Sarcoglycanopathies (LGMD R3, R4, R5 and R6)

Autosomal recessive limb-girdle muscular dystrophies caused by deficiency of α-, β-, γ- and δ-sarcoglycan

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Sarcoglycanopathies are four autosomal recessive limb-girdle muscular dystrophies caused by biallelic variants in SGCA, SGCB, SGCG or SGCD, which encode the sarcolemmal α-, β-, γ- and δ-sarcoglycans; in current nomenclature they are designated LGMD R3, R4, R5 and R6 [1, 2]. They predominantly manifest in childhood, with progressive proximal weakness of the pelvic and shoulder girdles that frequently leads to loss of ambulation in adolescence or early adulthood, and may involve the heart and respiratory muscles [2]. They account for approximately 10 to 25% of LGMD and are among the most severe recessive forms [14], with a spectrum ranging from presentations resembling Duchenne muscular dystrophy to asymptomatic hyperCKaemia or isolated exercise intolerance [2, 19].

Autosomal recessive transmission of a Duchenne-like dystrophy was recognised before its molecular characterisation: Kloepfer and Talley (1958), Dubowitz (1960) and Skyring and McKusick (1961) described forms with onset before 5 years, wheelchair dependence around 12 and death usually before 20 years, with pseudohypertrophy [7]. The modern clinical history begins in Tunisia. In 1983, Ben Hamida, Fardeau and Attia published a study of 93 children with severe progressive muscular dystrophy, with first symptoms between 3 and 12 years, predominantly girdle and trunk atrophy, almost constant calf hypertrophy, markedly elevated CK in the early stages, loss of ambulation generally between 10 and 20 years and a course often resembling Duchenne muscular dystrophy; the disease affected both sexes equally, appeared to follow autosomal recessive inheritance, was common in Tunisia and associated with high consanguinity, and varied in severity between siblings and families [32]; more than three-quarters of parental couples were closely consanguineous, compared with 16 to 23% in the general population [7]. The ENMC 282 report dates Ben Hamida's first communication, involving 31 children, to 1980 [2]. The entity became known as severe childhood autosomal recessive muscular dystrophy (SCARMD) [33, 34].

Molecular identification arose from biochemical studies of dystrophin and its associated glycoprotein complex [35]. In 1992, Matsumura and colleagues demonstrated deficiency of the 50 kDa subunit of the complex, adhalin, in SCARMD, and in 1994 Romero and colleagues described a French family with a milder form, absent adhalin and excluded linkage to 13q, distinguishing primary adhalin deficiency from deficiency secondary to a defect in another gene [5, 7]. In 1994, Roberds and colleagues cloned the complementary DNA of adhalin, the 50 kDa dystrophin-associated glycoprotein missing from muscle in patients with SCARMD, mapped the gene to chromosome 17q and identified missense variants in one family, demonstrating that not all forms of SCARMD were linked to the 13q locus described in North African families [33]. In 1995, Noguchi and colleagues showed that the primary defect in 13q12-linked SCARMD involved the 35 kDa γ-sarcoglycan, with frameshift deletions in three families and in one of four sporadic cases and disruption of the entire complex [34]. In the same year, two groups cloned the 43 kDa β-sarcoglycan at 4q12: Lim and colleagues identified a threonine→arginine missense variant in Amish families with LGMD2E [36], families from southern Indiana described since 1968, with a mean onset at 7.6 years (4–12), loss of ambulation between 12 and 38 years and marked intrafamilial variability [6], and Bönnemann and colleagues described a girl with truncating variants in both alleles and secondary loss of the entire complex [37]. In 1996, Nigro and colleagues mapped LGMD2F in two Brazilian families to chromosome 5q33–34 and demonstrated that a homozygous single-nucleotide deletion in the δ-sarcoglycan gene was the cause [38], identified in 8 patients from 4 families in northern Brazil, with absence of all four sarcoglycans on biopsy [8]. Also in 1996, Piccolo and colleagues described the γ-sarcoglycan founder variant C283Y in seven Roma families from Western Europe [15].

Subsequent frequency studies shaped diagnostic practice. Duggan and colleagues studied 556 biopsies from patients with myopathy and a normal dystrophin gene: α-sarcoglycan was reduced in 54 (10%), variants were found in 29 of the 50 patients studied (17 in SGCA, 8 in SGCB, 4 in SGCG), and the frequency of variants was 22% in severe childhood-onset Duchenne-like dystrophies and 6% in later-onset limb-girdle forms [39]. Fanin and colleagues estimated a prevalence of primary sarcoglycanopathies of 5.6 per million inhabitants in north-eastern Italy in 1996 [40].

The nomenclature was revised at the 229th ENMC workshop in 2017: the former LGMD2D, 2E, 2C and 2F became LGMD R3, R4, R5 and R6, respectively [1, 19]. In November 2024, the 282nd ENMC workshop brought together 29 participants in Amsterdam to harmonise the evidence on diagnosis and care, in the absence of international standards of care, and the report published in 2025 is now the principal consensus reference [2]. There is no GeneReviews chapter dedicated to sarcoglycanopathies: the LGMD overview chapter (Pegoraro and Hoffman, last updated in 2012) was withdrawn and retains only historical value, and the DCM overview chapter (NBK1309) mentions SGCD only as a non-syndromic DCM gene [29, 30]. There is no approved therapy; gene therapy with adeno-associated virus (AAV) vectors is the principal approach in clinical development, with the most advanced programme (bidridistrogene xeboparvovec, LGMD R4) in phase 3 and with the regulatory disruptions of 2025 described in section 7 [2, 19].

The scope of this article corresponds to LGMD R3–R6. Dystrophinopathies, the general approach to myopathies, dysferlinopathies, calpainopathy and FKRP-related LGMD R9 appear here only in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The sarcoglycan complex and muscle fibre membrane

The α-, β-, γ- and δ-sarcoglycans are transmembrane glycoproteins of the sarcolemma of skeletal and cardiac muscle fibres. The four subunits assemble as a complex in the endoplasmic reticulum and subsequently associate with other proteins to form the dystrophin-associated glycoprotein complex (DGC), which links the intracellular cytoskeleton to the extracellular matrix and contributes to structural integrity and signal transduction in striated muscle [19]. Within the DGC, the tetrameric sarcoglycan complex stabilises the association of dystrophin with dystroglycans and contributes to the stability of the plasma membrane cytoskeleton [29]. When one subunit is missing, the membrane becomes fragile, loses resistance to contractile stress and the fibre enters cycles of injury, necrosis and degeneration [19]. The β and δ subunits form the core of the complex and are essential for its assembly, explaining why variants in SGCB and SGCD tend to disrupt the entire tetramer [18]. The ε- and ζ-sarcoglycan genes encode proteins also present in the sarcolemma, but are not associated with muscular dystrophy [19]; ε-sarcoglycan (SGCE) is, in fact, the gene characterised in autosomal dominant myoclonus dystonia with reduced penetrance, an entity with no clinical relationship to limb-girdle dystrophies [41].

The interdependence of the four subunits has a direct diagnostic consequence. Pathogenic variants in any of the four genes cause secondary deficiency of all proteins of the complex on muscle immunostaining, so no immunohistochemical pattern reliably identifies the mutated gene [29]. Conversely, primary absence of dystrophin also reduces sarcoglycans, so dystrophin and sarcoglycan staining should be performed on the same sample [2, 29]. In cardiac cells, deletion of dystrophin exon 29 (the mid-rod region) disrupts sarcoglycan assembly in the myocardium but not skeletal muscle, a mechanism mentioned in the Oxford Desk Reference in relation to X-linked dilated cardiomyopathy [42].

Expression of the β and δ subunits in vascular smooth muscle has been invoked to explain the higher frequency and severity of cardiac involvement in the β and δ forms: the review by Borland and colleagues suggests that their presence in coronary vessels may add coronary injury, and in mice δ-sarcoglycan deficiency causes cardiomyopathy aggravated by coronary vascular irregularities, probably through absence of the protein in smooth muscle [18, 19]. Mechanical fragility does not explain the entire process: in mice lacking γ-sarcoglycan, muscle resisted eccentric contractions and intense exercise normally despite progressive dystrophy, leading Hack and colleagues (1999) to propose a non-mechanical mechanism, possibly involving signalling [7]. In mice lacking β-sarcoglycan, all sarcoglycans and sarcospan are lost, and the dystrophin–dystroglycan complex becomes unstable [6]. In animal models, the BIO14.6 hamster, carrying a deletion in Sgcd, develops dilated or hypertrophic cardiomyopathy depending on the strain, and in zebrafish δ-sarcoglycan is required for left–right cardiac asymmetry and myofibril organisation [18].

2.2. Genes, loci, nomenclature and identifiers

The revision of limb-girdle muscular dystrophy (LGMD) nomenclature, approved at the 229th European Neuromuscular Centre (ENMC) workshop in 2017, replaced the alphabetical designations (LGMD2C to 2F) with numbering according to mode of inheritance (R for recessive), assigning R3 to α-sarcoglycan, R4 to β, R5 to γ and R6 to δ [1, 2]. The correspondence does not follow the old alphabetical order: LGMD2D (α) became R3, LGMD2E (β) R4, LGMD2C (γ) R5 and LGMD2F (δ) R6, which should be borne in mind when reading literature predating 2018 [19].

Table sources: genes, cytobands and identifiers according to GeneGuidance and Orphanet; MANE Select transcripts confirmed using VariantValidator [3, 4, 9–13]. The acronym SCARMD (severe childhood autosomal recessive muscular dystrophy) designated the form described in Tunisia and corresponds to γ-sarcoglycanopathy [29]. OMIM phenotype 606685 (dilated cardiomyopathy 1L) is associated with SGCD with proposed dominant inheritance, but its validity is discussed in section 2.6 [3, 30].

2.3. Variant types and loss-of-function mechanism

Most genetic defects responsible for sarcoglycanopathies are missense variants, which produce misfolded sarcoglycans; these are recognised and eliminated by the cellular quality-control system (endoplasmic reticulum-associated degradation) despite retaining functional potential [2, 19]. Nonsense and frameshift variants are incompatible with protein production and are associated with early onset, rapid progression, early loss of ambulation and reduced life expectancy; missense and in-frame variants allow production of protein that passes through the endoplasmic reticulum, and a fraction escapes degradation and reaches the membrane, making the residual amount difficult to predict from the genotype [19]. The unifying principle is that severity is inversely related to the amount of residual protein in all subtypes [19].

Regarding distribution by gene, the 2025 review describes predominantly compound heterozygosity and missense variants for SGCA, with nonsense variants associated with more severe phenotypes; predominantly missense variants for SGCB; predominantly homozygosity and missense variants for SGCG, with nonsense variants being more severe; and homozygosity with frameshift, nonsense and splicing variants for SGCD, mostly affecting the extracellular domain [19]. In the international LGMD R6 cohort, all 23 patients were homozygous, 13 different variants were identified (six novel) and 30.4% of patients had large deletions of one or more exons, which may escape Sanger sequencing and require a quantitative method such as multiplex ligation-dependent probe amplification (MLPA) [18]. In SGCB, a homozygous microdeletion of approximately 400 kb at 4q11-q12, also including SPATA18, was described in a consanguineous family from Eastern Anatolia with a severe form, joint hypermobility and contractures, and three relatives died from heart failure at 20, 30 and 35 years [6]. One variant in this cohort, SGCD NM_000337.6:c.1_3del p.(Met1?) (published as p.Met1del), eliminates the initial methionine; protein may still be produced from a second methionine in exon 3, and patients carrying it showed expression of the complex on biopsy [18].

2.4. Recurrent and founder variants

The following table collates the recurrent variants cited in the sources consulted. Nomenclature was normalised to MANE Select transcripts using VariantValidator, and classification corresponds to the ClinVar record consulted in October 2026; historical designations are indicated when used in the literature.

The relative frequency of genes varies by population. In the North American and European literature on non-consanguineous populations, the reported order was α >> β >> γ >> δ, in a ratio of approximately 8:4:2:1 [29]; in the European consortium (439 patients recruited from 33 centres in 13 countries, 396 analysed) there were 159 patients with R3, 73 with R4, 157 with R5 and 7 with R6, and in each gene two or three variants accounted for most alleles [20]. Founder variants and consanguinity profoundly alter these regional proportions, as detailed in section 9.

2.5. Variant interpretation: specific rules and functional investigation

The ClinGen LGMD Variant Curation Expert Panel (VCEP) has published sarcoglycan-specific specifications for the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, already applied in the ClinVar records for the variants above. For SGCA, variant c.229C>T was classified as pathogenic based on observations in trans and in homozygosity (PM3_Strong), segregation in ten affected relatives from five families (PP1_Strong), a highly specific phenotype and reduction in α-sarcoglycan (PP4), and functional membrane-localisation assays (PS3_Supporting); the filtered allele frequency in gnomAD (0.0004392 in non-Finnish Europeans) was below the 0.0009 threshold defined by the panel for criterion BS1 [43]. For SGCG, variant c.525del received PVS1 only at Strong strength because an N-terminal antibody suggested production of truncated protein, and the panel notes that detection of γ-sarcoglycan absence depends on the antibody used (specifications version 2.0.0, December 2025) [46]. These specifications incorporate muscle histology as phenotypic evidence, which, according to ENMC 282, improves the performance of the rules in reaching a definitive diagnosis [2].

