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Limb-girdle muscular dystrophy

Limb-girdle muscular dystrophy
Author:
Basil T Darras, MD
Section Editors:
Douglas R Nordli, Jr, MD
Jeremy M Shefner, MD, PhD
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Oct 2022. | This topic last updated: Jan 04, 2022.

INTRODUCTION — The muscular dystrophies are an inherited group of progressive myopathic disorders resulting from defects in a number of genes required for normal muscle function. Some of the genes responsible for these conditions have been identified. Muscle weakness is the primary symptom.

The pathogenesis, genetics, and clinical characteristics of limb-girdle muscular dystrophy (LGMD) will be reviewed here. Other dystrophies are presented separately. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Emery-Dreifuss muscular dystrophy" and "Facioscapulohumeral muscular dystrophy" and "Myotonic dystrophy: Etiology, clinical features, and diagnosis" and "Oculopharyngeal, distal, and congenital muscular dystrophies".)

DEFINITION AND NOMENCLATURE — Limb-girdle muscular dystrophy (LGMD) is characterized by a predominantly proximal distribution of weakness. It includes a number of heterogeneous genetic disorders that vary in severity, phenotype, pathology, and age of onset, which ranges from childhood through adulthood [1,2]. The earlier definition, nomenclature, and classification system for LGMDs was replaced by a newer system in 2018; a comparison of the new and old systems is listed in the table (table 1).

Old classification

Definition – In the classification scheme for LGMD that was developed in the 1990s, LGMD was defined as a progressive muscle disease that starts in and predominantly affects the pelvic and/or shoulder girdle muscles [3].

Nomenclature – LGMDs were subdivided by inheritance into two main groups, with LGMD1 denoting autosomal dominant forms, and LGMD2 denoting autosomal recessive forms [3]. A letter was also assigned, based upon the order of discovery for each new causative gene or linked genetic locus. As an example, dysferlinopathy caused by recessive pathogenic variants in the DYSF gene was designated as "LGMD2B," since it was the second recessively inherited LGMD described.

Limitations – However, this classification scheme reached its limits once the number of genetic subtypes of LGMD exceeded the number of letters in the alphabet. In addition, advances in the molecular and pathogenetic understanding of LGMD subtypes have revealed inadequacies in the broad original phenotypic definition of LGMD. These problems led to a revision of the LGMD nomenclature and a new classification, as described in the section below [4].

New classification

Definition – A newer classification system for LGMD, developed in 2018, defines LGMD as a genetically inherited condition that primarily affects skeletal muscles and presents with progressive, predominantly proximal muscle weakness due to a loss of muscle fibers [4]. Subtypes of LGMD must meet several requirements:

Be described in at least two unrelated families with affected individuals achieving independent walking

Have an elevated serum creatine kinase level

Demonstrate degenerative changes on muscle imaging over the course of the disease

Have dystrophic changes on muscle histology, ultimately leading to end-stage pathology for the most affected muscles

Nomenclature – In the new system (table 1), the LGMD abbreviation is retained, but the mode of inheritance is designated by the letter "D" for dominant and "R" for recessive, the order of discovery is designated by a number, and the affected protein is listed. Thus the format is "LGMD, inheritance (R or D), order of discovery (number), affected protein" [4]. As an example, dysferlinopathy caused by recessive pathogenic variants in the DYSF gene and previously designated as "LGMD2B" is now designated as "LGMD R2 dysferlin-related."

Conditions no longer considered LGMD – As a result of the changes in definition, a number of conditions previously classified as LGMDs are now excluded from the new classification system [4]. These conditions and the reason for their exclusion are listed in the table (table 2).

Conditions now included as subtypes of LGMD – Although previously considered as separate from LGMD, Bethlem myopathy and milder laminin alpha-2 related muscular dystrophy have now been included as subtypes of LGMD because they fulfill the revised definition [4].

EPIDEMIOLOGY — Together, the group of disorders that constitute LGMD is the fourth most common genetic cause of muscle weakness, behind the dystrophinopathies (Duchenne and Becker muscular dystrophy), myotonic dystrophy, and facioscapulohumeral muscular dystrophy, with an estimated minimum prevalence between 10 and 23 per 100,000 [2].

The most prevalent LGMD subtypes are the following [2]:

Calpainopathy

Dysferlinopathies

Collagen 6-related

Sarcoglycanopathies

Anoctamin 5-related

FKRP-related

Autosomal recessive LGMDs are more common than the autosomal dominant ones.

CLINICAL FEATURES AND GENETICS — LGMD encompasses a heterogenous group of genetic disorders with both autosomal recessive and autosomal dominant inheritance patterns [4]. Major genetic categories of LGMD are reviewed in the sections below.

General features — The general features of the disorders that make up LGMD are progressive weakness and muscle atrophy mainly involving the shoulder girdle (scapulohumeral type), the pelvic girdle (pelvifemoral type), or both. The age of onset of LGMD varies from early childhood to adulthood [2]. Most childhood-onset cases have a pelvifemoral distribution of weakness. By comparison, adult-onset disease usually involves both shoulder and pelvic girdles with gradually increasing proximal limb weakness, thereby leading to restriction of mobility and eventually to wheelchair confinement.

Facial weakness is usually mild and, in some cases, totally absent. Extraocular muscles are completely spared in the LGMDs. Distal muscle strength is usually preserved, even at the late stage of the disease.

