sectional weakness/fatty replacement formed a continuum without separate proximal/distal groups. Labels largely depended on country, with “Miyoshi” favoured in Japan and “LGMD R2” in Europe/US. The authors recommended against treating these as separate clinical/trial cohorts or restricting future treatment access by phenotype [18]. Phenotypic names therefore describe presentation rather than distinct diseases.

Management remains supportive. GeneReviews, revised in December 2025, states that there are no consensus diagnostic criteria or disease-specific clinical practice guidelines; ENMC held a workshop on standards of care for the dysferlinopathies in 2022, whose full report had been announced but had not been located as published at the date of this article. The American Academy of Neurology (AAN) guideline on limb-girdle and distal dystrophies, from 2014, was withdrawn by the AAN in April 2025. This article therefore relies on GeneReviews, longitudinal COS data, the only published randomised trial and information from patient organisations, identifying the nature of each source [1, 19–21].

2. Molecular Genetics and Pathophysiology

2.1. Gene, protein and transcripts

DYSF lies at 2p13.2 and encodes approximately 237 kDa membrane dysferlin, with multiple calcium-sensitive C2 domains and an internal DysF domain containing many missense variants. Skeletal muscle plasma membrane expression supports membrane fusion/sarcolemmal repair, interacting with annexins A1/A2, caveolin-3 and AMP-activated protein kinase (AMPK) [1, 22, 23].

Multiple transcripts exist. MANE Select (Matched Annotation from NCBI and EMBL-EBI) NM_001130987.2 encodes NP_001124459.1, whereas most clinical literature/GeneReviews use NM_003494.4 (NP_003485.1). Coding segments differ and numbering offsets are not constant: NM_003494.4:c.2997G>T p.(Trp999Cys) corresponds to NM_001130987.2:c.3051G>T p.(Trp1017Cys), an 18-codon difference; NM_003494.4:c.5713C>T p.(Arg1905Ter) corresponds to NM_001130987.2:c.5830C>T p.(Arg1944Ter), a 39-codon difference. ClinVar currently presents MANE variants, while older articles/laboratory reports often use NM_003494 or historical cDNA numbering. Reports must state transcript/version; conversion requires validated tools rather than manually adding an offset [1, 3, 4].

2.2. Disease mechanism

Eccentric contraction/intense activity causes physiological sarcolemmal microinjury. In normal muscle, calcium entry recruits repair vesicles/proteins, with dysferlin sensing and mediating fusion to seal the membrane within seconds. Without dysferlin, calcium-dependent repair fails, vesicles accumulate below the sarcolemma and fibres undergo necrosis. The dystrophin–glycoprotein complex remains functional, explaining progressive murine dystrophy despite preserved structural stability [7].

Pathogenic variants cause loss of function, markedly reducing membrane dysferlin [1]. Among COS patients with protein testing, 68% had absent and 30% reduced protein; three with two missense variants had normal quantities, indicating disease through altered localisation/function without quantitative reduction [8]. Saudubray's table of extraneurological cellular-trafficking manifestations groups muscular vesicular-trafficking DYSF with LPIN1 and SIL1 [24].

Inflammation is part of pathophysiology rather than merely secondary. Frequent biopsy infiltration may lead to polymyositis diagnosis; models/biopsies implicate complement activation with C5b-9 deposition on non-necrotic sarcolemma, lipid dysregulation and fat accumulation [1, 25, 26]. Retrospective associations of intense adolescent exercise with earlier onset/wheelchair use are consistent with unrepaired mechanical injury, but remain retrospective observations [27].

2.3. Variant spectrum

COS found 175 distinct variants in 193 patients, 112 unique to one individual. Approximately half were truncating (49.2%: frameshift 32.8%, nonsense 16.4%), with 32.8% missense, 17.5% splicing and 0.6% in-frame duplications throughout the gene. Genotype class did not correlate with protein, onset or severity [8]. Among 209 Japanese families, 90 variants occurred, with 70.6% of missense in the internal DysF hotspot [28].

Deep intronic variants cause incomplete molecular diagnoses. Dominov and colleagues sequenced myogenic-cell RNA from two siblings with only one identified variant, finding a deep intron 50i substitution creating pseudoexon PE50.1 and premature termination. The same variant occurred in 23 patients from 17 families. They estimated one/both variants remain unresolved in approximately 17% with exon/flanking-intron-only analysis [29].

