Erb-Roth dystrophy: what it is and how it manifests itself

Erb-Roth dystrophy is a historical term for a heterogeneous group of inherited disorders now collectively known as limb-girdle muscular dystrophies (LGMDs). A common clinical feature is progressive proximal weakness of the pelvic and shoulder girdle muscles, with a gradual decline in endurance and impairment of daily activities. LGMDs differ from dystrophinopathies (Duchenne/Becker) and facioscapulohumeral dystrophy and have both autosomal recessive and autosomal dominant variants. [1]

The current classification has been revised by the European Neuromuscular Diseases Centre (ENMC): dominant forms are designated as LGMD-D (Dominant), recessive forms as LGMD-R (Recessive); for subtypes, the gene is specified. This simplifies patient routing and communication between clinicians and researchers. [2]

The classic "adolescent" and "young adult" forms described by Erb and Roth are now subdivided into dozens of genetic subtypes (calpainopathy, dysferlinopathy, sarcoglycanopathies, etc.), differing in the rate of progression, respiratory/cardiac muscle involvement, and response to rehabilitation. Therefore, a correct diagnosis relies on genetic confirmation. [3]

Epidemiology

LGMDs are rare diseases, but collectively they rank fourth among muscular dystrophies. Prevalence estimates vary by region and subtype: approximately 1.6-3 per 100,000 population, with a range from ≈1:44,000 to 1:123,000 in different studies and registries. This variation is explained by founder effects and differences in accounting methods. [4]

Some subtypes may be significantly more common in endemic regions (e.g., FKRP-associated LGMD-R9 or CAPN3-calpineopathy). The subtype structure varies across national cohorts, which is important to consider in first-line diagnosis. [5]

Disease onset most often occurs in childhood/adolescence or young adulthood, but a wide range of onset dates is known—from early childhood to the 5th or 6th decade, depending on the gene/variant. This complicates early diagnosis and requires vigilance among physicians of various specialties. [6]

Table. Epidemiological guidelines for LGMD

Indicator	Range/Remarks
Cumulative prevalence	≈1.6-3 per 100,000 (varies)
Orphanet ratings	1:44,000 - 1:123,000
Age of debut	Broad: childhood → 50+ years, depends on subtype
Common subtypes	CAPN3-R1, DYSF-R2, FKRP-R9, sarcoglycanopathies (by region)

Based on reviews, Orphanet and cohorts/registries. [7]

Reasons

LGMD are monogenic diseases caused by mutations in proteins of the sarcolemma, cytoskeleton, extracellular matrix, or enzymes (e.g., CAPN3/calpine-3, DYSF/dysferlin, sarcoglycan genes, FKRP, etc.). The inheritance pattern is autosomal recessive (LGMD-R) or autosomal dominant (LGMD-D). The gene determines the clinical phenotype and the risks of cardiac/respiratory involvement. [8]

Examples: calpainopathy (LGMD-R1/CAPN3) is one of the most common recessive LGMDs; dysferlinopathy (LGMD-R2/DYSF) produces the LGMD-R2 and Miyoshi myopathy phenotypes; ANO5-related spectrum ranges from hyperCKemia to LGMD-R12 and distal myopathies. [9]

Sarcoglycanopathies (LGMD-R3/R4/R5/R6) are associated with a risk of cardiomyopathy and are currently one of the priorities in gene therapy programs (AAV delivery of the relevant genes; early trials show protein expression and functional signals). [10]

Risk factors

As hereditary diseases, LGMDs are not dependent on modifiable external factors; the main "risk" is the carriage of pathogenic variants in parents (family history and consanguineous marriages increase the risk of autosomal recessive forms). Genetic counseling is the key to informed family decisions. [11]

The clinical trajectory is influenced by non-modifiable (gene/variant, gender, age of onset) and modifiable factors (physical activity strategy, body weight, contracture prevention, timely management of respiratory and cardiac dysfunction). Balanced activity and rehabilitation are associated with better functional outcomes. [12]