Cardiac involvement is common in LGMD R4 (beta-sarcoglycan-related) and LGMD R9 (FKRP-related) [5-8]. It is unusual in LGMD D1 (DNAJB6-related), LGMD R1 (calpain-3-related), and LGMD R3 (alpha-sarcoglycan-related). Dilated cardiomyopathy and cardiac conduction system abnormalities are the most common types of cardiac involvement [1,8]. (See 'Cardiac complications' below.)

Intellect is usually normal, though intellectual disability is a feature of LGMD R11 (POMT1-related) and has been reported in LGMD R14 (POMT2-related).

Many of the subtypes of LGMD have characteristic though nonspecific clinical manifestations. They are discussed below (table 1).

Calpainopathies — Calpainopathies are caused by autosomal recessive and autosomal dominant pathogenic variants in the calpain-3 gene (CAPN3) [9]. Thus, the classification for calpainopathy includes both types of inheritance:

LGMD R1, calpain-3-related (previously LGMD2A) for autosomal recessive disease

LGMD D4, calpain-3-related (previously LGMDD4) for autosomal dominant disease

Calpain-3, a calcium-dependent cysteine protease, helps regulate calcium outflow from the sarcoplasmic reticulum, interacts with cytoskeletal proteins such as titin and dysferlin, and plays a role in sarcomere assembly, remodeling, and repair [2,10,11]. While the precise mechanism of calpainopathy is uncertain, loss-of-function pathogenic calpain-3 variants lead to recessive disease with abnormal muscle sarcomeres and eventual muscle fiber death [9]. Autosomal dominant disease is due to certain single pathogenic CAPN3 variants that exert a dominant-negative deleterious effect on protein function [12].

Autosomal recessive calpainopathy (LGMD R1) is considered the most common type of LGMD worldwide, accounting for 15 to 40 percent of all cases of LGMD [13,14], with variation depending in part on the geographic region [9,15]. The onset of LGMD R1 occurs between 6 and 18 years of age in 71 percent but onset may occur through adulthood [16]. The phenotype is variable, and ranges from pelvic and shoulder girdle muscle weakness to asymptomatic disease with elevated serum creatine kinase levels (hyperCKemia) [9]. With more severe disease, there is significant involvement of the parascapular muscles, biceps, gluteus maximus, adductors, and hamstrings. Hip girdle muscles are weaker than shoulder girdle muscles, with severe weakness involving hip extension, adduction, and knee flexion. Scapular winging (albeit non-specific), abdominal laxity, hyperlordosis, and a waddling gait are common. Contractures are extensive and tend to develop early. Facial weakness may occur in cases with early-onset or severe disease [13]. Creatine kinase levels range from 500 to 20,000 units/L (usually more than five times upper limit of normal). Muscle biopsy often shows lobulated fibers. Cardiac and pulmonary involvement is unusual [17], though one retrospective study of 43 patients with LGMD R1 reported respiratory dysfunction in 21 percent [18]. Although course and severity are variable, requirement for a wheelchair occurs between the ages of 21 and 40 years in approximately 80 percent [16]. The scapular winging, abdominal laxity, and variable facial weakness can cause diagnostic confusion with fascioscapulohumeral muscular dystrophy. (See "Facioscapulohumeral muscular dystrophy".)

Although the inheritance of calpainopathy was long considered to be exclusively recessive, autosomal dominant transmission over several generations has been observed among some families in patients who carry a single in-frame c.643_663del21 deletion of the CAPN3 gene [12]. Patients with this autosomal dominant calpainopathy (LGMD D4) have a phenotype that resembles but is generally milder than the recessive form.

Dysferlinopathies — Dysferlinopathies encompass pathogenic variants in the dysferlin gene (DYSF) that cause two main types of muscular dystrophy, LGMD R2 and Miyoshi distal myopathy, and other muscle disorders with variable phenotypes ranging from asymptomatic hyperCKemia to severe disability [19]. The LGMD classification includes one type:

LGMD R2, dysferlin-related (previously LGMD2B) for autosomal recessive disease

In experimental mice, deficiency of dysferlin disrupts the ability to reseal injured sarcolemma, resulting in muscle degeneration [20,21]. Loss of dysferlin induces complement-mediated inflammation, which contributes to muscle injury in dysferlinopathy [19,22-27].

LGMD R2 is the second most common subtype of LGMD in the United States, accounting for 5 to 35 percent of all cases [13,14]. Studies from China and Korea suggest it is the most common subtype in Asia [2,28,29]. Prior to onset, development is normal and some individuals excel at athletics [30,31]. The typical age of onset ranges from 12 to 25 years, and legs are usually affected first [13]. Distal involvement is often present, with early weakness and atrophy of the gastrocnemius and inability to walk on the toes. When the involvement is only distal, it is known as Miyoshi distal myopathy. In LGMD R2, arm weakness may occur with progression, but scapular winging is not seen. Likewise, there is no facial weakness or dysphagia. Cardiac or pulmonary involvement is uncommon; when it does occur, it is usually asymptomatic and late in the course of the disease [1,32]. Serum creatine kinase levels can be highly elevated, and range from 1000 to 40,000 units/L [13]. Muscle biopsy shows inflammatory features in 40 percent or more of cases. LGMD R2 is usually slowly progressive, with need of a wheelchair 10 to 20 years after onset [13]. However, occasional patients have rapid onset and progression with loss of ambulation over one to two years, in some cases apparently triggered by pregnancy [30].