Table equivalents were established by VariantValidator genomic projection and match ClinVar record titles; classifications are those of October 2026 [3, 4].

2.4. Genotype–phenotype correlations and modifiers

Correlations are limited. GeneReviews highlights c.2997G>T with milder Miyoshi/LGMD and c.3373del with Miyoshi [1]. Japanese p.Trp999Cys occurred in 33.5%, including 19.2% of Miyoshi and 52.4% of limb-girdle phenotypes [28]. The same homozygous variant producing different Libyan Jewish phenotypes, and all three presentations across Sueca families, suggests unidentified genetic/environmental modifiers, although each Sueca family had one phenotype [12, 32]. Oxford notes that recessive LGMD genotypes may produce severe disease in one sibling and asymptomatic status in another [9].

2.5. Allelic disorders and spectrum limits

GeneReviews states that no germline DYSF phenotypes are known beyond those included in the dysferlinopathy spectrum [1]. Two recent observations should be read with this caveat. Folland and colleagues described a family with hyperCKaemia in all heterozygotes and late-onset dystrophy in four individuals, associated with a single C-terminal variant (NM_003494.4:c.6207del p.(Tyr2070MetfsTer4); MANE equivalent NM_001130987.2:c.6324del p.(Tyr2109MetfsTer4)) that does not trigger mRNA degradation, and proposed a possibly underrecognised dominant form [6]. In August 2026, a preprint not yet peer reviewed described a de novo gain-of-function variant, p.Pro1449Leu, in two girls with interleukin-1-mediated autoinflammatory disease and a vesicular trafficking defect; this is a hypothesis of a new allelic entity awaiting validation [33].

3. Clinical Spectrum and Manifestations by System

3.1. Phenotypes and relative frequencies

GeneReviews describes two major phenotypes, Miyoshi dystrophy and LGMD2B (LGMD R2), and two minor phenotypes, asymptomatic hyperCKaemia and DMAT [1]. The table reproduces Japanese Izumi (209 families)/Takahashi data cited by GeneReviews; cardiac/respiratory COS findings were not separated by phenotype.

Source: GeneReviews table 2, from Izumi 2020, Takahashi 2003 and Harris 2016 [1]. The article also gives Miyoshi onset 19.0 years, termed a mean among suggestive findings and a median in the summary, and mean CK 8,940 IU/L. Their relationship to table 2 is unspecified, so these figures should not be mixed in one comparison [1, 28].

These proportions reflect a Japanese series favouring the Miyoshi label. COS's 193 patients across eight countries self-reported LGMD2B in 60%, Miyoshi in 30%, proximodistal dysferlinopathy in 6%, hyperCKaemia in 3% and other diagnoses in 2%, including paravertebral dystrophy/pseudometabolic presentation. Miyoshi diagnosis was sevenfold more likely in Japan (odds ratio 7.01) and LGMD2B sixfold more likely in England (odds ratio 6.12) [8]. Relative phenotype frequency therefore reflects local classification rather than biology.

3.2. Miyoshi presentation

Young patients have predominant posterior lower-leg weakness/atrophy, particularly gastrocnemius and soleus. Early inability to stand on tiptoe contrasts with preserved heel walking. Weakness spreads over years into thighs/gluteals, impairing stairs, rising and walking. Forearm atrophy may reduce grip, but small hand muscles remain spared; later scapular involvement is possible [1, 16]. Oxford notes initial tiptoe difficulty and often clearly defined late-second-decade onset [9].

3.3. Limb-girdle presentation (LGMD R2)

LGMD R2 features early pelvic/scapular weakness and atrophy arising in adolescence or early adulthood and progressing slowly. Proximal lower-limb onset typically occurs in late adolescence or later; careful examination or muscle CT/MRI may identify subclinical distal involvement [1]. Oxford's LGMD table gives onset 16–25, often slow progression, proximal/distal presentations and normal sarcoglycans/calpain 3 in biopsy [9]. Orphanet adds frequent calf hypertrophy [5].

3.4. Anterior tibial distal myopathy, hyperCKaemia and rare forms

DMAT begins in the anterior compartment with foot drop. Illa and colleagues' family progressed rapidly to severe proximal weakness; Orphanet records wheelchair dependence [5, 34]. Asymptomatic hyperCKaemia is usually considered presymptomatic; enlarged calves may suggest dystrophinopathy [1]. However, Cheema and colleagues reported 22 years of CK 812–2,223 U/L without weakness, showing elevation does not necessarily predict weakness over decades. Two of three patients had a second-allele VUS, with reduced muscle dysferlin additionally supporting diagnosis [35].