Variants of uncertain significance (VUS) are a barrier to diagnosis, family planning and trial inclusion. In a saturation mutagenesis study, all 6340 possible missense variants in SGCB were tested for their ability to localise protein to the plasma membrane; the assay correctly identified the pathogenic variants recorded in ClinVar and correlated with age at onset [2]. Deep-learning approaches are being developed for the other sarcoglycans [2]. These functional results are classification tools; they do not replace demonstration of the two variants in trans or phenotypic concordance.

2.6. Allelism and isolated cardiac phenotypes

δ-Sarcoglycan is included in lists of dilated cardiomyopathy (DCM) genes. In the GeneReviews DCM overview (revised December 2024), SGCD appears among non-syndromic DCM genes with dominant inheritance, accounting for less than 1% of cases and with “limited” clinical validity in the ClinGen classification, with LGMD R6 as an allelic disorder [30]. Clinical Cardiogenetics lists SGCD with recessive inheritance and an estimated fraction below 0.01 of idiopathic DCM cases [53], and the Oxford Desk Reference states that SGCD variants can cause familial DCM without skeletal involvement or with subclinical involvement [42]. This dominant association was based on the variant NM_000337.6:c.451T>G p.(Ser151Ala), described in a family with three patients with severe DCM; its relevance was disputed when the variant was found, without cardiac disease, in members of a consanguineous family with LGMD R6 due to homozygous p.Ala131Pro (published designation; = NM_000337.6:c.391G>C p.(Ala131Pro)), and the murine knock-in model had a mild cardiac phenotype [18]. ClinVar currently classifies it as of uncertain significance [52]. The dominant SGCD–DCM relationship should therefore not support clinical decisions on its own.

A recessive isolated cardiac phenotype was demonstrated for SGCB in 2026. Integrated genome and transcriptome analysis of cardiac tissue from Japanese patients undergoing transplantation or ventricular assistance identified variant c.243+6T>A, which causes exon 2 skipping [49]. The variant has an allele frequency of 0.0003 in global gnomAD and 0.009 in East Asian populations; heterozygosity did not differ between 54,209 Japanese controls and 936 patients with DCM (1.05% and 1.39%), but homozygosity was present in 3 controls (0.006%) and 10 patients (1.07%), with an odds ratio of 227.55 (95% confidence interval [CI], 41.43–1249.71) [49]. In homozygous cardiac tissue, full-length β-sarcoglycan and the other subunits were reduced, whereas in skeletal myocytes derived from induced pluripotent stem cells the reduction in the other subunits did not reach statistical significance; the 12 biallelic patients had normal creatine kinase (CK), muscle strength similar to controls with TNNT2-related DCM and normal skeletal muscle T1 relaxation times on magnetic resonance imaging [49]. Compared with 50 patients with DCM without an identified variant, biallelic carriers had earlier onset of the composite outcome of ventricular assistance, transplantation or cardiovascular death (hazard ratio 2.90; 95% CI 1.07–7.88) [49]. ClinVar retains conflicting classifications for this variant [50]. The finding extends the allelic spectrum of SGCB to isolated DCM and shows that absence of myopathy does not exclude a sarcoglycan cause of cardiomyopathy, but the data come from a population with a particular allele frequency and have not yet been replicated in other populations in the sources consulted.

2.7. Heterozygotes

Inheritance is autosomal recessive for all four LGMDs [2]. Some heterozygotes for SGCA variants have been described with mild symptoms, such as scapular winging and calf hypertrophy, but normal levels of all four sarcoglycans on immunostaining [29]. In the GRASP-LGMD (Genetic Resolution and Assessment Solving Phenotypes) consortium substudy, individuals with a single pathogenic SGCA variant had approximately 30% of the α-sarcoglycan expression of healthy individuals [2]. These data describe observations in carriers and do not define a disease risk for heterozygotes.

3. Clinical Spectrum and Manifestations by System

3.1. General presentation and motor trajectory

The typical presentation begins in childhood with proximal girdle weakness: in the lower limbs, the gluteal muscles and adductors are affected early and the quadriceps later; in the upper limbs, the deltoid, triceps and biceps are involved in almost all patients, and involvement of the periscapular muscles frequently causes bilateral scapular winging [19]. Toe walking, difficulty climbing stairs, Gowers' sign and calf and tongue hypertrophy appear early; axial weakness progresses and causes scoliosis, and the hands and face tend to be spared [19]. The trajectory generally follows a proximal-to-distal pattern, with loss of ambulation expected in adolescence or early adulthood [2]. In the prospective study of 40 patients with R4 from Columbus (Ohio), performance improved until approximately 7 years, although below that of age-matched peers, plateaued until 10–12 years and declined thereafter; the ability to rise from the floor was the first milestone lost, and all those who could still do so covered 10 metres in less than 7.8 seconds [2].

The historical GeneReviews chapter distinguished two patterns: complete sarcoglycan deficiency, with onset between 3 and 15 years (mean 8.5), difficulty running and walking, calf hypertrophy and loss of ambulation around 15 years; and partial deficiency, with cramps and exercise intolerance and loss of ambulation in adolescence or early adulthood [29]. This gradient corresponds to the inverse relationship between residual protein and severity confirmed in recent cohorts (section 11) [20].

3.2. Differences between subtypes

Sources: European consortium with 396 patients analysed [20]; international cohort of 23 patients with R6 [18]; profiles according to the 2025 review [19].

α-Sarcoglycanopathy is the most common form in Europe and generally the mildest, but has the most variable phenotype, from asymptomatic hyperCKaemia to severe Duchenne-like disease with loss of ambulation and respiratory impairment; all patients have elevated CK [19]. In the French cohort of 100 patients, mean age at onset was 8 years in the α forms and 5.5 years in the γ forms, and after a mean follow-up of 22.9 years 65.3% used wheelchairs (66.7% α, 67.3% γ, 40% β) [54]. At the mild end, reports include patients with R3 presenting with exercise intolerance and rhabdomyolysis with myoglobinuria, normal immunohistochemistry and 27% and 35% of normal α-sarcoglycan expression on Western blot [45], a Portuguese patient with very late onset and normal biopsy [44], and three siblings with late onset and axial involvement, carrying a homozygous intronic SGCA deletion [55].

β-Sarcoglycanopathy accounts for 15 to 30% of sarcoglycanopathies; the mild form is rare and may manifest only as myoglobinuria or rhabdomyolysis before other signs appear, whereas the common form progresses rapidly and severely, and cardiac involvement affects more than 50% of patients in the 2025 review [19]. In the series of 32 patients with R4 reported by Semplicini and colleagues, cardiac involvement was observed in 63%, sometimes before overt muscle involvement, 19% required assisted ventilation and distal weakness appeared early in severe forms [48].

γ-Sarcoglycanopathy is the second most frequent form in many European and South American countries, is prominent in the Maghreb and India, and tends to cause a severe Duchenne-like phenotype, with atrophy, respiratory impairment, DCM and premature death [19]. In the European consortium, 87.2% of γ patients developed symptoms before 10 years and 84.4% lost ambulation before 18 years, indicating greater severity than described in earlier series [20]. The series of 40 Roma patients homozygous for C283Y showed a homogeneous phenotype, with mean onset at 5.3 years, half the patients non-ambulant by 12 years, 13% still walking after 16, absence of cardiomyopathy and mechanical ventilation required in five patients in the third decade [56]; however, in a study of 10 Roma patients with LGMD2C, ECG and echocardiography revealed mild subclinical right ventricular dysfunction [7].

δ-Sarcoglycanopathy is ultrarare. In the international cohort of 23 patients from nine countries, 91% were symptomatic, proximal weakness of all four limbs was the most common presentation, distal weakness appeared early in 56.5% and 60% had used wheelchairs since early adolescence [18]. At 15 years, 77.8% of patients without residual protein and 87.5% of those whose symptoms began before 5 years used wheelchairs, and 91.3% of the cohort lost ambulation before 18 years [18]. Toe walking due to Achilles tendon contracture occurred in 71.4% (median 9.5 years), and foot deformities, particularly pes cavus and clubfoot, reflect early distal weakness (figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9014751/figure/awab301-F2/) [18]. At the São Paulo centre, the R6 form showed early distal weakness with foot deformities before loss of ambulation, which also occurred earlier than in the other subtypes [2].

3.3. Heart

Cardiac involvement occurs in approximately one-fifth of patients, is progressive and predominates in the β and γ forms [2, 20]. In the European consortium, 19% of all patients had cardiac involvement, with no difference in age at detection between subtypes and with correlation with disease duration in the β and γ forms; the presence of cardiomyopathy was unrelated to age at onset, age at loss of ambulation or residual protein [20]. DCM predominated in the β and γ forms, whereas rhythm abnormalities predominated in α [20]. In the Italian series of 115 patients, cardiac disease was more frequent in R4 (38%) and R6 (50%) [2]; in the French cohort, DCM occurred in all subtypes, particularly the γ form [54]. Clinical Cardiogenetics estimates a DCM frequency of approximately 20%, progressing over time and with no difference in median age or muscular severity between patients with and without DCM [57]. Individual reports illustrate the potential severity: two men with LGMD2E died from DCM at 27 and 18 years, whereas an affected cousin of one had no cardiomyopathy [6], and a 13-year-old boy with α-sarcoglycan deficiency, initially diagnosed with Becker dystrophy, developed refractory heart failure and required left ventricular assistance for 6 weeks and cardiac transplantation [5]. In an Italian study of 20 patients assessed clinically and by electrocardiography, echocardiography and scintigraphy, cardiac function was normal in 31.3%, preclinical cardiomyopathy was present in 43.7%, arrhythmogenic cardiomyopathy in 6.3% and early signs of DCM in 18.7%, with no correlation between cardiac and skeletal involvement [58]. DCM may also occur in isolation, without myopathy, in homozygotes for SGCB variant c.243+6T>A [49]. The historical GeneReviews chapter considered cardiomyopathy rare in the α form [29], consistent with the 10.4% in the European consortium, but this does not remove the need for surveillance; in Tunisia, a paediatric clinic recorded no cardiac involvement in 23 patients with R3 and R5, all receiving ACE inhibitors [2].

3.4. Respiratory system

Respiratory impairment is restrictive and occurs mainly in later stages, often after loss of ambulation, requiring nocturnal and sometimes daytime NIV [19]. In the European consortium, up to 25% of patients required ventilatory support, at a mean age of 29.1 years (8–58), with no difference between subtypes; 69.1% of ventilated patients had scoliosis, compared with 31.9% of non-ventilated patients [20]. In the French series, 74% of patients had some degree of respiratory failure and 30% required assisted ventilation, and loss of ambulation was associated with low FVC [2]. In the study of 34 French adults with R5 and R3 followed at a home ventilation centre, baseline median vital capacity was 31% predicted, and respiratory events occurred in 38% of patients over a median of 6 years [59]. In the Italian study of 20 patients, respiratory function was normal in 23.5%, mildly impaired in 35.4%, moderately impaired in 29.4% and severely impaired in 11.7% [58].

3.5. Musculoskeletal system

Contractures (81.2%) and scoliosis (63.3%) are common complications [2]. In the European consortium, scoliosis occurred in 33.3% of α patients, 48.6% of β and 39.8% of γ patients with available information, at mean ages between 14.7 and 17.6 years, and scapular winging in 39.8% to 51.4% [20]. In the French series, initial symptoms were mainly lower-limb weakness and Achilles tendon contractures, and at the last assessment proximal weakness of all four limbs, axial weakness, contractures, scoliosis and scapular winging predominated [2]. Bone mineral density may be abnormal in non-ambulant patients [2].

3.6. Other manifestations

Muscle pain was the presenting manifestation in 23.8% of patients with R6 [18], and myalgia, cramps, exercise intolerance and myoglobinuria may dominate mild forms [19, 60]. Cognitive development is normal [2], and Orphanet describes usually normal neuropsychomotor development in the δ form [13]. Psychological involvement warrants attention: in the 1995 Tunisian study, children with R3 and R5 had low self-esteem, sadness and internalised guilt despite normal cognitive functioning [2]. Tongue hypertrophy has anaesthetic implications [28].

4. Clinical Recognition and Warning Signs

Recognition begins with a pattern of pelvic and shoulder girdle weakness, usually starting in childhood, with elevated CK and inheritance compatible with recessive transmission. The 2025 review recommends considering sarcoglycanopathy in all patients with proximal muscle weakness of suspected hereditary origin and assessing motor development, the ability to rise from the floor, spinal rigidity, scoliosis, contractures and the ability to run, jump and hop [19]. Typical features are onset in the first or second decade with proximal weakness, muscle hypertrophy, particularly of the calves and tongue, early gluteal weakness rapidly progressing to the proximal muscles of all four limbs, scapular winging and, later, Achilles tendon contractures and respiratory and cardiac involvement [19].

Source: visual reading of figure 1 of ENMC 282 [2].

For history-taking, the Oxford Desk Reference recommends a pedigree covering at least three generations with targeted enquiry about muscle weakness, premature cardiac death and heart failure; age at acquisition of motor milestones and performance in physical education; difficulty rising from chairs (pelvic girdle) and raising the arms above the head (shoulder girdle); exercise tolerance and dyspnoea; and sleep history, because orthopnoea suggests diaphragmatic weakness and difficulty waking in the morning may indicate nocturnal hypoventilation [61]. Examination looks for atrophy, weakness distribution, tendon reflexes and contractures; facial, early distal or oculomotor muscle involvement does not belong to the LGMD pattern [61].