Mounting evidence suggests that LGMD R2 and Miyoshi distal myopathy are clinically more homogeneous than once thought. One retrospective report followed 29 patients with pathogenic variants in DYSF (including 12 with LGMD R2 and 14 with Miyoshi myopathy as diagnosed by initial symptoms) for a mean of 6.4 years [33]. There were no differences between patients with LGMD R2 and Miyoshi myopathy in the rate of disease progression or functional status. In addition, the pattern of muscle involvement on magnetic resonance imaging (MRI) was the same; the adductor magnus and gastrocnemius medialis were the first affected muscles in both groups.

Collagenopathies — Collagen 6-related myopathies encompass several disorders, including Ullrich congenital muscular dystrophy, which typically presents with onset during infancy, and Bethlem myopathy, which is milder and generally of later onset [2]. The 2018 revision of LGMD classification added Bethlem myopathy as a subtype of LGMD because many patients with Bethlem myopathy fulfill the revised definition for LGMD [4]. Bethlem myopathy is predominately associated with autosomal dominant disease due to pathogenic variants in COL6A1, COL6A2, and COL6A3; patients with compound heterozygous COL6A2 pathogenic variants and recessive inheritance have been reported as well [34,35]. In the revised LGMD classification, Bethlem myopathy is designated as follows:

LGMD D5, collagen 6-related (for autosomal dominant inheritance)

LGMD R22, collagen 6-related (for autosomal recessive inheritance)

Bethlem myopathy is a slowly progressive disorder. Onset typically occurs in early childhood, though adult onset through the seventh decade has also been reported [2]. The disorder is characterized by proximal weakness, sometimes with truncal weakness, and flexion contractures involving primarily distal joints (eg, ankles and interphalangeal joints of the fingers) but also involving the knees, hips, elbows, shoulders, and neck [36-38].

Sarcoglycanopathies — Sarcoglycanopathies are early-onset autosomal recessive LGMDs caused by pathogenic variants in the genes coding for alpha (SGCA), beta (SCGB), gamma (SGCG), and delta (SGCD) sarcoglycans [39,40]. These sarcoglycan proteins are members of the dystrophin-associated glycoprotein complex (figure 1). The sarcoglycanopathies are designated as follows:

LGMD R3, alpha-sarcoglycan-related (previously LGMD2D)

LGMD R4, beta-sarcoglycan-related (previously LGMD2E)

LGMD R5, gamma-sarcoglycan-related (previously LGMD2C)

LGMD R6, delta-sarcoglycan-related (previously LGMD2F)

The sarcoglycanopathies together are a common cause of LGMD, accounting for 5 to 10 percent of cases [2,13,14,41]. Onset usually occurs at 5 to 15 years of age. Typical features include proximal leg weakness, scapular winging, calf hypertrophy (common), macroglossia, and lumbar lordosis, but cognitive function is preserved. Cardiac and respiratory involvement is frequent with disease progression; the exception is LGMD R3, in which cardiac involvement is less frequent [42], presumably because epsilon-sarcoglycan replaces alpha-sarcoglycan in the myocardium [43]. Serum creatine kinase levels range from 500 to 20,000 units/L. Muscle biopsy typically shows abnormal staining for all four sarcoglycans. There is progression to wheelchair use within 10 years of onset in many cases, but occasional patients have only mild disease characterized by exercise intolerance, myoglobinuria, minimal weakness, and slower progression.

Anoctaminopathies — The ANO5 gene encodes for anoctamin 5 (ANO5), a putative calcium-activated chloride channel. Recessive pathogenic variants in ANO5 are an important cause of LGMD, although the phenotype is variable [44]. The LGMD designation is as follows:

LGMD R12, anoctamin 5-related (previously LGMD2L)

LGMD R12 is a common LGMD subtype among people of Northern European origin [45]. It is characterized by later onset, usually from 20 to 50 years of age, slowly progressive proximal leg weakness, often with asymmetric muscle atrophy primarily affecting the quadriceps and biceps muscles, and elevated serum creatine kinase levels ranging from 2000 to 7000 units/L [2,45-47]. Females generally have milder manifestations than males [44]. A minority of patients may develop cardiomyopathy with reduced left ventricular ejection fraction, but pulmonary involvement is rare [2,48]. Most patients remain ambulatory, but with disease progression over 20 to 40 years, some affected individuals will require canes, walkers, or a wheelchair [2]. On muscle MRI, there is fatty degenerative changes predominately involving the medial gastrocnemius, soleus, posterior thigh, and biceps brachii muscles [2,44].

Other phenotypes caused by pathogenic variants in ANO5 include Miyoshi distal myopathy, persistently elevated serum creatinine kinase levels associated with exercise intolerance and/or myalgia without significant weakness, calf hypertrophy without significant weakness, and minimally symptomatic or asymptomatic hyperCKemia [45,47,49,50].

Dystroglycanopathies — Dystroglycanopathies include a variety of autosomal recessive muscular dystrophies caused by pathogenic variants in several genes, including FKRP, POMT1, POMT2, POMGnT1, DAG1, GMPPB, and CRPPA [51,52]. Pathogenic variants in these genes are associated with autosomal recessive LGMD variants with childhood or adult onset. The underlying mechanism for most of these variants is reduced glycosylation of the extracellular alpha-dystroglycan protein (ie, secondary dystroglycanopathies). The one exception is pathogenic variants involving DAG1, which lead to alteration of the core dystroglycan protein itself (ie, a primary dystroglycanopathy) [53].

Several of the pathogenic variants that cause secondary dystroglycanopathy are also associated with congenital muscular dystrophies, including Walker-Warburg syndrome, Fukuyama type of congenital muscular dystrophy, and muscle-eye-brain disease. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Congenital muscular dystrophies'.)