Other presentations include scapuloperoneal, congenital and exertional-myalgia pseudometabolic forms. Paradas reported two siblings with neonatal hypotonia, proximal/neck-flexor weakness, normal/mildly raised early CK and age-5 STIR oedema, homozygous p.Ala927LeufsTer21 [1, 31]. Orphanet's “markedly elevated” congenital CK description differs from early original values; normal early-childhood CK does not exclude this form [5, 31]. Non-exertional diffuse muscle pain resembling fibromyalgia and late-onset camptocormia have also been reported [36, 37].

3.5. Late onset

In an international series of 48 patients with onset at age 30 or older, the median age at onset was 37 years. Limb-girdle (26) and distal (10) patterns predominated. Atypical presentations were more frequent than in early-onset disease (7 versus 1), CK was lower (2,855 versus 4,394 U/L), functional status was better, and loss of ambulation tended to occur later (23 versus 16.3 years after onset). Biopsy showed less necrosis, regeneration and inflammation, and missense variants were more frequent [37].

3.6. System-specific manifestations

Low creatinine makes creatinine-based renal estimates uninformative [8]. Muscle-derived transaminases may prompt unnecessary liver investigations, as in a pregnant LGMD R2 patient reported in 2026 [40].

Cardiac involvement remains debated. COS structural ventricular dysfunction did not exceed age/comorbidity expectations; its authors regard significant cardiomyopathy unlikely to be part of the phenotype, unlike atrial electropathy [39]. Among 30 asymptomatic Indian patients, cardiac MRI found at least one abnormality in 36.7%, left ventricular systolic dysfunction in 16.7% and myocardial fibrosis in 16.7%. Newcastle's 2026 correspondence on these findings shows the question remains open [41, 42].

4. Clinical Recognition and Warning Signs

Recognition combines a previously often athletic young adult with lower-limb weakness, CK in the thousands and potentially inflammatory biopsy. Before symptoms, COS found frequent sport in 80% and regional/national competition in 19%; diagnosis followed incidental high CK in 24% and an affected relative in 13% [8].

Diagnostic delay has decreased. COS mean symptom–diagnosis interval fell from 20.5 years for 1970s onset to 3.1 for 2000s onset; median confirmed diagnosis age was 25 [8]. Jain Foundation estimates approximately one quarter initially diagnosed with polymyositis [44]. Contreras-Cubas reviewed 32 published inflammatory-myopathy misdiagnoses, mostly treated unsuccessfully with steroids/immunosuppressants [43].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No consensus clinical criteria are published. GeneReviews recommends suspicion with major phenotype findings and consideration with minor phenotypes. Miyoshi clues are late-childhood/early-adult onset, predominant early distal gastrocnemius/soleus weakness, slow progression, CK often 10–100× normal and myopathic electromyography (EMG). LGMD R2 clues are early girdle weakness/atrophy, proximal lower-limb onset in late adolescence or later, slow progression, massive CK and subclinical distal imaging involvement. Compatible probands with biallelic pathogenic/likely pathogenic DYSF variants have confirmed diagnosis [1].

Two interpretation rules matter. Two VUS, or pathogenic-plus-VUS, neither establish nor exclude diagnosis. Under American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards, both pathogenic and likely pathogenic categories inform clinical decisions [1, 45]. ClinGen's limb-girdle expert panel published DYSF specifications version 2.0.0 cited by GeneReviews, and has reviewed several ClinVar variants. Where available, expert-panel classification supersedes individual submissions [1, 4].

5.2. Biochemical and electrophysiological investigations

Serum CK screens disease. COS baseline mean was 4,562 IU/L, standard deviation 3,937, range 209–23,124, declining with age/duration as muscle mass decreases [8]. Moderate advanced-disease CK does not exclude; very high asymptomatic adolescent CK persisting after rest does not establish inflammation or exercise causation [43]. EMG is predominantly myopathic [1] but may be normal with isolated hyperCKaemia [35].