Three situations warrant particular attention. First, a girl with a Duchenne-like presentation and normal dystrophin should prompt consideration of sarcoglycanopathy; in the historical GeneReviews chapter, most severe childhood-onset LGMDs were due to variants in sarcoglycan genes, and a child with a Duchenne phenotype and normal dystrophin immunostaining probably had a primary sarcoglycanopathy [29]. Second, isolated hyperCKaemia in an asymptomatic child or adult may be the first manifestation: up to 23% of Italian patients were identified this way [2]. Third, exertional myoglobinuria or rhabdomyolysis, with exercise intolerance, may be the presenting feature, particularly in the α and β forms [2, 19]. DCM without myopathy in a patient of East Asian ancestry with SGCB homozygosity is a recent warning sign [49].

Diagnostic delay is a documented problem. In the international TREAT-NMD survey with 1285 respondents (87 with sarcoglycanopathy) from 68 countries, a mean of 6.4 years elapsed between the first medical consultation and LGMD diagnosis, and 31% of patients received another diagnosis before confirmation [2]. In the LGMD R6 cohort, median diagnostic delay was 10 years in patients with onset before 2010, in the Sanger sequencing era, and 2 years in those whose symptoms began after 2010, when NGS panels came into use (p = 0.001) [18]. ENMC 282 emphasises the importance of early diagnosis and intervention, within the first five years after symptom onset, and the role of the general paediatrician in recognising early signs [2].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Confirmation criterion

There are no formal clinical diagnostic criteria. ENMC 282 considers a presumptive clinical diagnosis genetically confirmed when two pathogenic or likely pathogenic variants in trans are identified in one of the four genes; VUS and single heterozygous variants should nevertheless be recorded and curated to enable reanalysis [2]. Phase confirmation (parental testing) is necessary when the two variants differ, and classification should follow ACMG/AMP criteria, which may require family segregation studies and functional tests [2].

5.2. ENMC 282 algorithm

The algorithm proposed by ENMC 282 (figure 2 of the report, consulted) starts from clinical suspicion defined by the signs in figure 1 and proceeds to genetic testing by next-generation sequencing (NGS) [2]:

Source: visual reading of figure 2 of Iammarino et al. 2025 [2].

The three-tier genetic strategy presented at the same workshop applies when suspicion is strong (clinical features, MRI pattern, reduced sarcoglycans on biopsy, family history or pedigree compatible with recessive inheritance). The first tier is sequencing of the four genes by Sanger or NGS, potentially preceded by testing for recurrent or founder variants in defined ethnic groups; the second is testing for copy number variants (CNV) by MLPA or CNV analysis in NGS data; the third is searching for non-coding variants affecting splicing or expression, by whole-gene or genome sequencing and/or analysis of muscle messenger RNA [2]. This escalation addresses a specific limitation: in the LGMD R6 cohort, almost one-third of patients had large deletions that Sanger sequencing would not detect [18]. The 2014 guideline from the American Academy of Neurology (AAN) and American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), now withdrawn and cited as a historical reference, recommended guiding genetic testing by phenotype, inheritance pattern, age at onset and associated manifestations (level B) and, when targeted testing was not diagnostic, using genetic consultation or panels, exome or genome sequencing (level C) [27].

5.3. Creatine kinase and other laboratory investigations

Serum CK is almost always elevated, usually above five times the upper limit of normal, but is not specific [19]. In figure 1 of ENMC 282, CK above 1000 is one of the early signs guiding suspicion [2]. In the Turkish series of 109 biopsies, CK was elevated in every case and above 2500 IU/L in all but five [2]. The Oxford Desk Reference indicates elevations frequently above ten times and up to one hundred times normal for recessive LGMDs in general [61]. Elevated CK may be the only manifestation: up to 23% of Italian patients and 25% of Turkish biopsies were identified through asymptomatic hyperCKaemia [2]. The baseline value is useful for comparison when perioperative rhabdomyolysis is suspected [28].

5.4. Muscle magnetic resonance imaging

The pelvic and lower-limb pattern is established: fatty infiltration of the adductor magnus, hamstrings and gluteal muscles, with relative or complete sparing of the remaining lower-leg muscles; the vastus lateralis shows a gradient, with the distal portion spared even in severely affected patients, and the iliopsoas is relatively spared among the pelvic muscles [2]. These findings are common to all four subtypes and help distinguish them from dystrophinopathies and α-dystroglycanopathies [2]. The international study establishing them included 69 MRI scans from 17 European and North American centres (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F) and found the same pattern irrespective of gene, with the thigh adductors, gluteal muscles and posterior thigh compartment affected first and most severely, the lower-leg muscles relatively spared even in advanced disease and a consistent proximodistal gradient in the vasti [62]. In the upper limb, the latissimus dorsi and subscapularis are key muscles, and tongue sparing helps distinguish sarcoglycanopathies from late-onset Pompe disease [2]. The 2025 review adds that the adductor magnus is affected first, that the small pelvic muscles, obturator, biceps femoris and proximal portions of the vasti become affected with progression, that the sartorius and gracilis tend to be spared even in late stages, and that the flexor digitorum longus and tibialis posterior remain spared even in the most advanced patients; early lower-leg involvement should prompt consideration of another diagnosis [19]. Figure 1 of the review illustrates these findings (https://pmc.ncbi.nlm.nih.gov/articles/PMC13142857/figure/fig1-22143602251324855/) [19]. Machine-learning algorithms applied to MRI, such as Myo-Guide, have been proposed as adjuncts [2].

5.5. Muscle biopsy, immunohistochemistry and Western blot

Biopsy is indicated mainly when genetic results are inconclusive; MRI can guide selection of a muscle that is affected but not completely replaced by fat [19]. Histology shows the dystrophic pattern common to LGMDs (variation in fibre size, central nuclei, endomysial fibrosis, necrosis and regeneration), sometimes only mild myopathic changes [19]. In the Turkish series, the pattern was dystrophic in 94% and mildly myopathic in 6%, and inflammatory infiltrates were present in 9% [2]; in the LGMD R6 cohort, inflammatory infiltrates occurred in 28.6% of biopsies [18], which may misleadingly suggest inflammatory myopathy.

Immunohistochemistry should include all four sarcoglycans and dystrophin [2, 19]. Protein analysis is sensitive for primary sarcoglycanopathies but is not specific, because other dystrophies cause secondary sarcoglycan reduction [19, 29]. There are no gene-specific patterns, although absence of all four sarcoglycans is usual in the β and δ forms and the γ form often shows isolated γ-sarcoglycan absence [19]. In the Turkish series, the panel of four sarcoglycan and three dystrophin antibodies showed deficiency of all four sarcoglycans in 60%, of two or three in 25% and isolated γ deficiency in 15%; dystrophin was reduced in 41%, particularly cases with deficiency of all four sarcoglycans, and in three patients with SGCA variants sarcoglycan immunostaining was normal, because mild deficiency may go undetected [2]. Western blot quantifies protein and has prognostic value, as residual expression above 30% is associated with milder disease [19]. Figure 2 of the 2025 review shows reduction of all four sarcoglycans in a patient with α-sarcoglycanopathy (https://pmc.ncbi.nlm.nih.gov/articles/PMC13142857/figure/fig2-22143602251324855/) [19].

5.6. Electromyography and cardiac and respiratory assessment at diagnosis

Electromyography shows a myopathic pattern without distinguishing between dystrophies [3]. At diagnosis, all patients should undergo cardiac clinical examination, electrocardiography (ECG), echocardiography and sitting and supine spirometry [2]. The 2014 AAN/AANEM guideline recommended cardiology referral, even without symptoms, for newly diagnosed patients with LGMD2C to 2K, for ECG and structural assessment by echocardiography or cardiac MRI (level B), and pulmonary function tests at diagnosis (level B) [27].

5.7. Test limitations and report contents

Sources: [2, 18, 19, 29]. Variability in techniques and antibodies between centres is identified as a limitation of quantification in the LGMD R6 cohort [18].

The proportion of variants detectable by a technique does not equal the clinical sensitivity of the test: a negative result on a panel without CNV analysis does not exclude the diagnosis when the phenotype and biopsy are suggestive. The report should state the gene, versioned transcript (NM_000023.4, NM_000232.5, NM_000231.3 or NM_000337.6), HGVS c. and p. nomenclature, zygosity, phase when known, ACMG/AMP classification and technical limitations [2, 4]. When the literature uses historical designations, such as del521-T for SGCG c.525del, the report and clinical record should document the correspondence to avoid variant duplication [27, 46].

5.8. Testing relatives and targeted screening

ENMC 282 recommends offering carrier testing to at-risk relatives and testing carriers' partners, particularly in endogamous populations or those with increased carrier frequency; initial testing for founder variants is an option in some ethnic groups [2]. Family testing may identify presymptomatic patients: in the LGMD R6 cohort, two children aged 4 and 5 years, relatives of affected patients, had neither symptoms nor signs at genetic diagnosis [18]. No newborn screening programmes for sarcoglycanopathies are reported in the sources consulted.

6. Differential Diagnosis

The first differential is dystrophinopathy. The Oxford Desk Reference emphasises that, with a limb-girdle dystrophy pattern, dystrophinopathy is empirically more likely than LGMD and should be excluded through gene and protein studies, both for prognosis and for the risk to female relatives; it recommends DMD deletion/duplication testing in patients without contractures unless biopsy has already excluded dystrophinopathy [61]. Sarcoglycanopathies share calf hypertrophy, markedly elevated CK and cardiomyopathy risk with dystrophinopathy [61], and secondary sarcoglycan deficiency in dystrophinopathy, as well as secondary dystrophin reduction in 41% of Turkish sarcoglycanopathy biopsies, make immunohistochemistry alone insufficient to distinguish them [2, 29]. Sex and pedigree help: recessive inheritance affects girls and boys equally, and absence of disease in the maternal line is the rule [3].

Figure 1 of ENMC 282 also lists features making sarcoglycanopathy unlikely: congenital-onset weakness, independent walking never acquired, cognitive impairment, early respiratory or cardiac involvement, distal weakness greater than proximal weakness and diffuse contractures; the exception is δ-sarcoglycanopathy, in which early distal contractures may occur, particularly in the lower limbs [2]. Consistently, in a 1995 cognitive and psychological study of Tunisian patients with R3 and R5, cognitive functioning was within normal limits (intelligence quotient 102 ± 3, mean ± standard error), although with low self-esteem and feelings of sadness and internalised guilt [2].

Nomenclature may confuse two clinically unrelated groups: ε-sarcoglycan (SGCE) is associated with dominant myoclonus dystonia and not LGMD [19, 41]. Likewise, the old LGMD1 and LGMD2 designations with other letters (for example, TCAP-related LGMD2G) do not belong to the sarcoglycan group [29].

7. Treatments and Risk Management Strategies

7.1. Context: no approved therapy

As of this article's update date, no medicine is approved for any sarcoglycanopathy in the United States or European Union, and ENMC 282 reiterates that there is no approved treatment for these diseases [2, 19]. Management is multidisciplinary and anticipatory, aiming to maintain strength, joint range of motion and respiratory and cardiovascular function [19]. The most recent group-specific reference document is the report of the 282nd ENMC workshop (Amsterdam, 8–10 November 2024; published September 2025), which brought together 29 participants, including clinicians, researchers, industry and patient representatives; this is expert consensus rather than an evidence-graded guideline, and the group itself concluded with a mandate to develop formal standards of care [2]. The North American 2014 AAN/AANEM guideline on LGMD and distal dystrophies, now withdrawn, remains the only formally graded guideline including the former LGMD2C to 2F and is cited as a historical reference [27]. No national sarcoglycanopathy-specific guidelines for the USA, Europe, Portugal or Brazil were identified in the sources consulted; this absence from the sources does not demonstrate that local documents do not exist.

The TREAT-NMD survey documents the gap between recommendations and practice: only 33% of respondents attended a multidisciplinary clinic, 13% did not seek care for LGMD and, among those not attending these clinics, 39% had never been referred; clinics assessed strength in 83%, pulmonary function in 68%, functional performance in 63% and patient-reported outcome questionnaires in 33% [2]. AAN/AANEM recommended referring all patients with muscular dystrophy to a clinic with access to physiotherapy, occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, respiratory medicine, orthopaedics and genetics (level B) [27].

7.2. Rehabilitation, exercise and orthoses

Specialist physiotherapy and occupational therapy assess strength and function over time, prescribe exercise and stretching programmes, orthoses, assistive devices, wheelchairs and standing programmes, advise on transfers and fall prevention, review upper-limb function, home adaptations and driving, and, depending on local organisation, monitor respiratory function and teach airway clearance techniques [2]. The 2025 review recommends starting physiotherapy immediately after diagnosis, choosing exercises the family considers useful and feasible, using hydrotherapy when available and night-time knee–ankle–foot orthoses to prevent contractures [19]. AAN/AANEM recommended periodic physiotherapy and occupational therapy, orthoses and assistive devices tailored to impairments and contractures (level B) [27].