The dystroglycanopathies encompass the following LGMD subtypes:

LGMD R9, FKRP-related (previously LGMD2I) is a frequent form of LGMD, accounting for 20 to 40 percent of all cases worldwide [13]. It is caused by mutations in the fukutin-related protein gene (FKRP). While phenotypically heterogeneous [54], common clinical features of LGMD R9 include proximal muscle weakness and atrophy, calf muscle hypertrophy, lumbar lordosis, scapular winging, macroglossia, and an increased incidence of cardiomyopathy, and elevated plasma levels of creatine kinase [55,56]. These features are similar to those of Becker muscular dystrophy. A majority of patients experience muscle pain with exercise, and myoglobinuria affects up to one-third [57]. Cardiac and respiratory involvement is frequent with disease progression but can also arise early in the course of the disease and may not correlate with the severity of skeletal muscle weakness [13]. Creatine kinase levels range from 500 to 20,000 units/L. Muscle biopsy shows reduced or absent immunostaining for alpha-dystroglycan. The disease course can be sporadic, with periods where the strength remains stable for years followed by deterioration [13]. Some patients maintain ambulation into the fifth decade of life, but up to 30 percent require noninvasive ventilation.

In a study that screened 102 patients with a suspected diagnosis of sporadic Duchenne or Becker muscular dystrophy who were negative for dystrophin gene deletions or duplications, a pathogenic FKRP variant that causes LGMD R9 was found in 13 percent of patients [56]. This result suggests that a substantial number of patients with a phenotype of Duchenne or Becker muscular dystrophy who are negative for dystrophin gene mutations may have a form of LGMD and should be tested for pathogenic variants in FKRP. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

LGMD R11, POMT1-related (previously LGMD2K) is characterized by intellectual disability and abnormal alpha-dystroglycan [58], and is caused by pathogenic variants in the POMT1 gene encoding the protein-O-mannosyltransferase 1 [59,60]. The same gene is associated with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A or MDDGA), which includes the phenotypes known as Walker-Warburg syndrome and muscle-eye-brain disease. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Dystroglycanopathies'.)

LGMD R14, POMT2-related (previously LGMD2N) is caused by pathogenic POMT2 variants [61,62]. Weakness primarily involves hamstring, paraspinal, and gluteal muscles [63]. Nearly all patients have cognitive impairment.

LGMD R15, POMGnT1-related (previously LGMD2O) is caused by pathogenic variants of POMGnT1. The first report was a female with a POMGnT1 mutation who lost ambulation at age 19 years and had hypertrophy of the calves and quadriceps, and severe myopia, but her cognition was normal [64]. Another report described an 11 year-old patient with normal cognition, profound weakness of anterior tibialis and shoulder girdle muscles, and absent reflexes [65].

LGMD R16, alpha-dystroglycan-related (previously LGMD2P) is a rare form of LGMD caused by pathogenic variants in DAG1 and is associated with variable severity, ranging from onset in early childhood with cognitive impairment to asymptomatic hyperCKemia [66-68].

LGMD R19, GMPPB-related (previously LGMD2T) is caused by pathogenic variants in GMPPB that encodes for GDP-mannose pyrophosphorylase B [69]. This is another rare form reported in several unrelated patients with variable clinical expression including microcephaly, intellectual delay, exercise intolerance, increased serum creatine kinase, and muscle biopsy notable for dystrophic findings [51].

LGMD R20, CRPPA-related (previously LGMD2U) is caused by pathogenic variants in the CRPPA gene (also known as the ISPD gene) [70]. Pathogenic CRPPA variants are also causative for phenotypes that include Walker-Warburg congenital muscular dystrophy. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Walker-Warburg syndrome'.)

Other types

LGMD R7, telethonin-related, (previously LGMD2G) is associated with an early foot drop [71,72].

LGMD R13, fukutin-related (previously LGMD2M) is associated with pathogenic variants in the FKTN gene (also known as the FCMD gene) and was first described in three ambulant affected children from two families that share an Israeli origin [73]. Clinical features include onset in infancy, LGMD phenotype, motor deterioration after febrile viral illnesses, marked serum creatine kinase elevations, normal intelligence and brain structure, and treatment responsiveness to glucocorticoid therapy. Two brothers of Japanese and White ancestry with juvenile onset of symptoms, high serum creatine kinase, normal cognitive development, and LGMD phenotype had compound heterozygosity for two FKTN missense variants [74]. Pathogenic variants involving the FKTN gene are more commonly associated with Fukuyama congenital muscular dystrophy in Japanese populations; therefore, the two conditions are allelic. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Fukuyama type'.)

LGMD D1, DNAJB6-related (previously LGMD1D) is characterized by adult-onset, slowly progressive muscle weakness with mild dystrophic changes, vacuoles, and abnormal protein aggregation on muscle biopsy [75-78]. The disorder is caused by autosomal dominant pathogenic variants in the DNAJB6 gene [79-81]. LGMD1 was the most common autosomal dominant form in an Italian registry of 370 patients [82].

LGMD D2, TNP03-related (previously LGMD1F) is caused by autosomal dominant pathogenic variants in the TNPO3 gene [83-85].

LGMD D3, HNRNPDL-related (previously LGMD1G), is caused by pathogenic variants in HNRNPDL [86,87].

EVALUATION AND DIAGNOSIS

When to suspect LGMD — The diagnosis of LGMD is suspected in patients who present with progressive weakness and muscle atrophy mainly involving the shoulder girdle, the pelvic girdle, or both, particularly if there is a family history of a similar disorder. An online algorithm (ALDA – Automated LGMD Diagnostic Assistant) provided by the Jain Foundation is a useful guide to the diagnosis of the more common presentations of LGMD subtypes [88].