5.3. Muscle magnetic resonance imaging

COS T1-weighted muscle MRI in 182 patients found abnormalities in 181. Medial gastrocnemius/soleus were most affected, each 99.45%. Early thigh involvement included posterior muscles, adductor magnus and vasti; sartorius/gracilis were late and rarely completely replaced. Patterns were similar across presentations; 41.8% had at least one asymmetric muscle and 34.2% of assessed patients had tongue fat replacement. Described rules include long biceps femoris at least as affected as short, adductor magnus at least as affected as longus, rectus femoris not spared when vasti involved, gluteus minimus worse than medius/maximus, paravertebrals at least as affected as abdominals, and peroneals at least as affected as anterior tibial [38]. Figure 1 illustrates the T1 pattern (link: https://pmc.ncbi.nlm.nih.gov/articles/PMC6166612/figure/F1/).

When these rules were tested against 1,000 MRIs from ten other genetic muscle disorders, a model with the five most discriminating criteria had a sensitivity of 95.9%, specificity of 46.1%, positive predictive value of 56% and negative predictive value of 94%. The patterns of FKRP-, ANO5- and CAPN3-related myopathies were similar to that of dysferlinopathy, whereas those of oculopharyngeal muscular dystrophy, laminopathies and dystrophinopathies were different [46]. In a COS subgroup, 63% of patients failed to meet at least one criterion and 13% failed three or more; these "atypical-pattern" patients had later onset (29.3 versus 20.5 years) [47]. MRI is therefore useful for guiding suspicion and choosing the muscle to biopsy, but it does not replace molecular diagnosis.

5.4. Muscle biopsy and protein assessment

Biopsy shows random fibre-size variation, necrosis/regeneration, type I predominance and frequent inflammation sometimes mistaken for polymyositis [1]. Dysferlin immunohistochemistry/immunoblot supports deficiency/VUS interpretation, but secondary reduction occurs in dystrophinopathies, sarcoglycanopathies, caveolinopathy and calpainopathy. Protein deficiency supports rather than independently establishes primary diagnosis [1]. Among 107 Japanese patients, both-technique deficiency occurred in 19% of unclassified LGMD and 75% of Miyoshi; DYSF variants occurred only in the latter group [48].

Blood cells also express dysferlin. COS accepted one pathogenic variant with monocyte expression ≤20% [8]. An Indian study found one or more DYSF variants in 98.2% of patients whose monocyte assay showed absent dysferlin [49]. A 2026 peripheral-smear neutrophil immunohistochemical validation showed very high sensitivity but sample quality/storage-dependent specificity: protein degraded above 30 °C and persisted up to 20 weeks at 4 °C. The authors propose screening/VUS support in resource-limited settings [22].

5.5. Molecular tests and their limitations

The 98.6%/1.4% values describe identified-variant distribution in Izumi, not clinical sensitivity. Unselected-cohort two-variant yield depends on phenotype, coverage and deep intronic variants; Dominov estimated approximately 17% with at least one unresolved allele after exon sequencing [1, 29]. Negative/single-variant tests do not exclude concordant phenotype, MRI and protein deficiency.

GeneReviews offers two routes. Suggestive phenotypes undergo DYSF sequencing, then deletion/duplication if one/no variant, or preferably a dystrophy panel with DYSF/differential genes. Unconsidered dysferlinopathy is usually identified by exome/genome [1]. Oxford adds dystrophinopathy exclusion for any girdle pattern: DMD deletion/duplication testing without contractures unless biopsy excludes it, ECG/echocardiography and specialist muscle-neurology referral [9]. Withdrawn AAN 2014 level B guidance recommended phenotype/inheritance/associated-feature-directed genetics [20].

Reports should state gene, transcript/version NM_001130987.2 or NM_003494.4 explicitly, c. and p. HGVS, zygosity, known phase confirmed through parents, ACMG/AMP classification and intronic/deletion-duplication limits. Include historical numbering alongside current nomenclature where relevant, such as c.4872del (1624delG) [1, 3, 45].

5.6. Practical algorithm

6. Differential Diagnosis

The initial distribution directs differentiation. Proximal forms overlap other recessive LGMD, usually more proximal than distal and sparing heart/bulbar muscles with subtype exceptions, and dystrophinopathies [1]. Oxford notes that girdle patterns are empirically more likely dystrophinopathy than LGMD, informing familial female counselling. Distal, facial or extraocular involvement is atypical of classic LGMD; dysferlinopathy is a distal-onset exception [9].