Regarding exercise, studies in neuromuscular diseases are small and mixed. In one, high-intensity training was not tolerated by patients with LGMD (CK elevation and muscle pain), but low-intensity strength training at 40% of maximum knee extension and elbow flexion strength improved strength after 6 months without CK elevation; aerobic programmes on a stationary bicycle or arm ergometer at approximately 65% of maximum oxygen consumption, for 12 to 52 weeks, increased work capacity and cardiac reserve and improved balance and walking without safety problems [2]. ENMC 282 recommends patient-centred programmes led by a specialist physiotherapist, aquatic activities and, when cardiac involvement is present, prior cardiology clearance before exercising in water, because hydrostatic pressure shifts fluid towards the heart [2]. AAN/AANEM considered aerobic exercise combined with supervised submaximal strength training probably safe (level C), recommended adequate hydration and avoiding exercise to exhaustion or at supramaximal intensity (level C), and educating patients about signs of overwork and myoglobinuria: feeling weaker 30 minutes after exercise, excessive muscle pain 24 to 48 hours later, severe cramps, limb heaviness and prolonged dyspnoea (level B) [27]. As exertional rhabdomyolysis may be the presenting feature, education on these signs applies directly to sarcoglycanopathies [2, 19].

7.3. Corticosteroids: use without sufficient evidence

Corticosteroids have no established indication in sarcoglycanopathies. Some studies reported improved or stabilised strength with deflazacort or prednisolone and possible improvement in ejection fraction, but the 2025 review concludes that limited evidence does not justify their use for muscle symptoms or cardiac involvement [19]. In practice, use is uncommon and heterogeneous: in the Italian series of 115 patients it was rare and varied between subtypes [2]. At a paediatric neurology clinic in Tunis, the 23 patients with R3 and R5 diagnosed between 2014 and 2024 received prednisone 0.75 mg/kg/day on a 10-days-on, 10-days-off schedule, a daily angiotensin-converting enzyme (ACE) inhibitor, rehabilitation and psychological support, and none had developed cardiac involvement [2]. This report describes single-centre experience without a control group and does not constitute a recommendation; prednisone has no approved indication for sarcoglycanopathies and its use is off-label, and phenotypic similarity to Duchenne muscular dystrophy does not justify importing that disease's protocols [3]. The OrphanAnesthesia anaesthetic recommendation notes that patients on chronic corticosteroids may require perioperative dose adjustment to prevent adrenal insufficiency [28].

7.4. Cardiac surveillance and treatment

Cardiac involvement is progressive and affects 21% of patients, with higher prevalence in R4 and R5; DCM is the most common form, followed by rhythm abnormalities [2]. Surveillance recommendations have changed over time:

This article adopts the ENMC 282 intervals, as it is the most recent group-specific document; the longer intervals in earlier sources reflect older data. Cardiac MRI is useful for assessing ventricular function and characterising tissue [2]. Treatment of heart failure with reduced ejection fraction should follow general guidelines, using sacubitril–valsartan, ACE inhibitors or angiotensin receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors; early initiation of ACE inhibitors/ARBs, beta-blockers and mineralocorticoid antagonists in asymptomatic ventricular dysfunction may delay progression, and preventive ACE inhibitor/ARB therapy from 10 years is considered reasonable, although without evidence [2]. Indications for an implantable cardioverter-defibrillator (ICD) for primary prevention follow general heart failure criteria, and cardiac transplantation or mechanical assistance is considered only in selected cases without respiratory impairment, following multidisciplinary assessment [2]. Clinical Cardiogenetics considers the perceived incidence of tachyarrhythmias and bradyarrhythmias low, but the issue unresolved [57]. Heart failure drug doses follow their respective labels and cardiology guidelines and are not detailed here; in children, use for this indication depends on each drug's label and age.

7.5. Respiratory surveillance and treatment

Forced vital capacity (FVC) declines by approximately 1.45 percentage points per year according to published data [2]. ENMC 282 recommends sitting and supine spirometry (FVC and forced expiratory volume in the first second), peak cough flow and blood gas analysis every 12 months in ambulant patients, with longer intervals acceptable in stable cases, and every 6 months in those close to losing or having already lost ambulation; nocturnal transcutaneous capnography is indicated for clinical signs of nocturnal hypoventilation with normal or borderline spirometry [2]. As there are no validated LGMD questionnaires, Respicheck, validated in myotonic dystrophy type 1, was proposed as a screening tool [2]. Non-invasive ventilation (NIV) is recommended for signs of nocturnal hypoventilation, significantly reduced FVC or elevated CO2 [2]. The 2025 review proposes nocturnal oximetry when FVC falls below 60% predicted and NIV when nocturnal hypoventilation or FVC below 50% is present [19].

A low peak cough flow indicates a need to review airway clearance and refer to the respiratory team for assisted coughing (air stacking, lung volume recruitment or mechanical insufflation–exsufflation) [2]; the threshold stated in the ENMC 282 report is 270, printed as ml/min, whereas Duchenne muscular dystrophy care standards state the same value, 270, in L/min as a criterion for manual and mechanical cough assistance [2, 63]. Inspiratory muscle training has not been studied in sarcoglycanopathies; data from other neuromuscular diseases suggest benefits for respiratory strength and chest compliance [2]. Annual influenza vaccination and early treatment of respiratory infections complete these measures [19]. AAN/AANEM recommended referral to respiratory or sleep medicine to consider NIV for patients with excessive daytime somnolence, unrefreshing sleep (frequent night-time awakenings, morning headaches, daytime fatigue) or respiratory failure on testing (level B) [27].

7.6. Orthopaedics, bone health, nutrition and swallowing

Contractures, scoliosis and scapular winging are common (contractures in 81.2% and scoliosis in 63.3% in a synthesis of cohorts) [2]. Surgery may be necessary to correct contractures or scoliosis compromising function [19], and AAN/AANEM recommended monitoring spinal deformities and referring to orthopaedic spinal surgery when necessary (level B) [27]. In the Italian series, densitometry, available in only 19% of patients, showed normal values in ambulant patients and abnormal Z-scores (−2 standard deviations) for total body less head and femur in non-ambulant patients, leading the authors to emphasise the need for systematic surveillance [2]. Weight management and nutritional support form part of the care package [3]. AAN/AANEM recommended swallowing or gastroenterology assessment for dysphagia, frequent aspiration or weight loss (level B) [27].

7.7. Anaesthesia and surgery

The OrphanAnesthesia recommendation for LGMD (2015) identifies a risk of cardiomyopathy, arrhythmia and respiratory failure in the former LGMD2C–F [28]. Inhalational anaesthetics and suxamethonium should be avoided because of the risk of hyperkalaemia and rhabdomyolysis; total intravenous anaesthesia is probably the best option when general anaesthesia is required, and regional anaesthesia should be preferred when feasible [28]. Neuromuscular blockers can be used with careful dosing and monitoring, with reports of safe rocuronium use reversed with sugammadex; short-acting opioids such as remifentanil reduce the risk of prolonged respiratory depression [28]. Preoperative assessment includes baseline CK, ECG, Holter when indicated, echocardiography, respiratory function tests and blood gas analysis when symptoms are present, and lower-limb venous Doppler ultrasonography in wheelchair users; tongue hypertrophy may complicate airway management; postoperative recommendations include early mobilisation, avoiding prolonged mechanical ventilation and considering NIV [28]. Clinical Cardiogenetics notes that arrhythmias and conduction disturbances may be precipitated perioperatively [57].

7.8. Transition, psychosocial support and advance planning

ENMC 282 distinguishes transfer (change of institution) from transition, a planned process preparing adolescents to manage their health in adulthood; it recommends starting transition early, if possible at 12 years, and continuing after transfer, using tools such as the Ready Steady Go programme or Transition Readiness Assessment Questionnaire [2]. Family support includes genetic counselling, psychological support and access to resources [2]. AAN/AANEM recommended anticipating, while respecting patient autonomy, decisions about loss of mobility, the need for assistance with daily activities, medical complications and end of life (level B) [27].

7.9. Gene therapy: principles and initial experience

Gene therapy with AAV vectors is the principal strategy under development, supported by preclinical studies with AAV1 and AAV8 showing sarcolemmal protein expression, histological improvement and increased strength in knockout mice of all four subtypes, and a preventive effect with early treatment [19]. ENMC 282 emphasises that efficacy requires expression in virtually all fibres and that, for such rare diseases, natural history cohorts may serve as external controls in trials without placebo [2].

The first human experiences were intramuscular. In a double-blind randomised trial in three patients with LGMD2D, the rAAV1.tMCK.hSGCA vector injected into the extensor digitorum brevis muscle, with saline on the contralateral side and methylprednisolone for 3 days, increased SGCA expression 4- to 5-fold and restored the entire sarcoglycan complex, without adverse effects [64]; in a second phase, expression persisted for 6 months in two of three patients, and failure in the third was associated with neutralising antibodies and T-cell immunity against AAV [65]. In the Généthon study, nine non-ambulant patients homozygous for SGCG c.525del (mean age 27 years) received AAV1-γ-sarcoglycan in the extensor carpi radialis, without serious adverse effects over 6 months, with seroconversion in all, one cytotoxic capsid response and γ-sarcoglycan expression in 4.7 to 10.5% of fibres in the three patients at the highest dose [66]. The AAN/AANEM guideline concluded that intramuscular SGCA transfer probably increases gene expression, with unknown clinical relevance, and that evidence in LGMD2C was insufficient [27]. Isolated limb perfusion with SRP-9004 (SGCA) in six patients demonstrated expression of 14 to 25% of normal on Western blot in the four biopsied patients, without improvement in 6-minute walk distance; the registry describes serious episodes of rhabdomyolysis, myoglobinuria and a femoral fracture [67, 68].

7.10. Bidridistrogene xeboparvovec (SRP-9003) in LGMD R4

Bidridistrogene xeboparvovec (SRP-9003; scAAVrh74.MHCK7.hSGCB) is the most advanced programme. In the phase 1/2 trial (NCT03652259), six children aged 4 to 15 years with biallelic SGCB variants received a single intravenous infusion of 1.85 × 10^13 vector genomes per kg (cohort 1, n = 3) or 7.41 × 10^13 vg/kg (cohort 2, n = 3), with prophylactic prednisone 1 mg/kg/day for 30 days in cohort 1 and at least 60 days in cohort 2, following one case of AAV-associated hepatitis [69]. At day 60, mean expression was 36.2% and 62.1% of normal and positive fibres 51% and 72%, respectively; at 2 years, expression was 54.0% and 60.3% [69]. The most frequent related adverse effects were vomiting (four of six) and increased gamma-glutamyltransferase (three of six); serious events (hepatitis with transient bilirubin increase at day 53, at the end of corticosteroid tapering, and severe dehydration due to vomiting) resolved with usual treatment; there was no thrombocytopenia, electrocardiographic change or clinical complement activation, and one patient died in an unrelated accident at day 220 [69]. NSAD increased by 5.7 and 4.0 points at year 1 and 5.7 and 0.5 points at year 2 in cohorts 1 and 2; in a post hoc comparison with five natural history patients, the mean difference in NSAD change at 2 years was 7.3 points (95% CI 0.7–13.9) [69]. The authors acknowledge the limitations of a small, open-label trial with interim analysis and an external comparator matched for age but not baseline NSAD, whose baseline function was better [69].

The phase 3 EMERGENE trial (NCT06246513; CTIS 2022-503112-17-00) is open-label, single-arm, includes patients aged 4 years or older with anti-AAVrh74 antibody titres below 1:400, and its primary outcome in cohort 1 is change in the percentage of β-sarcoglycan-positive fibres by immunofluorescence at day 60; it is active, not recruiting, with 17 patients treated (USA, Belgium, Germany, Italy, Spain, United Kingdom) [24]. The 60-day expression and 90-day safety results (data cut-off 20 March 2025) were presented as a poster at the October 2025 World Muscle Society congress, without peer-reviewed publication by the date of this article [70]. Of 20 patients assessed, 17 were enrolled and received 7.41 × 10^13 vg/kg: 11 ambulant (6 boys; mean age 12.7 years, range 5–21) and 6 non-ambulant (all female; mean age 25.8 years, range 13–50); the protocol specified a preceding 6-month observation phase, glucocorticoids from 24 hours before infusion (1 mg/kg/day up to 60 mg/day, with individualised tapering after day 60 according to gamma-glutamyltransferase) and 60 months of follow-up [70]. The primary outcome, mean change in the percentage of β-sarcoglycan-positive fibres at day 60 in ambulant patients, was 43.4% (standard deviation 29.9; p < 0.001); in non-ambulant patients it was 23.9% (14.2; p < 0.02; n = 5); on Western blot, change was 33.6% and 13.0% of normal control, and fibres with β- and δ-sarcoglycan colocalisation increased by 38.6% and 21.9%, respectively [70]. CK fell by a mean of 88.8% and 92.4% at day 60 [70]. The most common related adverse events were nausea (70.6%), decreased appetite (47.1%), vomiting (41.2%), upper abdominal pain (29.4%) and fatigue (29.4%); by the data cut-off, 7 patients (41.2%) had experienced acute liver injury events (5 ambulant, grade 2–3; 2 non-ambulant, grade 1), and after cut-off a further 4 patients experienced grade 1 events; there were no treatment-related deaths [70]. These are results from an open-label trial without a control group, with protein-expression and short-term safety outcomes, presented by the sponsor at a congress. The VOYAGENE study (NCT05876780) includes ambulant and non-ambulant patients aged 4 to 50 years [71].