Genetic testing is the principle method for confirming the diagnosis.

Referral to specialist — In general, patients with suspected muscular dystrophy should be referred to a specialist or center with expertise in neuromuscular disorders (where available) for evaluation and diagnosis, particularly because of the high degree of heterogeneity and overlap among the different subtypes of LGMD. Furthermore, a number of neuromuscular conditions characterized by proximal-predominant muscle weakness are more prevalent than LGMD, and should be excluded early in the evaluation [89]. The list includes the dystrophinopathies (Duchenne [DMD] and Becker muscular dystrophy [BMD]), acquired muscle disorders such as toxic, endocrine, and autoimmune myopathies, and nonmuscle disorders such as myasthenia gravis and spinal muscular atrophy. Pompe disease should also be excluded because it is treatable. (See 'Differential diagnosis' below.)

History and examination — The history of the presenting illness and past medical history should include questions about early gross motor development, presence of toe walking, onset and progression of neuromuscular symptoms, and any history of complications (eg, cardiac).

It is also important to obtain a thorough family history to determine ethnicity and likely inheritance pattern (eg, autosomal dominant, autosomal recessive, X-linked) of neuromuscular symptoms.

A detailed neurologic examination should determine the pattern of any muscle weakness (eg, limb-girdle, humeroperoneal, distal) and presence of muscle atrophy or hypertrophy (eg scapular winging, calf hypertrophy).

Laboratory studies — We obtain serum creatinine kinase for all patients with suspected myopathy. Serum creatine kinase concentration is usually modestly elevated in LGMD. However, it can be very high in certain LGMDs, including sarcoglycanopathies; dysferlinopathies; LGMD R9, FKRP-related (previously LGMD2I); and rippling muscle disease due to caveolinopathy.

Other studies are useful for excluding conditions in the differential diagnosis:

Tests that can help to distinguish toxic, endocrine, and autoimmune myopathies from inherited conditions (eg, LGMD) include:

Thyroid function testing (for hypothyroid myopathy)

Parathyroid hormone levels (for hyperparathyroid myopathy)

Calcium, phosphorus (for hyperparathyroid myopathy)

Metabolic panel

Serum lactic acid (for mitochondrial myopathies or encephalomyopathies)

C-reactive protein (CRP; for inflammatory myopathies)

Erythrocyte sedimentation rate (ESR; for inflammatory myopathies)

Anti-nuclear antibodies (ANA; for inflammatory myopathies)

Rheumatoid factor (for rheumatoid arthritis, inflammatory myopathies)

Factor VIII antigen (for inflammatory myopathies, vasculitis)

Anti-HMGCR and anti-SRP antibodies, even if no statin exposure (for immune-mediated necrotizing myopathy)

Antibodies to cytoplasmic 5'-nucleotidase (cN1A; NT5C1A [for inclusion body myositis])

Acid alpha-glucosidase enzyme activity assay can help exclude Pompe disease if testing for pathogenic variants in GAA is not included in the LGMD gene panel.

Electromyography — Electromyography typically shows myopathic changes with small polyphasic potentials.

Muscle imaging — Magnetic resonance imaging (MRI) of muscle can help to define the pattern of muscle involvement and is also useful if there is suspicion for inflammatory myopathies. MRI can demonstrate areas of muscle inflammation, edema with active myositis, fibrosis, fatty replacement, and calcification. As an example, leg MRIs of patients with sarcoglycanopathies typically reveal fatty replacement and fibrosis in the thigh adductors, glutei, and posterior thigh muscles, with a proximal to distal gradient of vastus lateralis involvement [90]. Unlike muscle biopsy, MRI can assess large areas of muscle (eg, both thighs), thereby avoiding problems with sampling error. A limitation of MRI is that the muscle changes can be nonspecific and may not distinguish the changes of muscular dystrophy from those that occur in inflammatory myopathy, rhabdomyolysis, or metabolic myopathy. Additionally, denervation may also present with muscle edema on MRI that is radiographically indistinguishable from that of myositis.

Genetic testing — For patients suspected of having LGMD, broad genetic testing (rather than muscle biopsy) has moved to the forefront of diagnostic investigations [2]. Broad genetic testing should be obtained with an LGMD or neuromuscular gene panel, which analyzes multiple genes associated with LGMDs and other muscular dystrophies/myopathies. Whole-exome sequencing or whole genome sequencing can be used if gene panel sequencing is not diagnostic [91,92]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

This approach is replacing single-gene testing, which requires that the clinical findings point to a particular subtype of LGMD, as guided by the inheritance pattern, age at onset, pattern of muscle weakness, and associated features such as cardiac or respiratory involvement [1]. Single-gene testing may be directed to CAPN3 (calpainopathies); DYSF (dysferlinopathies); COL6A1, COL6A2, and COL6A3 (collagenopathies); SGCA, SCGB, SGCG, and SGCD (sarcoglycanopathies); ANO5 (anoctaminopathies); FKRP (dystroglycanopathies); and other LGMD genes. Genetic testing for FKRP is indicated in all patients with a DMD/BMD phenotype and no detectable dystrophin gene mutations, and testing for LMNA is indicated in patients with an Emery-Dreifuss muscular dystrophy phenotype.

Muscle biopsy — A muscle biopsy is appropriate if genetic and protein testing for LGMD is uninformative or unavailable. A muscle biopsy reveals dystrophic changes with degeneration and regeneration of muscle fibers, fiber-splitting, internal nuclei, fibrosis, moth-eaten, and whorled fibers.

