Limb-Girdle Muscular Dystrophies

Limb-girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of autosomally inherited skeletal muscle disorders characterized by progressive proximal weakness, elevated creatine kinase (CK), and dystrophic changes on muscle biopsy. First recognized by Stevenson in 1953 and further delineated by Walton and Nattrass in 1954, LGMDs are collectively the fourth most prevalent muscular dystrophy after dystrophinopathies, myotonic dystrophies, and facioscapulohumeral dystrophy, with a pooled prevalence of approximately 16.3 per million. The 2017 European Neuromuscular Centre (ENMC) workshop reformed the classification to include 5 dominantly inherited forms (LGMD D1–D5) and 29 recessively inherited forms (LGMD R1–R29). Advances in next-generation sequencing (NGS) have transformed the diagnostic approach, and early-stage gene therapy trials—including the first phase 3 programs—offer the prospect of disease-modifying treatment for selected subtypes.

Classification: The 2017 ENMC System

The original 1995 ENMC workshop standardized LGMD nomenclature using an alphanumeric system: LGMD1 (dominant) and LGMD2 (recessive), each followed by a letter reflecting the order of gene discovery. By 2016, 26 recessive subtypes had exhausted the alphabet (LGMD2A through LGMD2Z), necessitating reform. The 2017 ENMC workshop replaced this system with a clearer nomenclature: LGMD D for autosomal dominant and LGMD R for autosomal recessive forms, each followed by a sequential number. Sarcoglycanopathies are organized by their Greek alphabet designations rather than discovery order. The updated classification also requires documentation in at least two unrelated families and that affected individuals achieved independent walking, distinguishing LGMD from congenital muscular dystrophy.

Dominant Forms (LGMD D1–D5)

Dominant LGMDs generally have later onset, lower CK levels (normal to mildly elevated), milder weakness, and slower progression compared with recessive forms.

Common Recessive Forms

Pathomechanistic Groups

Approximately half of all LGMD subtypes can be classified into three mechanistic groups, which aids in understanding shared clinical features and guiding diagnostic evaluation.

Alpha-Dystroglycanopathies

Alpha-dystroglycanopathies are the largest group, comprising 11 LGMD-R subtypes (R9, R11, R13–R16, R18–R21, R24). They result from defective glycosylation of alpha-dystroglycan, which disrupts the link between the dystrophin-associated glycoprotein complex and the extracellular matrix. Reduced alpha-dystroglycan immunoreactivity on muscle biopsy is the pathological hallmark. The clinical spectrum ranges from severe congenital muscular dystrophy with brain and eye involvement (Walker-Warburg syndrome, muscle-eye-brain disease) to milder LGMD with preserved cognition. Common features across LGMD-R alpha-dystroglycanopathies include calf pseudohypertrophy, cardiopulmonary involvement, and variable cognitive impairment. LGMD R9 (FKRP-related) is the most common and best-studied subtype in this group.

Muscular Dystrophies with Defective Membrane Repair

This group includes LGMD R2 (dysferlinopathy) and LGMD R12 (anoctaminopathy-5). When the sarcolemma is disrupted, dysferlin, anoctamin-5, and annexins coordinate membrane resealing. Both subtypes can present as either proximal (LGMD) or distal (Miyoshi) phenotypes. Shared features include calf atrophy, asymmetric weakness, metabolic myopathy-like presentations (exercise intolerance, rhabdomyolysis), and relative sparing of cardiac and respiratory function. Both may show intramuscular amyloid deposition without systemic amyloidosis. Muscle biopsy in dysferlinopathy often shows prominent inflammatory infiltrates, which can be misdiagnosed as inflammatory myopathy.

Sarcoglycanopathies

The sarcoglycan complex (α, β, γ, δ subunits) is a tetrameric sarcolemmal assembly within the dystrophin-associated glycoprotein complex. Sarcoglycanopathies (LGMD R3–R6) typically present with early childhood-onset severe weakness resembling Duchenne muscular dystrophy, with wheelchair dependence often by the teenage years. Dilated cardiomyopathy and respiratory insufficiency are common. LGMD R3 (α-sarcoglycanopathy) is the most frequent subtype. Muscle biopsy shows dystrophic features with attenuated or absent immunoreactivity of the affected sarcoglycan subunit, often with secondary reduction of other subunits.