GeneReviews also lists unknown-gene distal myopathy with pes cavus/areflexia (15–50 onset, CK 2–6×, rimmed vacuoles, dysphonia/dysphagia) and new Finnish distal myopathy (after 30, CK up to approximately 3×) [1]. In this comparison, CK in the thousands, young-adult onset, relatively spared distal upper limbs and no significant cardiomyopathy favour dysferlinopathy; early cardiomyopathy favours sarcoglycan, FKRP or lamin disease [8, 39, 51].

7. Treatments and Risk Management Strategies

7.1. Principles

No dysferlinopathy therapy is approved; symptomatic treatment should be individualised by patient/presentation. GeneReviews considers appropriate general care capable of extending survival/improving quality of life [1]. AAN 2014 guidance, withdrawn in 2025, recommended multidisciplinary-access clinics (level B), and against gene therapy, myoblast transplantation, myostatin-neutralising antibodies or growth hormone outside efficacy/safety studies (level R) [20, 21].

7.2. Initial assessments and manifestation-specific treatment

7.3. Exercise

Exercise advice is more specific than in other dystrophies. COS reported moderate activity several times weekly or vigorous weekly adolescent activity associated with onset approximately four years earlier (20.2 and 20.6 versus 24.8; hazard ratios 1.56 and 1.54) and greater wheelchair risk: partial-use HR 3.57/5.44 and permanent-use HR 4.11 in the most active group. Retrospective recall-dependent data led authors to suggest asymptomatic patients consider limiting intense exercise and early identification of affected siblings [27]. Jain Foundation recommends non-weight-bearing/concentric swimming or moderate cycling, individualised by specialist physiotherapy: stretching 4–6 times weekly, resistance 2–3 times weekly and approximately 45-minute aerobic activity 3–4 times weekly [44]. These are patient-organisation recommendations rather than trial results.

7.4. Corticosteroids: avoidance and rationale

GeneReviews lists corticosteroids among the agents to avoid and recommends weight control to prevent obesity [1]. The recommendation rests on the only randomised trial published in the disease. Walter and colleagues followed 25 genetically diagnosed patients through one year of natural history and then randomised them, in a double-blind crossover design, to deflazacort and placebo for six months each, with a three-month washout between phases; the trial regimen was 1 mg/kg/day in the first month and 1 mg/kg on alternate days from the second to the sixth month. This regimen differs from the Emflaza® label, whose only indication is Duchenne muscular dystrophy, at approximately 0.9 mg/kg/day as a single daily dose, with no maximum dose defined in the label; in dysferlinopathy its use is off-label and discouraged [52]. Planned recruitment was 35 patients, but the trial was stopped for futility; 23 were randomised [10].

Source: trial full text/table 1 [10]. Natural-history CIDD strength fell approximately 2%; dynamometry decrease was 76 N in the abstract versus table 72 N, an internal discrepancy. Authors concluded deflazacort ineffective, off-label use unjustified and corticosteroids unsuitable for patients often misdiagnosed with polymyositis [10]. CK reduction without strength benefit cautions against CK response markers. COS prior steroid use exceeded 60% in Germany but was absent in Australia, partly attributed to this trial [8]. Dissociative steroid vamorolone evidence is exclusively preclinical: it stabilised deficient-fibre membranes/improved murine repair, whereas prednisolone worsened weakness/atrophy in the same model [53].

7.5. Regulatory status

Neither US Food and Drug Administration (FDA) nor European Medicines Agency (EMA) authorises dysferlinopathy treatment. Discussed medicines are authorised for other diseases; dysferlinopathy use is off-label and, for corticosteroids, contrary to available evidence.

Without an authorised disease treatment, specific Portuguese INFARMED or Brazilian ANVISA/CONITEC reimbursement questions do not apply. Duchenne medicines' national availability was outside indication scope and not checked.