Immunohistochemical testing – In cases of LGMD, a specific biopsy diagnosis (eg, alpha-sarcoglycanopathy) may be achieved via immunohistochemical testing with antibodies directed against dystrophin, alpha and beta dystroglycans, merosin (LGMD R23 laminin alpha-2-related), dysferlin, sarcoglycans (alpha-, beta-, gamma-, and delta-), and other LGMD-related proteins [93]. While antibodies against most proteins are commercially available, muscle biopsy immunohistochemistry testing has been superseded by the availability of DNA testing for most LGMD subtypes.

When a biopsy that suggests a myopathic process is accompanied by normal DNA testing and normal immunohistochemistry for all the above-mentioned proteins, testing for myotilin (myofibrillar myopathy), telethonin (LGMD R7 telethonin-related), TRIM32 (LGMD R8 TRIM 32-related), titin (LGMD R10 titin-related), or other LGMD genes (table 1 and table 2) may be needed [71,94-97].

Muscle RNA sequencing – If next-generation sequencing and conventional muscle biopsy are indeterminate, we try to do muscle RNA sequencing in a research or commercial laboratory, despite the high cost, if insurance approval can be obtained. Muscle RNA sequencing can detect pathogenic variants caused by pseudoexons, skipped exons due to alternative splicing, exon deletions/duplications, small-scale mutations, post-transcription modifications, structural variants, gene fusions, and other changes.

DIFFERENTIAL DIAGNOSIS — There is a broad differential diagnosis for proximal-predominant muscle weakness [89]. The list includes inherited muscle disorders, acquired muscle disorders, and nonmuscle disorders. Note that many conditions (Duchenne and Becker muscular dystrophy, acquired toxic, metabolic, endocrine, and autoimmune myopathies, and nonmuscle disorders such as myasthenia gravis and spinal muscular atrophy) are more prevalent than LGMD and should be excluded early in the evaluation of patients with suspected LGMD.

The history can inform the differential; acquired myopathies typically have an acute or subacute onset, whereas genetic myopathies typically have a chronic course. Tests that can help to distinguish toxic, endocrine, and autoimmune myopathies are reviewed above. (See 'Laboratory studies' above.)

The main considerations in the differential are listed below.

Hereditary muscle disorders

Dystrophinopathies – The pattern of weakness in LGMD is reminiscent of Duchenne muscular dystrophy (DMD), and patients with a phenotype of DMD and Becker muscular dystrophy (BMD) fulfill the revised definition for LGMD [4]. However, DMD and BMD were not included in the revised classification for LGMD because they are well-established disease entities. In a male child with muscular weakness and a serum creatine kinase level of >1000 units/L or 10 times the upper limit of normal, in whom nonmyopathic motor unit disorders (eg, spinal muscular atrophy) are less likely, gene mutation analysis for a disease-causing mutation of the DMD gene should be obtained. Such testing should also be obtained in girls with similar serum creatine kinase elevation who are suspected of being symptomatic DMD/BMD carriers. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

An affected child with autosomal recessive LGMD, particularly one with LGMD R9 FKRP-related (previously LGMD2I), may be indistinguishable on examination from a child with Duchenne or Becker muscular dystrophy. However, unlike Duchenne muscular dystrophy, cognitive function is typically normal in children with autosomal recessive LGMDs. Exceptions are certain dystroglycanopathies like LGMD R11 POMT1-related (previously LGMD2K), which is associated with intellectual disability when presenting early in life. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

Laminopathies and Emery-Dreifuss muscular dystrophy – Laminopathies are caused by mutations in the LMNA gene encoding lamin A/C and encompass a number of conditions with diverse phenotypes [98,99], including autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). Note that some patients with pathogenic variants in LMNA and limb-girdle or humeroperoneal weakness were previously considered to have autosomal dominant LGMD1B in the old classification (table 2), but because of the significant overlap with autosomal dominant EDMD, these are now excluded from the LGMD classification and reclassified as EDMD [4]. (See "Emery-Dreifuss muscular dystrophy", section on 'Laminopathies'.)

The onset of EDMD is usually in the first or second decade of life. The major features are early contractures, slowly progressive humeroperoneal muscle weakness and wasting, and a cardiac involvement. The disorder exhibits significant variability both within and between families. There are X-linked, autosomal dominant, and autosomal recessive forms of EDMD. Genetic testing may confirm the diagnosis.

Caveolinopathies and rippling muscle disease – Caveolinopathies are caused by pathogenic variants in the caveolin 3 gene (CAV3). Caveolin acts as a scaffolding protein in the formation of caveolae, which are small invaginations of the cell membrane involved in T-tubule formation [100,101]. Caveolin 3 localizes to the sarcolemma of skeletal and cardiac muscle and plays a role in signal transduction, sodium channel function, vesicular trafficking, and maintenance of plasma membrane integrity [102].

The phenotypes of caveolinopathies are broad and partially overlapping; they include asymptomatic creatine kinase elevation, myalgias and cramps, rippling muscle disease, distal myopathy, and limb-girdle weakness (ie, LGMD). Familial isolated hypertrophic cardiomyopathy has also been described [103]. The LGMD phenotype of pathogenic CAV3 variants was previously recognized as LGMD1C in the old classification system [104]. However, since the main clinical features are similar to rippling muscle disease, LGMD1C was excluded from the new classification [4], as listed in the table (table 2).