7.11. The July 2025 clinical hold and status in October 2026

In April 2025, Sarepta announced that the FDA had confirmed SRP-9003 eligibility for the accelerated approval pathway and anticipated submitting a marketing application (BLA, Biologics License Application) in the second half of 2025 [72]. On 16 July 2025, as part of restructuring, the company suspended most LGMD programmes while retaining SRP-9003 [73]. On 18 July 2025, the FDA placed Sarepta's LGMD gene therapy trials on clinical hold, citing three deaths potentially related to AAVrh74 products and unacceptable risks to participants, and revoked the AAVrh74 platform technology designation [22]. The third death occurred in an adult man with LGMD treated in a clinical trial, hospitalised less than two months after therapy with elevated transaminases, who progressed to liver failure and died 80 days after administration [74]. Sarepta identified him as a 51-year-old non-ambulant patient treated in a phase 1 trial of SRP-9004 (LGMD2D/R3), with a dose and manufacturing process different from the Duchenne muscular dystrophy therapy [75]. Results from that phase 1b study (SRP-9004-102, DISCOVERY) were presented as a poster in March 2026 [76]. Four patients received patidistrogene bexoparvovec 7.41 × 10^13 vg/kg: three ambulant 11-year-olds and one non-ambulant 51-year-old man [76]. At day 60, mean change in α-sarcoglycan-positive fibres was 19.5% in ambulant patients and 3.9% in the non-ambulant patient, and on Western blot 20.0% and −1.3% of normal control; CK in ambulant patients fell 53.1% at day 90 [76]. All experienced adverse events, predominantly grade 1–2 (nausea, fatigue, hepatotoxicity, increased transaminases), and there were two related serious events: grade 3 hepatotoxicity in an 11-year-old child, resolved with corticosteroids, and fatal acute liver failure (grade 5) in the 51-year-old patient, 77 days after administration [76]. This patient, diagnosed at 16 years and non-ambulant for approximately 2 years, was not receiving respiratory support or prior corticosteroids, had a history of two pulmonary emboli and hypogonadism and was taking testosterone and apixaban; he was hospitalised for acute liver injury approximately 11 weeks after infusion and treated with intravenous corticosteroids and other immunomodulators, including sirolimus from day 66, and liver failure, attributed to the product, caused death approximately 12 weeks after administration [76]. The authors conclude that the SRP-9004 programme is paused and sirolimus prophylaxis is being evaluated in other gene therapy programmes to reduce acute liver injury [76]. The poster identifies the study as NCT01976091, which on ClinicalTrials.gov corresponds to the isolated limb perfusion trial of 2015–2019; the record whose design and timeline match the 2025 systemic study is NCT06747273 [68, 76, 77]. The hold covered SRP-9003, SRP-9004, SRP-6004 (LGMD R2) and SRP-9005 (LGMD R5) [78]. In December 2025, the FDA confirmed continuation of the hold and stated that it requires data from the sirolimus immunosuppression study before accepting an SRP-9003 BLA; in its August 2026 quarterly report, the company continued to suspend all LGMD development except SRP-9003, and no document announcing removal of the hold was found up to 7 October 2026 [23]. This absence reflects the sources consulted and does not prove that no subsequent changes occurred.

Sources: [21–23, 25, 26, 68, 76, 77, 79–82]. No sarcoglycanopathy medicine appears in the FDA list of approved cellular and gene therapy products (updated September 2026) or the EMA medicines database; the earlier Généthon orphan designations (γ and α) and those for kifunensine (2011) were withdrawn [26, 83]. In the FDA orphan designation database (OOPD), consulted on 7 October 2026, there are also, without trials identified in the sources consulted, a designation dated 27 February 2026 for an AAV containing the full human γ-sarcoglycan coding sequence in LGMD2C/R5 (Evolyra Therapeutics) and a designation dated 18 July 2017 for one to four phosphorodiamidate morpholino antisense oligonucleotides intended for LGMD2C with variants or deletions in SGCG exons 4 to 7 (Kurt+Peter Foundation); all sarcoglycanopathy-related designations have “designated” status, without approval for the orphan indication [21]. OOPD uses generic names; correspondence with sponsors' codes is supported by the cited trial records and announcements. Orphan designations, whether American or European, do not constitute authorisation or guarantee access. There are therefore no reimbursement or national access data to record for Portugal (INFARMED) or Brazil (ANVISA/CONITEC).

7.12. Clinical trials and natural history studies

Results from these studies do not allow comparisons between products: populations, doses, protein quantification methods (immunofluorescence, Western blot) and assessment time points differ, protein expression is a surrogate outcome and functional gains depend on non-randomised external comparators. Data from EMERGENE, systemic SRP-9004 and ATA-200 come from congress posters or sponsor announcements, without peer-reviewed publication. Regarding safety, acute liver injury was the main problem in available data, including the 2025 death, despite prophylactic corticosteroids specified in protocols; according to ENMC 282, Sarepta's LGMD trials had not recorded complement-mediated adverse events [2]; the FDA considered the safety evidence for the AAVrh74 platform insufficient after the 2025 deaths [22, 69].

For ATA-200, according to the sponsor, the first two patients, treated with 1.0 × 10^14 vg/kg, had more than 90% γ-sarcoglycan-positive fibres at 6 months (90.2% and 92.1%), sustained CK and transaminase reductions at 12 months and no serious adverse effects among the four treated patients; the announcement describes children aged 6 to 13 years, a range differing from that registered on ClinicalTrials.gov (6 to under 12 years) [25, 85]. The programme was licensed to Atamyo from Généthon's work, which showed dose-dependent restoration of protein, histology, biomarkers and strength with systemic AAV8 in mice [2].

7.13. Other approaches under investigation

All remaining approaches are preclinical. Cystic fibrosis transmembrane conductance regulator (CFTR) correctors, developed for CFTR folding variants, rescue sarcoglycan missense mutants: C17 restored the sarcolemmal complex in primary myogenic cells from patients with R3 and R4 and, in a humanised murine LGMD R3 model with variant R98H (published designation; corresponding in humans to NM_000023.4:c.293G>A p.(Arg98His)), restored the complex and muscle strength [2, 89, 90]; pharmacokinetic studies show good distribution to the heart and skeletal muscle [91]. Nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis, reduced fibrosis and improved muscle function in Sgca-/- mice treated with 50 mg/kg every 12 hours for 10 weeks, with weight loss as an adverse effect [92]. P2X7 receptor antagonists and metformin have also been proposed, with animal model data [19]. Among earlier experimental approaches, ε-sarcoglycan overexpression replaced α in the complex and prevented membrane injury in mice lacking α-sarcoglycan, and arterially administered mesoangioblasts restored adhalin and corrected the phenotype in the same model [5]. No human trials of CFTR correctors or nintedanib in sarcoglycanopathies were found [93]. The historical AAN/AANEM recommendation not to offer gene therapy outside research studies (level R) remains consistent with the current status [27].

8. Reproductive Options and Family Counselling

All four sarcoglycanopathies have autosomal recessive inheritance [2]. When both parents are carriers, each pregnancy has a 25% probability of an affected child, 50% of a carrier child and 25% of a child without the variant; clinically unaffected siblings of a patient have a two-thirds probability of being carriers. Absence of disease in parents and equal distribution between sexes are the rule, as Ben Hamida already observed in the Tunisian families described in 1980 [2]. The Oxford Desk Reference notes that, in LGMD without a molecular diagnosis and with healthy parents, recessive inheritance is most likely, but approximately 10% of cases may result from a de novo dominant variant, which is why accurate counselling requires genetic confirmation [61]. The same book and the historical GeneReviews chapter describe marked intrafamilial variability: patients with the same variant, even in the same family, may range from a severe course to mild or asymptomatic forms, as in two siblings with SGCA variants, one developing symptoms at 20 years and the other asymptomatic at 35 [29, 61]. This variability limits prediction of severity in an affected sibling based on the index case.

ENMC 282 recommends offering carrier testing to at-risk relatives to enable informed family planning with prenatal or preimplantation genetic diagnosis, and genetic testing of carriers' partners, particularly in endogamous communities or those with high carrier frequency [2]. Prenatal diagnosis by chorionic villus sampling is possible when familial variants are known [61]; the first prenatal diagnosis of LGMD2E by direct variant detection was published in 1999 [6]. ACMG/AMP guidelines state that a variant of uncertain significance should not be used in clinical decision-making [94], excluding its isolated use for prenatal diagnosis or embryo selection.

Risk estimation for a partner without a family history depends on carrier frequency in the relevant population. The historical GeneReviews chapter derived a sarcoglycanopathy carrier frequency of approximately 1:211 from the prevalence of 1:178,000 estimated in north-eastern Italy [29, 40]; the 1:150 value attributed by that chapter to Hackman and colleagues corresponds, in the original article, to the carrier frequency of SGCA variant c.229C>T (R77C) in Finland [17]. With a carrier frequency of 1:211, the risk of a known carrier having an affected child with an untested, non-consanguineous partner from the general population would be approximately 1:844 (carrier frequency multiplied by one-quarter); this is an illustrative calculation using an old regional estimate, which does not apply to populations with founder variants or consanguineous unions, or to residual risk after a negative partner test, which depends on the method used. Consanguinity was present in 87% of patients in the LGMD R6 cohort [18] and, according to ENMC 282, sarcoglycanopathies account for 44% of LGMD cases in consanguineous populations [2].

In populations with a known founder variant (SGCG c.525del in the Maghreb, SGCG c.848G>A in European Roma, SGCB c.452C>G in the Indiana Amish community, SGCD c.657del in Brazil), ENMC 282 allows initial testing for those variants [2, 16, 27]. A negative founder-variant result does not exclude the disease, because endogamous North African populations show high allelic diversity and unrelated patients may be homozygous for different variants [2].

Heterozygous carriers generally do not have disease; mild symptoms have been described in some SGCA heterozygotes [29]. Counselling should include psychological support and access to resources, preparation for transition to adult care and information on clinical trials and patient registries [2]. In the gene therapy context, counselling should make clear that no treatment is approved; the AAN/AANEM guideline recommended not offering gene therapy outside research studies (level R) [27], and the current status of programmes is described in section 7. When planning pregnancy in a woman with sarcoglycanopathy, respiratory and cardiac function should be considered; the OrphanAnesthesia anaesthetic recommendation considers regional anaesthesia a good option for caesarean section and delivery, avoiding triggering drugs and reducing opioid-related respiratory depression [28].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Global frequency and what each estimate measures

Sarcoglycanopathies account for approximately 10 to 25% of LGMD [14]; Clinical Cardiogenetics states approximately 25% [57]. ENMC 282 described them as the third most common form of recessive LGMD worldwide, with global prevalence between 0.27 and 0.56 per 100,000 and a proportion of 44% of LGMD cases in consanguineous populations [2]. These estimates have very different origins and are not interchangeable:

Older studies of patients with a Duchenne presentation help quantify the diagnostic problem: in 415 families with at least one patient with a Duchenne phenotype, an estimated 1 in 8 (11.8%) sporadic male patients with a Duchenne phenotype had an autosomal form, mainly LGMD2C or LGMD2D [7]; in Japan, adhalin deficiency accounted for 4% of patients diagnosed with Duchenne or Becker dystrophy, with an estimated prevalence of approximately 1 per million [5]; and in the USA, SGCA sequencing in 30 patients found only one case, leading the authors to consider it uncommon in North America [5]. LGMD2F accounted for approximately 4% (2 of 54) of North American patients with α-sarcoglycan deficiency on immunostaining [8]. The genetic estimator measures expected biallelic genotype frequency from population databases rather than diagnosed patients; for SGCG, the global value of 0.12 per million contrasts with the published 70 per million for Tunisia, reflecting the contribution of founder variants and consanguinity, poorly represented in databases [95]. Hospital series, in turn, measure the composition of referred cohorts rather than population prevalence. δ-Sarcoglycanopathy is ultrarare: the international cohort authors, after contacting 128 units in 38 countries and reviewing 9610 patients studied by NGS in large projects without finding any cases, suggest a prevalence probably of the order of one case per million inhabitants, without a formal population denominator [18].

9.2. Europe

In the European consortium of 33 centres in 13 countries (Spain, Portugal, Italy, the Netherlands, United Kingdom, Finland, Czech Republic, Hungary, Slovenia, France, Germany, Denmark and Belgium), the β form was more prevalent in northern countries (the Netherlands, United Kingdom, Denmark) and the γ form in southern countries (Spain, Italy and Portugal); among γ patients, 27.7% were of Roma and 17.8% of Maghrebi origin, and most α and β patients were of Caucasian origin [20]. In Finland, SGCA variant R77C is enriched, with a shared haplotype of at least 790 kb and carrier frequency of 1:150, leading to an expected birth of one homozygous patient every one or two years [17]. The French cohort of 100 patients comprised mainly γ (54) and α (41) forms, with only 5 β [54]. α-Sarcoglycanopathy is the most common form in Europe [19]. The French national SARCO registry, established in May 2025 with AFM-Téléthon support at FILNEMUS network centres, included 23 confirmed patients (6 R3 and 17 R5) according to a 2026 poster [96].