7.6. Human trials and studies

These data must be interpreted with caution. The only controlled trial was negative; the two gene therapy studies included two patients each and the most recent ended without published results; the reports with rituximab and eculizumab are uncontrolled observations in a slowly and variably progressive disease, in which improvement in one patient may reflect fluctuation, expectation effect or regression to the mean. The doses given are those of the reports and do not constitute a recommendation. They correspond to the induction regimens of the labels in other diseases and, in dysferlinopathy, are off-label use: rituximab 375 mg/m² weekly for 4 weeks is the FDA-label induction in adult granulomatosis with polyangiitis and microscopic polyangiitis (and the per-infusion dose in B-cell lymphoma) [64]; eculizumab 900 mg weekly for 4 weeks is the FDA-label induction in adult generalised myasthenia gravis and atypical haemolytic uraemic syndrome, followed by 1200 mg in the fifth week and then every 2 weeks, with meningococcal vaccination at least 2 weeks beforehand and enrolment in the REMS programme [65]. The improvement after eculizumab is nevertheless consistent with the hypothesis of complement-mediated injury and justifies controlled studies [25]. The COS authors calculated that a one-year trial with the a-NSAA (adapted North Star) assessment as outcome would require 46 moderately affected patients [66].

7.7. Preclinical research and recent developments

One third of COS patients have nonsense variants, motivating readthrough interest [8]. No approach in this table has demonstrated patient clinical benefit.

7.8. Anaesthesia, surgery and other circumstances

The Jain Foundation recommends pulmonary function testing in sitting and supine positions before surgery and informing the surgical team of the diagnosis. It states that no cases of malignant hyperthermia have been recorded in the dysferlinopathy literature [44]. The Oxford textbook associates breathing difficulty when supine with diaphragmatic weakness and recommends sitting and supine FVC measurement in LGMD, with nocturnal oximetry when indicated [9]. Smoking should be avoided [44]. Because serum creatinine is low in approximately 70% of patients, COS authors caution that creatinine-dependent methods of assessing renal function provide limited information [8].

7.9. Diagnosis-centred risk management

The principal risk-management intervention concerns diagnosis: avoiding prolonged immunosuppression in a patient with muscular dystrophy. The authors of the case described in section 10 suggest excluding muscular dystrophy before establishing “definite” or “probable” polymyositis using the Bohan and Peter criteria or those of the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) [43]. Angelini and colleagues proposed an algorithm in which a lack of response to corticosteroids and disease progression lead to dysferlin assessment by Western blot, followed by gene analysis [50].

8. Reproductive Options and Family Counselling

Dysferlinopathy follows autosomal recessive inheritance. The parents of an affected individual are obligate heterozygotes, and molecular testing of both parents is recommended to confirm that the variants are in trans and to calculate recurrence risk reliably. If only one parent carries a variant, possibilities include a de novo variant in the proband, parental postzygotic mosaicism, or uniparental isodisomy of chromosome 2 carrying the variant, resulting in homozygosity in the affected individual [1].

Carrier testing, prenatal diagnosis by chorionic villus sampling or amniocentesis, and preimplantation genetic testing require prior identification of both familial variants [1, 9]. Genetic risk and reproductive options should be discussed before pregnancy, and counselling should be offered to young adults who are affected, carriers or at risk of being carriers. Professionals and families differ in their views on prenatal and preimplantation diagnosis, and most centres regard the decision as a personal one [1].

Asymptomatic sibling counselling has particular implications. COS's intense-exercise/earlier-onset association led authors to suggest presymptomatic exercise limitation and early affected-sibling identification [27]. Testing asymptomatic minors should weigh this unproven prospective behavioural benefit, absent modifying treatment and future autonomy. Partner screening is especially informative with Libyan Jewish ~10% c.4872del and Caucasus Jewish ~4% c.2779del carrier frequencies [12, 30].

Pregnancy information is limited: GeneReviews does not address it, and ENMC's pregnancy/immunological/endocrine/nutritional group has no published recommendations [1, 19]. A 2026 pregnant LGMD R2 muscle-derived hypertransaminasaemia report cautions against automatically attributing ALT/AST to liver disease [40]. Without specific data, maintain section 11's general respiratory surveillance, particularly with reduced FVC [39].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

GeneReviews states that prevalence is unknown [1]. For northern England, Orphanet reports point prevalences of 0.13 per 100,000 for LGMD R2 and 0.26 per 100,000 for Miyoshi myopathy, derived from Norwood’s study of a population of approximately three million. It also reports an annual incidence of 0.22 per 100,000 for Miyoshi myopathy in Japan, based on expert opinion [5, 11]. In the same English study, the prevalence of all LGMD combined was 2.27 per 100,000 [11]. The 2014 AAN guideline estimated prevalences of 0.07–0.43 per 100,000 for most LGMD subtypes and noted variation by ancestry; this range concerns LGMD generally rather than dysferlinopathy specifically [20]. The English figures come from a referral clinic and measure diagnosed patients rather than allele frequency. COS itself showed that use of the Miyoshi or LGMD R2 label varies by country, making the combined estimate for the two entities unstable [8, 18].