Rippling muscle disease (RMD) is an allelic autosomal dominant genetic disorder with a phenotype that overlaps that of LGMD [104-107]. While some patients with RMD have mutations in the CAV3 gene, sporadic immune-mediated cases associated with myasthenia gravis have also been reported [108-110]. RMD disease typically starts in childhood or adolescence with myalgias, cramps, and stiffness induced by exercise, but rarely presents in adulthood [111]. The most frequently affected muscles are the quadriceps and biceps brachii. Associated muscle hypertrophy, particularly of the calves, is common. Direct percussion of muscle produces continuous rolling, rippling waves of muscle contractions that spread across the muscle, sometimes with a distinctive rapid muscle contraction, and in some patients with a painful mounding up of the muscle. Percussion of muscle may also produce a contraction very similar to percussion myotonia. Muscle rippling is accompanied by needle electromyographic silence. In the absence of family history of RMD, an evaluation for myasthenia gravis may be necessary, particularly if genetic testing for CAV3 mutations is negative. In patients with severe stiffness and painful cramps, treatment with dantrolene sodium or benzodiazepines may be helpful [111,112].

Although inheritance is autosomal dominant, the lack of a family history does not exclude the diagnosis of RMD. Laboratory testing shows a 3- to 25-fold elevation of creatine kinase [104], and muscle biopsy demonstrates nonspecific myopathic findings with normal sarcoglycan, merosin, and dystrophin staining [104,105]. However, staining for caveolin 3 may be reduced or absent in the sarcolemma, and electron microscopy shows diminished density or loss of caveolae in the muscle membranes. Genetic testing confirms the diagnosis.

Pompe disease – The juvenile and adult forms of Pompe are characterized by skeletal myopathy, usually in a limb-girdle distribution, and a protracted course leading to respiratory failure. Pompe disease was previously classified as an LGMD (designated LGMD2V), but it is excluded in the new classification system (table 2) [4]. It is caused by pathogenic variants in the GAA gene. Gene sequencing is the preferred test to confirm the diagnosis, which can also be made by demonstration of reduced acid alpha-glucosidase activity in leukocytes, fibroblasts, or muscle. (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)".)

RYR1-related myopathies – Pathogenic variants in RYR1 have been implicated as a cause of a broad range of phenotypes and disorders, including a number of congenital myopathies (central core disease, multiminicore disease, centronuclear myopathy, and congenital fiber type disproportion), an LGMD phenotype, distal myopathy, and malignant hyperthermia susceptibility [2,113,114]. The diagnosis is made by genetic analysis. (See "Congenital myopathies" and "Susceptibility to malignant hyperthermia: Evaluation and management".)

Facioscapulohumeral muscular dystrophy – The typical or classic form of facioscapulohumeral muscular dystrophy is characterized by muscle weakness involving the facial, scapular, upper arm, lower leg, and abdominal muscles. However, the face may be spared in variant forms (eg, scapulohumeral dystrophy phenotype with facial sparing). Genetic testing is the principle method for confirming the diagnosis. (See "Facioscapulohumeral muscular dystrophy".)

Myofibrillar myopathies – Myofibrillar myopathies are a group of rare, genetically heterogeneous disorders characterized by slowly progressive muscle weakness, which usually involves distal or proximal and distal muscles, but can sometimes occur in a limb-girdle distribution [115-117]. Cardiac involvement is frequent. The diagnosis is based upon clinical features, muscle biopsy, and genetic analysis. Pathogenic variants in 17 or more genes have been linked to a myofibrillar myopathy phenotype [117].

In the old LGMD classification, some phenotypes of myofibrillar myopathy were considered as forms of LGMD; these were designated as LGMD1A caused by pathogenic variants in MYOT, LGMD1E caused by autosomal dominant pathogenic variants in DES, and LGMD2R caused by autosomal recessive pathogenic variants in DES. These subtypes are no longer considered to be forms of LGMD [4]; reasons for exclusion from the new LGMD classification system are noted in the table (table 2).

Metabolic myopathies – Metabolic myopathies can be caused by glycogen storage diseases, disorders of lipid metabolism, and mitochondrial diseases. Most patients with a metabolic myopathy have dynamic rather than static symptoms, and therefore complain of exercise intolerance, muscle pain, and muscle cramps rather than fixed weakness with exercise. Nevertheless, some patients may develop progressive muscular weakness that is usually proximal in distribution. A general approach to the diagnosis of metabolic myopathies is presented elsewhere. (See "Approach to the metabolic myopathies".)

Acquired muscle disorders

Toxic, endocrine, and autoimmune myopathies – In most acquired myopathies, muscle weakness is mainly proximal. The diagnosis is suspected based upon the clinical setting and associated systemic manifestations. However, the diagnosis of such a myopathy can be difficult to establish if it is the presenting manifestation of an endocrine or autoimmune disease (eg, polymyositis). Observational reports suggest that a significant proportion of patients with LGMD R2, dysferlin-related (previously LGMD2B) were initially misdiagnosed with polymyositis and treated with immune therapies without benefit [2]. (See "Myopathies of systemic disease", section on 'Endocrine myopathies' and "Drug-induced myopathies" and "Pathogenesis of inflammatory myopathies" and "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations" and "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Clinical manifestations and diagnosis of inclusion body myositis" and "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis".)