Organizational factors - access to genetic diagnostics and specialized rehabilitation, respiratory/cardiac monitoring - reduce the risk of complications and speed up routing to clinical trials. [13]

Pathogenesis

Common mechanisms include disruption of muscle fiber structural integrity (sarcolemma/sarcoglycan/dystrophin-associated complex defects), calcium imbalance, repeated membrane microtears, and initiation of fibro-fatty replacement. This leads to a progressive decline in proximal muscle strength and endurance. [14]

In calpineopathy, deficiency of the calcium-dependent protease CAPN3 impairs sarcomere remodeling; in dysferlinopathy, membrane repair following mechanical stress is impaired; in sarcoglycanopathies, the sarcolemmal framework and mechanotransduction are weakened. Differences in pathogenesis are reflected in the patterns of damage and cardiac/respiratory risks. [15]

The result is myofibrillar damage and chronic latent inflammation with subsequent degeneration and fibrosis; MRI demonstrates characteristic fatty infiltration maps useful for phenotyping and stratification.[16]

Symptoms

The main manifestations are "girdle" weakness: difficulty climbing stairs, rising from a chair, and running; a "duck-like" gait, and frequent falls. The shoulder girdle includes difficulty raising the arms and holding objects above shoulder level. Symptoms progress over years, often asymmetrically at onset, but generally symmetrically. [17]

A number of subtypes may present with myalgia, episodes of severe post-exertional weakness, and elevated creatine kinase; calf pseudohypertrophy, contractures, and scoliosis may also occur. Respiratory weakness and/or cardiomyopathy are associated with some forms, requiring targeted screening. [18]

The age of onset and rate of progression strongly depend on the genetic variant: with CAPN3, the onset is often adolescent/young adulthood; with ANO5, late manifestation is common; with DYSF, the spectrum ranges from the LGMD phenotype to Miyoshi myopathy. [19]

Forms and stages

Taxonomically, LGMD-D (dominant) and LGMD-R (recessive) groups are distinguished, and then further by gene/protein. In practice, phenotypically, "slowly progressive" and "rapidly progressive" variants are distinguished, as well as subtypes with probable cardiac/respiratory involvement. [20]

Classic staging is based on functions: level of daily activity, walking distance, need for assistive devices, and respiratory/cardiac support. Validated scales and MRI maps of fatty infiltration are used for monitoring. [21]

Table: Examples of LGMD subtypes and clinical features (partial list)

Designation	Gene/protein	Frequent accents
LGMD-R1 (capainopathy)	CAPN3	Common subtype; onset in adolescence/young adulthood, proximal weakness
LGMD-R2 (dysferlinopathy)	DYSF	LGMD/Miyoshi phenotypes; controversial frequency of cardiac/respiratory involvement → monitoring as indicated
LGMD-R3-R6 (sarcoglycanopathies)	SGCA/B/CG/CD	Risk of cardiomyopathy; target for AAV gene therapy in early studies
LGMD-R9	FKRP	Variable severity; regional clusters

According to reviews, GeneReviews, ENMC. [22]

Complications and consequences

Variably expressed respiratory weakness and cardiac disorders (cardiomyopathy, arrhythmia) in a number of subtypes are key factors in prognosis and quality of life; regular screening and early initiation of supportive therapy are required. [23]

Chronic pain and fatigue, contractures, falls, and secondary deformities (scoliosis) impair mobility and autonomy. Psychosocial consequences (limited employment, quality of life) are more pronounced in recessive forms. [24]

Without specialized monitoring, the risk of late diagnosis of respiratory failure and “silent” arrhythmias increases, which increases hospitalizations and reduces survival; multidisciplinary NMZ clinics improve outcomes. [25]