9.2. Founder populations

Leshinsky-Silver also notes Italian clusters reported before 2007 [30]. COS found c.2779del in three Hispanic patients and c.5713C>T in four of diverse ethnicities [8].

9.3. US, European and other regional data

COS enrolled 193 across 15 centres/eight countries: UK, Spain, Germany, Italy, France, US, Japan and Australia. Ethnicity was 71% white, 17% Asian, 6% Hispanic, 3% black and 3% other [8]. Longitudinal fatty-replacement models found no trajectory differences by these ethnic groups, variant or residual protein; women had absolute lower-leg fat fractions 8.8% higher [73]. Indian series demonstrate frequent consanguinity and blood-assay usefulness where biopsy is less accessible [22, 49, 72].

Principal sources yielded no Portuguese/Brazilian frequency data, without proving studies absent. São Paulo researchers contributed 1998 LGMD2B gene identification [17]; section 10's Latin American case is Mexican [43].

9.4. Networks and resources

ERN EURO-NMD unites European referral centres [13]. The US Jain Foundation specifically supports dysferlinopathy, funded COS and maintains a registry. According to the Foundation, COS assessed over 300 genetically diagnosed patients for 2–10 years each [14]. GeneReviews also lists US Muscular Dystrophy Association (MDA) and Muscular Dystrophy UK [1]. Portugal's Associação Portuguesa de Neuromusculares (APN) and Brazil's Associação Brasileira de Distrofia Muscular (ABDIM) support muscular dystrophy patients [74, 75].

10. Illustrative Clinical Case

Contreras-Cubas and colleagues reported in 2022 a 14-year-old Mexican boy referred to rheumatology after incidental asymptomatic CK 26,372 IU/L. There was no neuromuscular family history, consanguinity or myotoxic drug/substance exposure. He trained in high-performance sport three hours daily without myalgia, cramps or pigmenturia. Initially attributed by neurology to exercise, CK remained >20,000 IU/L after sport ceased. Neuromuscular/systemic examination, EMG and conduction were normal without cardiac/respiratory abnormalities; myositis-specific/associated and antinuclear antibodies were negative, thyroid function normal [43].

Sex/CK suggested dystrophinopathy, but multiplex PCR/MLPA found no DMD deletions. Six months later, right quadriceps biopsy showed necrosis/endomysial and perivascular lymphocytes without fibrosis/fat (figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC9208210/figure/Fig1/), and repeat EMG became myopathic. Diagnosed juvenile polymyositis, he received intravenous methylprednisolone then prednisone/methotrexate. Despite CK falling from 28,457 to 21,671 IU/L, proximal lower-limb weakness developed and worsened after another methylprednisolone course, sparing upper limbs. Very high CK, steroid-emergent weakness and prominent inflammation suggested LGMD; steroids/methotrexate were stopped, without complete strength recovery [43].

Exome confirmed compound heterozygous DYSF LGMD R2: maternal exon32 nonsense reported as c.3851C>T p.(Gln1160Ter), and paternal exon53 c.5979dup p.(Glu1994ArgfsTer3), Sanger-confirmed (figure 2 pedigree/chromatograms: https://pmc.ncbi.nlm.nih.gov/articles/PMC9208210/figure/Fig2/) [43]. No transcript is given. VariantValidator finds the second consistent with NM_003494.4, equivalent MANE NM_001130987.2:c.6096dup p.(Glu2033ArgfsTer3). The first combination is inconsistent: NM_003494.4 c.3851 is not cytosine, while NM_001130987.2 c.3851C>T would give p.(Pro1284Leu). Protein p.(Gln1160Ter) would correspond to NM_003494.4:c.3478C>T, but authors have not confirmed this correction; do not use it for segregation/database assertions without verification by the original laboratory [3].