Clinical Approach

Pattern of Weakness

The hallmark presentation is gradual-onset, symmetric, proximal weakness predominantly affecting the pelvic girdle before the shoulder girdle. Key clinical observations that help narrow the differential include:

• Hip extensors, adductors, and knee flexors affected first: Characteristic of calpainopathy (LGMD R1) and FKRP-related dystrophy (LGMD R9)
• Scapular winging: Prominent in LGMD D1, D2, R1, and R9; may mimic facioscapulohumeral dystrophy
• Asymmetric weakness: Strongly suggests dysferlinopathy (R2) or anoctaminopathy-5 (R12)
• Calf atrophy (rather than pseudohypertrophy): Early in LGMD D1, R2, and R12
• Dysphagia: Uncommon in LGMD but reported in ~50% of LGMD D1 (DNAJB6)
• Early contractures: Collagen VI-related LGMD (D5 and R22) and some LGMD R1 patients

CK Elevation Patterns

CK levels provide important diagnostic clues. In LGMD-D, CK is typically normal to mildly elevated. In LGMD-R, CK is usually >1000 U/L, and may exceed 10,000 U/L in sarcoglycanopathies and dysferlinopathy. Some patients present initially with asymptomatic or paucisymptomatic hyperCKemia, exercise intolerance, or rhabdomyolysis (reported in LGMD R1, R2, R3–R6, R9, R12, and R19) before fixed weakness develops.

Diagnostic Algorithm

Step 1: Clinical Assessment and Initial Testing

Establish the pattern of weakness, family history (autosomal dominant vs. recessive vs. sporadic), and CK level. Review medications for potential toxic myopathies. Obtain screening labs for both acquired and hereditary myopathies, including myositis-specific antibodies (anti-HMGCR, anti-SRP) to exclude immune-mediated necrotizing myopathy, which can closely mimic LGMD. EMG helps confirm myopathic features and exclude neurogenic disorders.

Step 2: Genetic Testing (First-Line)

NGS gene panels have replaced muscle biopsy as the primary diagnostic tool. Panels should include:

• All LGMD genes (34 subtypes)
• Other hereditary myopathies (myofibrillar myopathies, metabolic myopathies, mitochondrial genes)
• Congenital myasthenic syndrome genes (especially DOK7, GFPT1, PLEC, GMPPB)

Important limitations: Standard NGS panels do not detect nucleotide repeat expansions (myotonic dystrophy type 2), large deletions (facioscapulohumeral dystrophy), or mitochondrial DNA mutations. If the panel is negative, specific testing for these conditions should follow. Variants of uncertain significance (VUS) require detailed analysis, family segregation studies, and often correlation with muscle biopsy findings.

Step 3: Muscle Biopsy (When Needed)

Muscle biopsy is reserved for patients with negative or inconclusive genetic testing and for validating VUS pathogenicity. Key immunohistochemical markers include:

Step 4: Advanced Genetic Testing

If the gene panel and muscle biopsy are inconclusive, consider whole-exome sequencing, whole-genome sequencing, or RNA sequencing. Whole-genome sequencing can also detect nucleotide repeat expansions in noncoding regions, assisting in the diagnosis of myotonic dystrophy type 2 if specific testing has not been performed.

Muscle MRI Patterns

Each LGMD subtype exhibits a relatively consistent pattern of muscle involvement on MRI, which can support diagnosis and help validate VUS. While overlap exists between subtypes, several patterns are considered characteristic:

• Posterior compartment predominance: Most LGMD subtypes show preferential fatty infiltration of the posterior thigh muscles, with the posterior compartment being the most severely affected overall
• LGMD R1 (calpainopathy): Early involvement of the posterior thigh (adductor magnus, semimembranosus, biceps femoris) and medial gastrocnemius; relative sparing of rectus femoris and sartorius
• LGMD R2 (dysferlinopathy): Both proximal and distal phenotypes show similar MRI patterns; fatty infiltration of the posterior thigh and medial gastrocnemius; edema in lower leg muscles may be seen early
• LGMD R9 (FKRP): Variable; posterior thigh involvement with relative quadriceps sparing early; resembles LGMD R1 pattern
• LGMD R12 (anoctaminopathy-5): Markedly asymmetric involvement; selective fatty replacement of quadriceps and hamstrings
• Collagen VI-related (D5, R22): Characteristic “outside-in” pattern—fatty replacement beginning from the peripheral region of the vasti muscles and moving centrally

Differential Diagnosis

The combination of proximal weakness and elevated CK is common to many hereditary and acquired myopathies. The differential diagnosis is particularly broad in sporadic cases.

Extramuscular Manifestations and Surveillance

Cardiac Involvement

Cardiomyopathy and arrhythmias are significant in sarcoglycanopathies (R3–R6), alpha-dystroglycanopathies, LGMD R7 (telethonin), LGMD R10 (titin), and LGMD R25 (POPDC1, which may cause atrioventricular block and syncope). Cardiac involvement is uncommon in calpainopathy (R1, D4), dysferlinopathy (R2), and anoctaminopathy-5 (R12).

Respiratory Involvement

Respiratory insufficiency is common in sarcoglycanopathies, collagen VI-related LGMDs (D5, R22), alpha-dystroglycanopathies, and advanced LGMD D1. In LGMD R1, respiratory insufficiency affects approximately 20% of patients, typically in advanced stages, though most do not require ventilatory support.