9.3. Founder and endogamous populations

9.4. Brazil and Portugal

In Brazil, in a multicentre cohort of 370 patients from 305 families with recessive LGMD at 13 centres, sarcoglycanopathies were the most frequent childhood-onset subtype and accounted for 21% of families [98]. At ENMC 282, they were described as the third most common LGMD in Brazil (second in some referral centres), with female predominance, onset in the first decade and loss of ambulation by 18 years in most; at the University of São Paulo centre, R3 was the most frequent subtype (6 patients) and each of the others had 5 patients [2]. R6 prevalence appears higher in Brazil than other countries [2], consistent with the original description of LGMD2F in two Brazilian families [38]. At a centre in southern Brazil, sarcoglycanopathies accounted for 13% of 23 genetically resolved patients with recessive LGMD (one R3, one R4 and one R5), and the R4 patient had heart failure [99]. In 140 patients from 40 Brazilian families with recessive LGMDs, all patients with LGMD2E and LGMD2F had severe phenotypes and, among sarcoglycanopathies, CK was highest in LGMD2D; in a series of 25 families with Duchenne-like dystrophy that included the original Brazilian families, LGMD2F accounted for at least 13% [6, 8]. The historical GeneReviews chapter cited a study in which sarcoglycanopathies accounted for 68% of severe recessive LGMDs in the Brazilian population, a finding of historical value only [29].

In Portugal, data available in the sources consulted comprise participation of Portuguese centres in the European consortium, with predominance of the γ form in southern European countries [20], and the report of a Portuguese patient with very-late-onset LGMD R3, unremarkable biopsy and α-sarcoglycan immunostaining, predominantly symmetrical thigh involvement on MRI and, to a lesser degree, posterior lower-leg compartment involvement, and homozygosity for SGCA NM_000023.4:c.850C>T p.(Arg284Cys) [44]. No Portuguese prevalence data were found in the sources consulted; this absence does not demonstrate that studies do not exist.

9.5. Networks and resources

In the European Union, the relevant reference network is ERN EURO-NMD (rare neuromuscular diseases) [31]. TREAT-NMD coordinated the international LGMD care survey cited in ENMC 282 [2, 100]. Among patient organisations, participants in the workshop included the Spanish association Proyecto Alpha, dedicated to limb-girdle dystrophies caused by sarcoglycan deficiency, and an LGMD community advisory board from the Netherlands [2, 101]. Other organisations active in LGMD include the LGMD Awareness Foundation and Muscular Dystrophy Association in the USA, Muscular Dystrophy UK in the United Kingdom, cited by the Oxford Desk Reference, the Associação Portuguesa de Neuromusculares (APN) in Portugal and Associação Brasileira de Distrofia Muscular (ABDIM) in Brazil [61, 102–105]. The JOURNEY (NCT04475926) and GRASP-LGMD (NCT03981289) natural history studies and French SARCO registry are the main prospective data collection initiatives [2, 96].

10. Illustrative Clinical Case

10.1. γ-Sarcoglycanopathy (LGMD R5) due to a homozygous chromosome 13 inversion

In 2022, Pluta and colleagues described in Germany a young woman whose gestation, delivery and early psychomotor development were uneventful, who showed the first signs of weakness at 7–8 years during physical education classes [35]. At 10 years she was assessed at a children's hospital with proximal weakness, positive Gowers' sign and CK up to 15,000 U/L (normal below 150 U/L); progressive muscular dystrophy was suspected, but the family did not wish to pursue investigation at that time [35]. At 15 years she still walked without support, only short distances and often with assistance, and had marked thoracic scoliosis, a Trendelenburg gait and biceps and hamstring atrophy (strength 2/5), with less extensor involvement (4/5). ECG, echocardiography and pulmonary function tests were normal, and lower-limb MRI showed symmetrical lipomatous dystrophic changes and oedematous lesions [35].

Vastus lateralis biopsy showed absent γ-sarcoglycan on immunofluorescence and Western blot, with reduced α- and β-sarcoglycans (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9601614/figure/genes-13-01752-f001/) [35]. Despite this lead, Sanger sequencing of all four sarcoglycan genes, a 65-muscle-gene panel, SGCG MLPA and analysis of a 1706-gene virtual panel using exome data, including CNV testing, did not identify the cause. Her parents and brother were healthy and no consanguinity was reported [35].

Short-read genome sequencing first found two homozygous intronic variants of uncertain significance in SGCG intron 1, inherited from both parents. Homozygosity mapping revealed a homozygous region of approximately 5.5 Mb on chromosome 13 including SGCG (figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC9601614/figure/genes-13-01752-f002/), and structural abnormality analysis detected, in SGCG intron 2, read pairs approximately 350 kb apart, whose mates mapped downstream of LINC00621, with AluY repeats showing 87% identity at both sites (figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC9601614/figure/genes-13-01752-f003/) [35]. PCR and Sanger sequencing confirmed a homozygous inversion with the breakpoint narrowed to 19 bp, inherited from both heterozygous parents (figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC9601614/figure/genes-13-01752-f004/), and complementary DNA from muscle yielded neither SGCG nor LINC00621 transcript (figure 5: https://pmc.ncbi.nlm.nih.gov/articles/PMC9601614/figure/genes-13-01752-f005/) [35]. According to the authors, this was the first published case of an inversion involving a sarcoglycan gene [35].

The published report does not describe treatment or follow-up after diagnosis. The case illustrates three points: the concordance between phenotype and absent γ-sarcoglycan on biopsy justifies pursuing the gene when routine tests are negative; exon sequencing and MLPA do not detect inversions with intronic breakpoints; and the ENMC 282 three-tier strategy, which includes genome sequencing and RNA analysis, was the one that resolved the diagnosis [2, 35]. The absence of cardiac and respiratory involvement at 15 years does not remove the need for the annual surveillance recommended for R5 [2].

10.2. Paucisymptomatic α-sarcoglycanopathy with 25 years of follow-up

Dosi and colleagues described two Italian adults with biallelic SGCA variants [60]. The first, a 36-year-old man with normal development, was assessed at 10 years for persistently elevated resting CK (1700–8000 IU/L) with a normal neuromuscular examination; at 20 years, after developing exercise intolerance and sporadic myoglobinuria after competitive exercise, he had two episodes of atrial fibrillation, recovered and continued running and cycling long distances, with occasional muscle pain and moderate calf hypertrophy [60]. The second, a 31-year-old woman with hyperCKaemia since childhood (500–4500 IU/L), myalgia and exercise intolerance, had an asymptomatic uncle with elevated CK; over 25 years of annual assessments, neurological, cardiac and respiratory examinations remained normal, with minimal calf hypertrophy, and MRI showed only fatty infiltration of the right gluteus minimus (figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC7783442/figure/fig001/) [60]. Each patient underwent two biopsies, with minimal myopathic changes; the text describes normal α-sarcoglycan immunofluorescence, but the figure 2 legend states decreased expression in patient 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC7783442/figure/fig002/) [60]. An NGS panel identified homozygous NM_000023.4:c.850C>T p.(Arg284Cys) in the first patient and compound heterozygous NM_000023.4:c.739G>A p.(Val247Met) and c.850C>T in the second, with family segregation (figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC7783442/figure/fig003/) [60].

The authors propose blood NGS as first-tier testing in paucisymptomatic hyperCKaemia, reserving biopsy for uncertain or negative results, and recommend not labelling hyperCKaemia idiopathic without genetic investigation, while monitoring the risk of exertional myoglobinuria and rhabdomyolysis [60]. Both variants are among the most frequent in SGCA in the European consortium [20], and homozygous c.850C>T was also described in a Portuguese patient with very-late-onset LGMD R3 and normal biopsy [44]. The two cases show the mild end of the spectrum and the limitations of immunostaining, in contrast to case 10.1.

11. Prognosis and Long-Term Follow-up

11.1. Prognostic factors

Prognosis depends on the gene, age at onset and residual protein amount. In the European consortium, age at onset correlated with age at loss of ambulation (r = 0.61), and onset before 10 years significantly separated time to wheelchair use, both overall and in each subtype; the 20 patients whose weakness began after 18 years did not lose ambulation during follow-up [20]. In multivariate analysis, age at onset (odds ratio 1.37 per year; 95% CI 1.18–1.59) and residual protein below 30% (odds ratio 10.7; 95% CI 2.04–56.22) were independent factors for loss of ambulation before 18 years; the cut-off of 27.5% expression on Western blot had 83.3% sensitivity and 100% specificity for this outcome, and onset by 6 years had 69.3% sensitivity and 68.6% specificity [20]. The protein effect was significant in α patients; in β there was only a trend, and in γ the difference was between absence or less than 30% and more than 30% [20]. At ENMC 282, patients with onset after 18 years were described as ambulant until 50–60 years [2]. The French cohort confirmed age at onset as an independent predictor of severity and time to loss of ambulation, and associated absence of protein on biopsy with earlier loss of ambulation [54]. In the δ form, absence of protein was associated with earlier onset (4.1 versus 10.3 years) and earlier loss of ambulation (10.9 versus 17.3 years) [18].

These figures come from retrospective studies of referred cohorts, with missing data and heterogeneous protein quantification between centres, and describe natural history without disease-modifying therapies [18–20]. The 2025 review emphasises the absence of prospective longitudinal data on muscle, respiratory and cardiac function, which complicates trial design [19].

11.2. Mortality

Mortality data are scarce. In the French cohort of 100 patients followed for a mean of 22.9 years, 30 were ventilated and 6 died [54]. In the study of 34 adults with R5 and R3 followed at a home ventilation centre (median age 30 years, median vital capacity 31% predicted, 38% with ejection fraction below 50%), respiratory events occurred in 38%, cardiac events in 14% and death in 20% over a median of 6 years; ejection fraction and left ventricular end-diastolic diameter were associated with mortality, and respiratory parameters and home ventilation with respiratory events [59]. This was a selected cohort of patients with severe respiratory failure, whose figures do not apply to all patients. In the LGMD R6 cohort there were no deaths by the last assessment, at a median age of 17 years [18]; this absence of events during short follow-up does not indicate zero risk.

11.3. Follow-up schedule

Motor assessment tools recommended by ENMC 282 include the North Star Assessment for limb-girdle type muscular dystrophies (NSAD), the 100-metre test, four-stair climb, timed up and go, pulmonary function and Performance of Upper Limb (PUL), which are being used in natural history studies after validation in other LGMD subtypes; in non-ambulant patients the Egen-Klassifikation scale may be used, and quality-of-life tools include ACTIVLIM, the QoL-gNMD questionnaire and PROMIS (figure 3 of the report) [2]. In the prospective R4 study, NSAD was the only measure showing significant decline after one year (median 2 points), and at 24 months NSAD, 100 m, 10 m and PUL changed significantly [2]. In GRASP-LGMD, with 30 patients, mostly R4, measures showed between-day reliability with an intraclass correlation coefficient above 0.99 and approximately 5% decline in NSAD and PUL over 12 months, and a difference of approximately 3 points separated patients reporting no change in quality of life from those reporting it as slightly worse [2].

12. Summary and Final Considerations

Sarcoglycanopathies result from loss of any of the four subunits of a transmembrane complex that stabilises the link between the cytoskeleton and extracellular matrix; as the subunits assemble together, deficiency of one reduces the others, and biopsy points to the group but not the gene [19, 29]. Diagnosis rests on identifying two pathogenic variants in trans in one of the four genes, with CNV analysis and, when suspicion persists, genome sequencing and RNA investigation, as illustrated by the SGCG inversion case that escaped exome sequencing and MLPA [2, 35]. Biopsy with protein quantification and muscle MRI, with its adductor, gluteal and posterior thigh pattern and gradient in the vasti, resolve single variants and VUS and add prognostic information [2, 62].

The spectrum is broad. The α form is the most common in Europe and the most variable, from hyperCKaemia or exercise intolerance to a Duchenne-like presentation; the β and γ forms generally have early onset and rapid progression, with more frequent dilated cardiomyopathy; the δ form is ultrarare, very severe and features early distal weakness [18–20]. Onset before 10 years and residual protein below 30% are the most robust prognostic factors for loss of ambulation before 18 years [20]. Geographic distribution is shaped by founder variants in the Maghreb, European Roma, the Amish community, Finland and Brazil, and prevalence estimates vary with method and consanguinity [2, 95].

There is no approved therapy. Care is multidisciplinary, with cardiac surveillance from diagnosis (annually in R4 and R5), annual or six-monthly spirometry according to stage, NIV and assisted coughing when indicated, rehabilitation with low-intensity exercise, specific anaesthetic care, genetic counselling with carrier testing and transition planning [2, 28]. Corticosteroids have no established indication [19]. Systemic AAV gene therapy has demonstrated sarcoglycan expression and functional signals in phase 1/2 studies, but the most advanced programme was interrupted by an FDA clinical hold following an acute liver failure death in a trial for another sarcoglycanopathy using the same vector, and the AAV8 programme for the γ form is in phase 1, with preliminary sponsor data; detailed status is given in section 7 [22, 23, 69, 85].

For the geneticist, the central tasks are recognising sarcoglycanopathy in a child with a Duchenne-like presentation and normal dystrophin and in an adult with hyperCKaemia or exertional rhabdomyolysis, selecting tests capable of detecting CNV and non-coding variants, interpreting variants using ClinGen specifications and histology, counselling families from endogamous populations, including partner testing, and preparing patients for clinical trials with registries and standardised outcome measures [2, 43].