The authors reviewed 32 inflammatory-myopathy/polymyositis misdiagnoses, noting that Bohan–Peter criteria do not specify other-myopathy exclusion and recommending dystrophy exclusion before “definite”/“probable” juvenile polymyositis [43]. The case illustrates presymptomatic athletic-adolescent hyperCKaemia, inflammatory biopsy's inability to distinguish dystrophy/myositis, and steroid worsening as both diagnostic clue and avoidable harm, already seen in Walter [8, 10]. Its treatment sequence describes the report rather than guidance and exemplifies what sources advise avoiding.

11. Prognosis and Long-Term Follow-up

11.1. Natural history

Progression is slow but highly variable. Japanese mean walking-stick requirement was 16 years after Miyoshi onset and 13.6 after LGMD R2; wheelchair dependence 22.8 and 21.4 respectively [1]. COS median symptom duration was 17 years, with 25% non-ambulant. Over 30% remained mild/moderate at ≥30 years, a similar proportion severe by ≤17; approximately 30% were moderate after five years [8]. India's 124-patient series found 18.6% lost ambulation during follow-up, median 120 months to independent-ambulation loss [72]. Late-onset loss occurred later, 23 versus 16.3 years [37]. All same-variant homozygous Libyan Jews remained ambulant until at least 33 [12].

Consulted sources do not document reduced life expectancy. Two died during three-year COS follow-up, considered unlikely to have died directly from dysferlinopathy [39]. This short observation cannot establish normal survival.

11.2. Progression measures and prognostic factors

11.3. Surveillance

Respiratory/cardiac recommendations differ. GeneReviews restricts respiratory testing to advanced, symptomatic or initially abnormal patients and cardiac follow-up to symptoms/initial abnormalities. Longitudinal COS published after GeneReviews' full 2021 update found FVC <80% in up to 30%, including ambulant patients, and atrial abnormalities in over half. Authors recommend FVC at every review, palpitation enquiry/pulse palpation and Holter with symptoms/irregular pulse, but no routine periodic cardiology. Orphanet conversely describes LGMD R2 without cardiac/respiratory involvement. Oxford's ENMC2003-based position finds no routine LGMD2B cardiac need but recommends regular sitting/supine FVC across LGMD [1, 5, 9, 39]. The following integrates these positions, favouring recent longitudinal evidence.

The term “biannual” used by the COS authors and the Jain Foundation is ambiguous in English (twice yearly or every two years); this article reports it without converting it into a single interval [39, 44]. Transition from paediatric to adult care is rarely relevant, because onset is typically in young adulthood, but it applies to congenital forms and to adolescents diagnosed through hyperCKaemia [31, 43].

12. Summary and Final Considerations

Dysferlinopathy is an autosomal recessive muscular dystrophy caused by loss of function of dysferlin, the protein that enables muscle fibres to repair sarcolemmal injury through a calcium-dependent process. Miyoshi myopathy, LGMD R2, anterior tibial-onset distal myopathy and asymptomatic hyperCKaemia are presentations of the same disease. COS data show a continuum of proximal and distal involvement, with labels depending more on the country than on the muscle first affected.

Recognition combines an often athletic young adult, calf/pelvic weakness, CK in the thousands and potentially inflammatory biopsy. Characteristic MRI is non-specific and overlaps ANO5, CAPN3 and FKRP. Two pathogenic DYSF variants establish diagnosis. Sequencing finds most known variants, but deep intronic changes require RNA/protein investigation after single-variant findings. MANE NM_001130987.2 and clinical-literature NM_003494.4 numbering differs by a non-constant offset.

No therapy is approved. Management consists of rehabilitation, orthoses, regular respiratory surveillance, attention to cardiac rhythm, weight control and an exercise programme that avoids intense eccentric loading. Corticosteroids are not indicated: the randomised deflazacort trial was negative and associated with loss of strength, while misdiagnosis as polymyositis continues to expose patients to prolonged immunosuppression. Gene therapies using dual AAV vectors, oligonucleotides targeting pseudoexons, modulation of membrane repair and complement inhibition remain preclinical or limited to case reports. The only intravenous gene therapy trial ended after enrolling two patients, with protein expression below expectations.

Clinical geneticists should confirm parental phase, interpret VUS cautiously using protein/RNA, recognise Libyan/Caucasus Jewish, Sueca and Japanese founders, and counsel asymptomatic siblings for whom exercise information may help. ENMC care standards in preparation since 2022 and ongoing COS cohorts should consolidate cardiorespiratory surveillance, exercise and pregnancy guidance.

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