Management

Supportive Care

There are currently no approved disease-modifying therapies for any LGMD subtype. Management is multidisciplinary and includes:

• Physical and occupational therapy: Low-impact aerobic exercise (stationary cycling, swimming) and supervised submaximal strength training are likely safe; avoid high-resistance and eccentric exercises (heavy weightlifting, downhill running) due to the risk of muscle damage
• Exercise precautions: Counsel patients to hydrate adequately and avoid exercising to exhaustion; warning signs include weakness within 30 minutes after exercise, severe muscle pain 24–48 hours later, muscle swelling, or dark urine
• Assistive devices: Mobility aids, wheelchairs, and adaptive equipment as needed; orthotics for contracture management
• Speech pathology: For patients with dysphagia (primarily LGMD D1)
• Targeted pharmacotherapy: Patients with LGMD R17 (PLEC) or R19 (GMPPB) who demonstrate decrement on repetitive nerve stimulation may benefit from acetylcholinesterase inhibitors for their associated congenital myasthenic syndrome component

Genetic Counseling

Genetic counseling is an essential component of LGMD care, particularly for family planning. Preimplantation genetic testing with in vitro fertilization can reduce the risk of transmitting pathogenic variants. This approach is more commonly used for autosomal dominant forms; for autosomal recessive forms, carrier testing of the healthy partner may be considered if the variant gene has a high carrier frequency, if the couple comes from a region with elevated carrier rates, or if consanguinity is present. It is important to recognize that a negative family history does not exclude LGMD—de novo variants, incomplete penetrance, and small pedigrees can all obscure autosomal inheritance.

Gene Therapy Pipeline

Gene therapy for LGMD has advanced rapidly, with viral vector-based gene replacement therapies progressing through preclinical and early clinical stages for the most common recessive subtypes (R1–R6, R9).

SRP-9003 (Bidridistrogene Xeboparvovec) for LGMD R4

SRP-9003, developed by Sarepta Therapeutics, is an AAVrh74-based gene therapy delivering a functional β-sarcoglycan transgene for LGMD R4. Phase 1/2 data demonstrated safety over 4–5 years of follow-up with sustained β-sarcoglycan protein expression. The phase 3 EMERGENE trial (SRP-9003-301) completed enrollment in December 2024 and met its primary endpoint, showing a mean 43.4% increase in β-sarcoglycan expression from baseline in ambulatory patients and 23.9% in non-ambulatory patients. However, the FDA placed clinical holds on all AAVrh74-based programs in 2025 following the death of a 51-year-old patient from acute liver failure in a phase 1 trial of SRP-9004 (for LGMD R3). The FDA also revoked the platform technology designation for the AAVrh74 vector.

BBP-418 (Ribitol) for LGMD R9

BBP-418, developed by BridgeBio Pharma, takes a fundamentally different approach. Ribitol is a pentose alcohol and precursor of cytidine diphosphate-ribitol, the substrate of the FKRP enzyme. Supraphysiologic levels of exogenous ribitol enhance the residual activity of variant FKRP enzyme and restore glycosylation of alpha-dystroglycan. The phase 3 FORTIFY trial reported positive results in October 2025: a highly significant increase in glycosylated alpha-dystroglycan (1.8-fold change from baseline, p<0.0001) sustained at 12 months, with improvements in walking speed and forced vital capacity versus placebo. BridgeBio plans to pursue FDA submission in 2026, which would make BBP-418 the first approved therapy for LGMD R9.

Other Emerging Approaches

• Sarepta pipeline: Gene therapy programs in various stages for LGMD R1, R2, R3, and R5, together representing >70% of known LGMD cases; all programs using the AAVrh74 vector are currently on clinical hold
• Combination therapy: Preclinical studies in LGMD R9 mouse models showed that combining FKRP gene replacement therapy with ribitol was more effective than either treatment alone
• Gene editing and exon skipping: Emerging approaches for dominant LGMDs that aim to silence or correct harmful gain-of-function variants rather than replace defective genes

Natural History and Prognosis

Disease progression varies substantially across LGMD subtypes and even within the same subtype. Key prognostic data from a 2022 systematic review include mean age at loss of ambulation stratified by onset age:

Sarcoglycanopathies (R3–R6) consistently have the earliest loss of ambulation across all onset categories, reflecting their severe, Duchenne-like course. LGMD R12 has the latest loss of ambulation in adult-onset cases. Earlier symptom onset universally correlates with more rapid progression to wheelchair dependence across all subtypes.

Conditions Previously Classified as LGMD

The 2017 ENMC reclassification removed several previously recognized LGMD subtypes that did not meet updated criteria. Notable exclusions include:

• LGMD1A (MYOT) and LGMD1E/2R (DES): Reclassified as myofibrillar myopathies due to predominantly distal weakness
• LGMD1B (LMNA): Reclassified as Emery-Dreifuss muscular dystrophy phenotype
• LGMD1C (CAV3): Reclassified as rippling muscle disease due to muscle rippling and myalgia rather than typical LGMD features
• LGMD2V (GAA): Recognized as late-onset Pompe disease, an established metabolic disorder with available enzyme replacement therapy

Clinicians should remain aware of these reclassified entities, as patients diagnosed under the older nomenclature may still carry the legacy LGMD designation in their medical records.

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