13. References

1. Straub V, Murphy A, Udd B. 229th ENMC international workshop: Limb girdle muscular dystrophies - Nomenclature and reformed classification Naarden, the Netherlands, 17-19 March 2017. Neuromuscul Disord. 2018;28(8):702-710. doi:10.1016/j.nmd.2018.05.007. PMID: 30055862.
2. Iammarino MA, Alonso-Pérez J, Stojkovic T, Pegoraro E, Lowes L, Díaz-Manera J. 282nd ENMC international workshop - standards of diagnosis and care for the sarcoglycanopathies. 8-10 November 2024, Amsterdam, Netherlands. Neuromuscul Disord. 2025;54:106212. doi:10.1016/j.nmd.2025.106212. PMID: 40997622.
3. GeneGuidance. Records for the SGCA, SGCB, SGCG and SGCD genes and associated conditions [database]. Version dated 26 September 2026. Accessed 7 October 2026.
4. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. PMID: 28967166. Service accessed 7 October 2026 (MANE Select transcripts and normalisation of the cited variants): https://rest.variantvalidator.org
5. Online Mendelian Inheritance in Man (OMIM). #608099 Muscular dystrophy, limb-girdle, autosomal recessive 3; LGMDR3. Baltimore (MD): Johns Hopkins University; accessed 7 October 2026. Available at: https://omim.org/entry/608099
6. Online Mendelian Inheritance in Man (OMIM). #604286 Muscular dystrophy, limb-girdle, autosomal recessive 4; LGMDR4. Baltimore (MD): Johns Hopkins University; accessed 7 October 2026. Available at: https://omim.org/entry/604286
7. Online Mendelian Inheritance in Man (OMIM). #253700 Muscular dystrophy, limb-girdle, autosomal recessive 5; LGMDR5. Baltimore (MD): Johns Hopkins University; accessed 7 October 2026. Available at: https://omim.org/entry/253700
8. Online Mendelian Inheritance in Man (OMIM). #601287 Muscular dystrophy, limb-girdle, autosomal recessive 6; LGMDR6. Baltimore (MD): Johns Hopkins University; accessed 7 October 2026. Available at: https://omim.org/entry/601287
9. Orphanet. Qualitative or quantitative defects of sarcoglycan (ORPHA:207052) [Internet]. Paris: INSERM; accessed 7 October 2026. Available at: https://www.orpha.net/en/disease/detail/207052
10. Orphanet. Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3 (ORPHA:62) [Internet]. Paris: INSERM; accessed 7 October 2026. Available at: https://www.orpha.net/en/disease/detail/62
11. Orphanet. Beta-sarcoglycan-related limb-girdle muscular dystrophy R4 (ORPHA:119) [Internet]. Paris: INSERM; accessed 7 October 2026. Available at: https://www.orpha.net/en/disease/detail/119
12. Orphanet. Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5 (ORPHA:353) [Internet]. Paris: INSERM; accessed 7 October 2026. Available at: https://www.orpha.net/en/disease/detail/353
13. Orphanet. Delta-sarcoglycan-related limb-girdle muscular dystrophy R6 (ORPHA:219) [Internet]. Paris: INSERM; accessed 7 October 2026. Available at: https://www.orpha.net/en/disease/detail/219
14. Vainzof M, Souza LS, Gurgel-Giannetti J, Zatz M. Sarcoglycanopathies: an update. Neuromuscul Disord. 2021;31(10):1021-1027. doi:10.1016/j.nmd.2021.07.014. PMID: 34404573.
15. Piccolo F, Jeanpierre M, Leturcq F, Dodé C, Azibi K, Toutain A, et al. A founder mutation in the gamma-sarcoglycan gene of gypsies possibly predating their migration out of India. Hum Mol Genet. 1996;5(12):2019-22. doi:10.1093/hmg/5.12.2019. PMID: 8968757.
16. ClinVar. VCV000008712: NM_000232.5(SGCB):c.452C>G (p.Thr151Arg); ClinGen LGMD VCEP classification (SGCB specifications V1.0.0, 9 January 2025). Accessed 7 October 2026. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/8712/
17. Hackman P, Juvonen V, Sarparanta J, Penttinen M, Aärimaa T, Uusitalo M, et al. Enrichment of the R77C alpha-sarcoglycan gene mutation in Finnish LGMD2D patients. Muscle Nerve. 2005;31(2):199-204. doi:10.1002/mus.20267. PMID: 15736300.
18. Alonso-Pérez J, González-Quereda L, Bruno C, Panicucci C, Alavi A, Nafissi S, et al. Clinical and genetic spectrum of a large cohort of patients with δ-sarcoglycan muscular dystrophy. Brain. 2022;145(2):596-606. doi:10.1093/brain/awab301. PMID: 34515763. PMC9014751.
19. Borland H, Diaz-Manera J. Sarcoglycanopathies: From clinical diagnosis to new promising therapies. J Neuromuscul Dis. 2025;12(4):463-472. doi:10.1177/22143602251324855. PMID: 40129306. PMC13142857.
20. Alonso-Pérez J, González-Quereda L, Bello L, Guglieri M, Straub V, Gallano P, et al. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy. Brain. 2020;143(9):2696-2708. doi:10.1093/brain/awaa228. PMID: 32875335.
21. U.S. Food and Drug Administration. Orphan Drug Designations and Approvals (OOPD) [database]: searches for “girdle” and “sarcoglycan”, all designations from 1 January 1983 to 7 October 2026. Accessed 7 October 2026. Available at: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/
22. U.S. Food and Drug Administration. FDA requests Sarepta Therapeutics suspend distribution of Elevidys and places clinical trials on hold [press release]. 18 July 2025. Available at: https://www.fda.gov/news-events/press-announcements/fda-requests-sarepta-therapeutics-suspend-distribution-elevidys-and-places-clinical-trials-hold
23. Sarepta Therapeutics, Inc. Form 10-Q, quarterly report for the period ended June 30, 2026. U.S. Securities and Exchange Commission; 5 August 2026. Available at: https://www.sec.gov/Archives/edgar/data/873303/000119312526335003/srpt-20260630.htm
24. ClinicalTrials.gov. NCT06246513: A trial to learn more about an experimental gene therapy called bidridistrogene xeboparvovec (SRP-9003) (EMERGENE). Last updated 2 March 2026; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT06246513
25. ClinicalTrials.gov. NCT05973630: ATA-200 gene therapy trial in patients with LGMDR5. Last updated 29 January 2026; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT05973630
26. European Medicines Agency. Orphan designations: EU/3/20/2365, EU/3/23/2753, EU/3/25/3031, EU/3/22/2616, EU/3/04/233, EU/3/08/573 and EU/3/11/905–908 [data report]. Accessed 7 October 2026. Available at: https://www.ema.europa.eu/en/documents/report/medicines-output-orphan_designations-json-report_en.json
27. Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, Carter G, et al. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies [RETIRED]: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2014;83(16):1453-63. doi:10.1212/WNL.0000000000000892. PMID: 25313375. PMC4206155.
28. López Álvarez A, Roman Fernandez A. Anesthesia recommendations for patients suffering from limb-girdle muscular dystrophy. OrphanAnesthesia; April 2015. Available at: https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines/limb-girdle-muscular-dystrophy-1.html
29. Pegoraro E, Hoffman EP. Limb-Girdle Muscular Dystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2000 (updated 30 August 2012). Available at: https://www.ncbi.nlm.nih.gov/books/NBK1408/
30. Hershberger RE, Jordan E. Dilated Cardiomyopathy Overview. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2007 (updated 29 July 2021; revised 12 December 2024). Available at: https://www.ncbi.nlm.nih.gov/books/NBK1309/
31. ERN EURO-NMD. European Reference Network for rare neuromuscular diseases [Internet]. Accessed 7 October 2026. Available at: https://ern-euro-nmd.eu/
32. Ben Hamida M, Fardeau M, Attia N. Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle Nerve. 1983;6(7):469-80. doi:10.1002/mus.880060702. PMID: 6633560.
33. Roberds SL, Leturcq F, Allamand V, Piccolo F, Jeanpierre M, Anderson RD, et al. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell. 1994;78(4):625-33. doi:10.1016/0092-8674(94)90527-4. PMID: 8069911.
34. Noguchi S, McNally EM, Ben Othmane K, Hagiwara Y, Mizuno Y, Yoshida M, et al. Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy. Science. 1995;270(5237):819-22. doi:10.1126/science.270.5237.819. PMID: 7481775.
35. Pluta N, Hoffjan S, Zimmer F, Köhler C, Lücke T, Mohr J, et al. Homozygous Inversion on Chromosome 13 Involving SGCG Detected by Short Read Whole Genome Sequencing in a Patient Suffering from Limb-Girdle Muscular Dystrophy. Genes (Basel). 2022;13(10):1752. doi:10.3390/genes13101752. PMID: 36292638. PMC9601614.
36. Lim LE, Duclos F, Broux O, Bourg N, Sunada Y, Allamand V, et al. Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nat Genet. 1995;11(3):257-65. doi:10.1038/ng1195-257. PMID: 7581448.
37. Bönnemann CG, Modi R, Noguchi S, Mizuno Y, Yoshida M, Gussoni E, et al. Beta-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Nat Genet. 1995;11(3):266-73. doi:10.1038/ng1195-266. PMID: 7581449.
38. Nigro V, de Sá Moreira E, Piluso G, Vainzof M, Belsito A, Politano L, et al. Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the delta-sarcoglycan gene. Nat Genet. 1996;14(2):195-8. doi:10.1038/ng1096-195. PMID: 8841194.
39. Duggan DJ, Gorospe JR, Fanin M, Hoffman EP, Angelini C. Mutations in the sarcoglycan genes in patients with myopathy. N Engl J Med. 1997;336(9):618-24. doi:10.1056/NEJM199702273360904. PMID: 9032047.
40. Fanin M, Duggan DJ, Mostacciuolo ML, Martinello F, Freda MP, Sorarù G, et al. Genetic epidemiology of muscular dystrophies resulting from sarcoglycan gene mutations. J Med Genet. 1997;34(12):973-7. doi:10.1136/jmg.34.12.973. PMID: 9429136. PMC1051145.
41. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Dystonia. p. 139.
42. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Dilated cardiomyopathy (DCM). p. 394–5.
43. ClinVar. VCV000009437: NM_000023.4(SGCA):c.229C>T (p.Arg77Cys); ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel classification (SGCA specifications V1.0.0). Accessed 7 October 2026. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/9437/
44. Oliveira Santos M, Coelho P, Roque R, Conceição I. Very late-onset limb-girdle muscular dystrophy type 2D: A milder form with a normal muscle biopsy. J Clin Neurosci. 2020;72:471-473. doi:10.1016/j.jocn.2019.12.003. PMID: 31836381.
45. Tarnopolsky M, Hoffman E, Giri M, Shoffner J, Brady L. Alpha-sarcoglycanopathy presenting as exercise intolerance and rhabdomyolysis in two adults. Neuromuscul Disord. 2015;25(12):952-4. doi:10.1016/j.nmd.2015.09.010. PMID: 26453141.
46. ClinVar. VCV000189243: NM_000231.3(SGCG):c.525del (p.Phe175fs); ClinGen LGMD VCEP classification (SGCG specifications V2.0.0, 23 December 2025). Accessed 7 October 2026. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/189243/
47. ClinVar. VCV000002006: NM_000231.3(SGCG):c.848G>A (p.Cys283Tyr); ClinGen LGMD VCEP classification (1 May 2026). Accessed 7 October 2026. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/2006/
48. Semplicini C, Vissing J, Dahlqvist JR, Stojkovic T, Bello L, Witting N, et al. Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E. Neurology. 2015;84(17):1772-81. doi:10.1212/WNL.0000000000001519. PMID: 25862795. PMC4424130.
49. Li F, Shinomiya H, Kuramoto Y, Kanaoka K, Sakahashi Y, Ishihara Y, et al. Homozygous SGCB splice-site variant causes isolated dilated cardiomyopathy through sarcoglycan complex destabilization in East Asians. J Clin Invest. 2026;136(11). doi:10.1172/JCI198675. PMID: 42222889. PMC13221219.
50. ClinVar. VCV000516368: NM_000232.5(SGCB):c.243+6T>A. Accessed 7 October 2026. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/516368/
51. ClinVar. VCV000008171: NM_000337.6(SGCD):c.657del (p.Thr220fs). Accessed 7 October 2026. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/8171/
52. ClinVar. VCV000008176: NM_000337.6(SGCD):c.451T>G (p.Ser151Ala). Accessed 7 October 2026. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/8176/
53. Cowan JR, van Spaendonck-Zwarts KY, Hershberger RE. Dilated Cardiomyopathy. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 78, 82. doi:10.1007/978-3-030-45457-9_5.
54. Guimarães-Costa R, Fernández-Eulate G, Wahbi K, Leturcq F, Malfatti E, Behin A, et al. Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies. Eur J Neurol. 2021;28(2):660-669. doi:10.1111/ene.14592. PMID: 33051934.
55. Gonzalez-Quereda L, Gallardo E, Töpf A, Alonso-Jimenez A, Straub V, Rodriguez MJ, et al. A new mutation of the SCGA gene is the cause of a late onset mild phenotype limb girdle muscular dystrophy type 2D with axial involvement. Neuromuscul Disord. 2018;28(8):633-638. doi:10.1016/j.nmd.2018.06.002. PMID: 30007747.