Diagnostics

Algorithm: (1) clinical phenotype of LGMD (proximal weakness), (2) increased CK (often significant), myopathic EMG pattern, (3) MGC/MRI of muscles for lesion map, (4) priority - molecular diagnostics (panel/exome/genome); biopsy - if indicated (immunohistochemistry/Western blot) if the genetic result is unclear. [26]

Guidelines (AAN, profile statements) recommend early initiation of genetic testing, which improves accuracy, predicts cardiac/respiratory risks, and paves the way for clinical trials. [27]

Basic cardio- and pulmonary screening is mandatory (ECG/ECHO, FVD with FGJ; further - by subtype/dynamics), since some forms remain “muscular” for a long time with hidden systemic involvement. [28]

Table. Mini-algorithm for primary diagnostics in case of suspected LGMD

Step	Action	Comment
1	Clinic + CC, EMG	Confirmation of the myopathic process
2	MRI of muscles	Damage card → subtype hint
3	Genetics (panel/exam)	Priority; biopsy "if necessary"
4	Cardio/breathing	ECG/ECHO, FVD; frequency - according to risk subtype

According to the AAN guidelines and modern reviews. [29]

Differential diagnosis

Dystrophinopathies (Duchenne/Becker), fascio-scapulohumeral and Emery-Dreifuss dystrophies, late congenital myopathies, Pompe disease, congenital myasthenic syndromes, and proximal neuropathies are excluded. The key is genetics + the nature of the MRI/biopsy. [30]

In adults - also drug/endocrine myopathies, inflammatory myositis; in case of isolated gastrocnemius weakness - differentiation with Miyoshi myopathy (often DYSF spectrum). [31]

Treatment

There is currently no etiotropic therapy that can alter the course of most subtypes; the basis is long-term rehabilitation (aerobic dosed activity, gentle strength training without "exhaustion"), contracture prevention, orthotics/mobility assistance, nutritional support, and treatment of associated pain. Highly intensive, "destructive" regimens are avoided. [32]

Monitoring and management of respiration (pulmonary function test, respiratory muscle training, non-invasive ventilation as indicated) and the heart (ECG/ECHO, standard heart failure/arrhythmia therapy) are the cornerstones of improving survival and quality of life. [33]

Interventional research areas: AAV gene therapy for sarcoglycanopathies (proves gene expression and efficacy signals in early phases), the research platform is expanding but safety and accessibility issues remain; careful selection and monitoring in clinical trials is required. [34]

Table. LGMD Management Components (Program Core)

Direction	Content	Comments
Education + activity	Dosed aerobic/strength training, without going to failure	Minimize overexertion; water/swimming is helpful
Contractures/orthoses	Stretching, orthotics, technical assistance, fall prevention	Individual selection
Breathing/heart	Screening and treatment according to protocols	Affect the prognosis
Nutrition/pain	Weight/protein support, multimodal analgesia	As needed
Clinical trials	Gene therapy/new approaches for specific subtypes	Strict inclusion criteria

According to MDA, reviews of rehabilitation and cardiopulmonary management. [35]

Prevention

Primary prevention as prevention of mutation is not possible; genetic counseling, information about the risks of recessive inheritance, and prenatal/preimplantation testing options in families with a known variant are important. [36]

Secondary prevention of complications - regular visits to the NM clinic, planned cardio- and respiratory screening, vaccination (respiratory infections), prevention of contractures and falls, adaptation of the environment and movement techniques. [37]

Behavioral prevention of overload: avoid super-intense, eccentric “to failure” loads; prioritize moderate, regular activity with recovery breaks and hydration. [38]

Forecast

The prognosis ranges from a slowly progressive course with independent walking for decades to a more rapid deterioration with the early inclusion of assistive devices. Outcome is influenced by the subtype/gene, age of onset, early detection and management of respiratory/cardiac function, and access to rehabilitation. [39]

In some recessive forms, quality of life is lower than in dominant forms; however, multidisciplinary programs and modern support measures significantly improve functioning. Prospects for therapy are linked to the development of genetic approaches, but remain in the realm of clinical research. [40]