56. Merlini L, Kaplan JC, Navarro C, Barois A, Bonneau D, Brasa J, et al. Homogeneous phenotype of the gypsy limb-girdle MD with the gamma-sarcoglycan C283Y mutation. Neurology. 2000;54(5):1075-9. doi:10.1212/wnl.54.5.1075. PMID: 10720277.
57. Schade van Westrum SM, Wahbi K, Bonne G, van der Kooi AJ. Hereditary Neuromuscular Diseases and Cardiac Involvement. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 373–4, 381. doi:10.1007/978-3-030-45457-9_22.
58. Politano L, Nigro V, Passamano L, Petretta V, Comi LI, Papparella S, et al. Evaluation of cardiac and respiratory involvement in sarcoglycanopathies. Neuromuscul Disord. 2001;11(2):178-85. doi:10.1016/s0960-8966(00)00174-7. PMID: 11257475.
59. Fayssoil A, Ogna A, Chaffaut C, Chevret S, Guimarães-Costa R, Leturcq F, et al. Natural History of Cardiac and Respiratory Involvement, Prognosis and Predictive Factors for Long-Term Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D. PLoS One. 2016;11(4):e0153095. doi:10.1371/journal.pone.0153095. PMID: 27120200. PMC4847860.
60. Dosi C, Rubegni A, Cassandrini D, Malandrini A, Maggi L, Donati MA, et al. Alpha-sarcoglycanopathy presenting as myalgia and hyperCKemia in two adults with a long-term follow-up. Case reports. Acta Myol. 2020;39(4):218-221. doi:10.36185/2532-1900-025. PMID: 33458577. PMC7783442.
61. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Limb–girdle muscular dystrophies. p. 476–9.
62. Tasca G, Monforte M, Díaz-Manera J, Brisca G, Semplicini C, D'Amico A, et al. MRI in sarcoglycanopathies: a large international cohort study. J Neurol Neurosurg Psychiatry. 2018;89(1):72-77. doi:10.1136/jnnp-2017-316736. PMID: 28889091.
63. Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 2018;17(4):347-361. doi:10.1016/S1474-4422(18)30025-5. PMID: 29395990. PMC5889091.
64. Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G, et al. Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol. 2009;66(3):290-7. doi:10.1002/ana.21732. PMID: 19798725. PMC6014624.
65. Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, et al. Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol. 2010;68(5):629-38. doi:10.1002/ana.22251. PMID: 21031578. PMC2970162.
66. Herson S, Hentati F, Rigolet A, Behin A, Romero NB, Leturcq F, et al. A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C. Brain. 2012;135(Pt 2):483-92. doi:10.1093/brain/awr342. PMID: 22240777.
67. Mendell JR, Chicoine LG, Al-Zaidy SA, Sahenk Z, Lehman K, Lowes L, et al. Gene Delivery for Limb-Girdle Muscular Dystrophy Type 2D by Isolated Limb Infusion. Hum Gene Ther. 2019;30(7):794-801. doi:10.1089/hum.2019.006. PMID: 30838895. PMC6648191.
68. ClinicalTrials.gov. NCT01976091: A gene transfer therapy study to evaluate the safety of SRP-9004 (patidistrogene bexoparvovec) (results posted in the registry). Last updated 15 June 2023; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT01976091
69. Mendell JR, Pozsgai ER, Lewis S, Griffin DA, Lowes LP, Alfano LN, et al. Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results. Nat Med. 2024;30(1):199-206. doi:10.1038/s41591-023-02730-9. PMID: 38177855. PMC10803256.
70. Connolly AM, Laverty CG, Proud CM, Diaz Manera J, Claeys KG, Comi G, et al. Expression of SGCB and safety following bidridistrogene xeboparvovec treatment in patients with LGMD2E/R4: results from the EMERGENE phase 3 study [poster 734LBP]. 30th Annual International Congress of the World Muscle Society; 7–11 October 2025; Vienna, Austria. Available at: https://investorrelations.sarepta.com/static-files/d092d8eb-6369-434a-ab1f-8995aefeaa95
71. ClinicalTrials.gov. NCT05876780: A gene transfer single dose study to evaluate the safety, tolerability and efficacy of SRP-9003 (VOYAGENE). Last updated 19 February 2026; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT05876780
72. Sarepta Therapeutics. Press release on the LGMD gene therapy programme [15 April 2025]. Available at: https://investorrelations.sarepta.com/node/24291
73. Sarepta Therapeutics, Inc. Form 8-K, Exhibit 99.1 (restructuring announcement). U.S. Securities and Exchange Commission; 16 July 2025. Available at: https://www.sec.gov/Archives/edgar/data/873303/000095017025096257/srpt-ex99_1.htm
74. U.S. Food and Drug Administration. FDA investigating deaths due to acute liver failure following treatment with Sarepta's AAVrh74 gene therapies [safety communication]. 18 July 2025. Available at: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-deaths-due-acute-liver-failure-following-treatment-sareptas-aavrh74-gene-therapies
75. Sarepta Therapeutics. Sarepta Therapeutics provides statement on ELEVIDYS [press release]. 18 July 2025. Available at: https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-provides-statement-elevidys
76. Connolly AM, Proud CM, Cochran K, Feng T, Thomas-Ahner J, Haugh J, et al. Expression of SGCA and safety following treatment with patidistrogene bexoparvovec in patients with LGMD2D/R3: results from a phase 1b study [poster 319T]. 2026 MDA Clinical & Scientific Conference; 8–11 March 2026; Orlando, FL. Available at: https://investorrelations.sarepta.com/static-files/9e04eb36-ba86-4dec-b35e-432343272634
77. ClinicalTrials.gov. NCT06747273: Study to evaluate the safety, tolerability, and efficacy of SRP-9004 administered by systemic infusion in limb-girdle muscular dystrophy type 2D/R3. Last updated 4 September 2025; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT06747273
78. Sarepta Therapeutics, Inc. Form 8-K. U.S. Securities and Exchange Commission; 21 July 2025. Available at: https://www.sec.gov/Archives/edgar/data/873303/000119312525161516/d882671d8k.htm
79. ClinicalTrials.gov. NCT06952686: A study of SRP-9005 in limb girdle muscular dystrophy type 2C/R5 pediatric and adult participants (COMPASS). Last updated 6 August 2025; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT06952686
80. Clinical Trials Information System (CTIS). Trial 2023-506440-16-00 (ATA-200, LGMD R5). Accessed 7 October 2026. Available at: https://euclinicaltrials.eu/ctis-public-api/retrieve/2023-506440-16-00
81. Clinical Trials Information System (CTIS). Trial 2022-503112-17-00 (SRP-9003, EMERGENE). Accessed 7 October 2026. Available at: https://euclinicaltrials.eu/ctis-public-api/retrieve/2022-503112-17-00
82. Atamyo Therapeutics. IND for ATA-200, a gene therapy for the treatment of limb-girdle muscular dystrophy type 2C/R5 (LGMD2C/R5), cleared to proceed by FDA [press release]. 12 November 2024. Available at: https://atamyo.com/press-releases/ind-for-ata-200-a-gene-therapy-for-the-treatment-of-limb-girdle-muscular-dystrophy-type-2c-r5-lgmd2c-r5-cleared-to-proceed-by-fda/
83. U.S. Food and Drug Administration. Approved cellular and gene therapy products [Internet]. Updated 17 September 2026; accessed 7 October 2026. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
84. ClinicalTrials.gov. NCT03652259: Gene delivery clinical trial of SRP-9003 (bidridistrogene xeboparvovec) for participants with LGMD2E. Last updated 20 January 2026; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT03652259
85. Atamyo Therapeutics. ASGCT Conference 2026 – Atamyo Therapeutics presents promising results in the first patients treated with its ATA-200 gene therapy in the clinical trial targeting LGMD-R5 [press release]. 13 May 2026. Available at: https://atamyo.com/press-releases/2026/asgct-conference-2026-atamyo-therapeutics-presents-promising-results-in-the-first-patients-treated-with-its-ata-200-gene-therapy-in-the-clinical-trial-targeting-lgmd-r5-limb-girdle-muscular-dystroph/
86. Zelikovich AS, Joslin BC, Casey P, McNally EM, Ajroud-Driss S. An Open Label Exploratory Clinical Trial Evaluating Safety and Tolerability of Once-Weekly Prednisone in Becker and Limb-Girdle Muscular Dystrophy. J Neuromuscul Dis. 2022;9(2):275-287. doi:10.3233/JND-210741. PMID: 35124660. PMC9028668.
87. ClinicalTrials.gov. NCT04475926: A study of the natural history of participants with LGMD2E/R4, LGMD2D/R3, LGMD2C/R5 and LGMD2A/R1 (JOURNEY). Last updated 6 November 2025; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT04475926
88. ClinicalTrials.gov. NCT03981289: Defining clinical endpoints in limb girdle muscular dystrophy (GRASP-LGMD). Last updated 27 February 2026; accessed 7 October 2026. Available at: https://clinicaltrials.gov/study/NCT03981289
89. Scano M, Benetollo A, Nogara L, Bondì M, Dalla Barba F, Soardi M, et al. CFTR corrector C17 is effective in muscular dystrophy, in vivo proof of concept in LGMDR3. Hum Mol Genet. 2022;31(4):499-509. doi:10.1093/hmg/ddab260. PMID: 34505136. PMC8863415.
90. Scano M, Benetollo A, Dalla Barba F, Akyurek EE, Carotti M, Sacchetto R, et al. Efficacy of Cystic Fibrosis Transmembrane Regulator Corrector C17 in Beta-Sarcoglycanopathy-Assessment of Patient's Primary Myotubes. Int J Mol Sci. 2024;25(24):13313. doi:10.3390/ijms252413313. PMID: 39769077. PMC11676211.
91. Benetollo A, Parrasia S, Scano M, Biasutto L, Rossa A, Nogara L, et al. The novel use of the CFTR corrector C17 in muscular dystrophy: pharmacological profile and in vivo efficacy. Biochem Pharmacol. 2025;233:116779. doi:10.1016/j.bcp.2025.116779. PMID: 39864467.
92. Alonso-Pérez J, Carrasco-Rozas A, Borrell-Pages M, Fernández-Simón E, Piñol-Jurado P, Badimon L, et al. Nintedanib Reduces Muscle Fibrosis and Improves Muscle Function of the Alpha-Sarcoglycan-Deficient Mice. Biomedicines. 2022;10(10):2629. doi:10.3390/biomedicines10102629. PMID: 36289891. PMC9599168.
93. ClinicalTrials.gov. Search of API v2 for studies on sarcoglycanopathies, nintedanib and CFTR correctors in muscular dystrophies. Accessed 7 October 2026. Available at: https://clinicaltrials.gov/api/v2/studies
94. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. doi:10.1038/gim.2015.30. PMID: 25741868. PMC4544753.
95. Liu W, Pajusalu S, Lake NJ, Zhou G, Ioannidis N, Mittal P, et al. Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases. Genet Med. 2019;21(11):2512-2520. doi:10.1038/s41436-019-0544-8. PMID: 31105274.
96. Glandier R, Stojkovic T, Wahbi K, Leturcq F, Desguerre I, Salort-Campana E, et al. French national SARCO sarcoglycanopathy registry [poster 162, RARE 2026; title consulted only in the poster file]. Évry: AFM-Téléthon; 2026. Available at: https://www.afm-telethon.fr/sites/default/files/media/documents/Poster_SARCO_RARE2026_162.pdf
97. Xie Z, Hou Y, Yu M, Liu Y, Fan Y, Zhang W, et al. Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients. Orphanet J Rare Dis. 2019;14(1):43. doi:10.1186/s13023-019-1021-9. PMID: 30764848. PMC6376703.
98. Winckler PB, da Silva AMS, Coimbra-Neto AR, Carvalho E, Cavalcanti EBU, Sobreira CFR, et al. Clinicogenetic lessons from 370 patients with autosomal recessive limb-girdle muscular dystrophy. Clin Genet. 2019;96(4):341-353. doi:10.1111/cge.13597. PMID: 31268554.
99. Lorenzoni PJ, Kay CSK, Ducci RD, Fustes OJH, Rodrigues PRDVP, Hrysay NMC, et al. Single-centre experience with autosomal recessive limb-girdle muscular dystrophy: case series and literature review. Arq Neuropsiquiatr. 2023;81(10):922-933. doi:10.1055/s-0043-1772833. PMID: 37852290. PMC10631857.
100. TREAT-NMD Neuromuscular Network [Internet]. Accessed 7 October 2026. Available at: https://www.treat-nmd.org/
101. Proyecto Alpha – Asociación Distrofia Muscular de Cinturas por déficit de sarcoglicanos [Internet]. Accessed 7 October 2026. Available at: https://www.proyectoalpha.org/
102. LGMD Awareness Foundation [Internet]. Accessed 7 October 2026. Available at: https://www.lgmd-info.org/
103. Muscular Dystrophy Association. Limb-girdle muscular dystrophy (LGMD) [Internet]. Accessed 7 October 2026. Available at: https://www.mda.org/disease/limb-girdle-muscular-dystrophy
104. Associação Portuguesa de Neuromusculares (APN) [Internet]. Accessed 7 October 2026. Available at: https://www.apn.pt/
105. Associação Brasileira de Distrofia Muscular (ABDIM) [Internet]. Accessed 7 October 2026. Available at: https://www.abdim.org.br/