Nonmuscle disorders

Myasthenia gravis – The cardinal feature of myasthenia gravis is fluctuating skeletal muscle weakness. Involvement of the limbs in generalized myasthenia typically produces proximal weakness similar to other muscle diseases. Unlike LGMD, ptosis, diplopia, and facial weakness are common though not universal features of myasthenia gravis. However, occasional patients present with proximal limb weakness alone. In particular, congenital myasthenic syndromes may have a limb-girdle pattern of weakness, particularly those that present after infancy (eg, Dok-7 myasthenia syndrome) [2]. The diagnosis of myasthenia gravis should be confirmed, if possible, by immunologic and/or electrophysiologic testing. Genetic testing is necessary to confirm the diagnosis of congenital myasthenic syndromes. (See "Clinical manifestations of myasthenia gravis" and "Neuromuscular junction disorders in newborns and infants", section on 'Congenital myasthenic syndromes' and "Diagnosis of myasthenia gravis".)

Spinal muscular atrophy – In many cases of suspected LGMD, the inheritance pattern cannot be determined. Although uncommon or rare, sporadic presentations of autosomal dominant LGMD and even autosomal recessive LGMD with modest creatine kinase elevation may be clinically indistinguishable from spinal muscular atrophy type 3, which can have a modest creatine kinase elevation (<1000 units/L). Electromyography is particularly useful in this setting for differentiating a neurogenic from a myopathic process and determining whether to proceed with genetic testing for possible spinal muscular atrophy versus genetic testing and/or a muscle biopsy for a potential myopathy. (See "Spinal muscular atrophy", section on 'Diagnosis'.)

MANAGEMENT — The management of LGMD is supportive; no disease-modifying treatments are available. Goals of therapy include maintaining mobility and functional independence, managing associated complications, and maximizing quality of life [1]. Multidisciplinary treatment involving physical and occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics at centers with experience in neuromuscular disorders is recommended to provide optimal care.

Rehabilitative therapies and exercise — An important aspect of care in LGMD is the prevention of contractures, which can result in substantial disability. A passive stretching physical therapy program should be instituted early.

Preliminary evidence from a study of nine ambulatory adult patients with LGMD R9, FKRP-related (previously LGMD2I) suggested that low-intensity aerobic exercise may be safe and beneficial [118]. Another small study found that patients with LGMD who had low and high intensity resistance training showed increased muscle strength and endurance [119]. Although these data are not definitive, they suggest that low-impact aerobic exercise and supervised submaximal strength training routines are probably safe for patients with LGMD [1]. Confirmation of these findings in larger trials is needed before exercise can be routinely recommended for patients with LGMD.

Based upon theoretical concerns that patient with muscular degeneration due to muscular dystrophy are at increased risk for exercise-induced muscle injury, national guidelines advise that patients with muscular dystrophy should maintain adequate hydration, avoid supramaximal, high-intensity exercise, and avoid exercising to exhaustion [1]. In addition, they should be informed about warning signs of excessive exercise and myoglobinuria, which include feeling weaker rather than stronger within 30 minutes after exercise, excessive muscle soreness 24 to 48 hours after exercise, severe muscle cramping, feeling heaviness in the limbs, and prolonged shortness of breath. These symptoms suggest that the exercise program is too aggressive and should be reduced.

There are only limited data supporting the use of other rehabilitative therapies for LGMD, such as bracing, assistive devices, and computer-based interventions [1].

Cardiac complications — Many subtypes of LGMD have associated cardiac involvement, including LGMD D1 DNAJB6-related (previously LGMD1D), the sarcoglycanopathies, and many of the dystroglycanopathies. In many cases, patients with these subtypes lack overt symptoms of cardiac disease that may herald cardiac morbidity or sudden death [1]. Therefore, all patients with these LGMD subtypes and those with an LGMD phenotype who do not have a specific genetic diagnosis should have a baseline cardiology evaluation that includes examination, ECG, and structural heart studies with echocardiography or cardiac MRI to guide management [120]. Patients with abnormal findings on these studies or those with symptoms suggesting arrhythmias (eg, dizziness, palpitations, or syncope) should have prolonged cardiac event monitoring. Patients with the sarcoglycanopathies and LGMD R9, FKRP-related (previously LGMD2I) who are asymptomatic with normal cardiac findings should have follow-up cardiac evaluations every two years to include examination, ECG, and echocardiography; patients with abnormal cardiac findings should have such follow-up annually [120]. Heart transplantation has been successful in some patients with LGMD R9, FKRP-related (previously LGMD2I) who developed severe congestive failure [121].

Pulmonary complications — A few LGMDs (eg, LGMD R9, FKRP-related [previously LGMD2I]) are associated with weakness of respiratory or oropharyngeal muscles and an increased risk of respiratory failure with disease progression [1]. Similar to cardiac involvement, patients with respiratory compromise due to LGMD often lack symptoms that herald the onset of respiratory failure. Therefore, patients at risk for pulmonary complications should have pulmonary function testing or referral for pulmonary evaluation at the time of diagnosis. Periodic pulmonary function testing or pulmonary follow-up is indicated if testing identifies pulmonary disease or if the LGMD subtype is associated with a high risk of respiratory failure.

Patients with LGMD who have evidence of respiratory insufficiency, daytime somnolence, or symptoms of sleep-disordered breathing may benefit from noninvasive ventilation [1].

Swallowing and feeding complications — Dysphagia and arm weakness associated with LGMDs can lead to difficulties maintaining adequate nutrition [1]. Patients with inadequate intake, swallowing problems, aspiration, or weight loss should be evaluated with swallowing studies or referred to a gastroenterologist. Such patients may benefit from techniques to improve swallowing, such as altering food consistency or use of the chin tuck maneuver, or placement of a feeding tube.

Orthopedic complications — Individuals with LGMD may be at increased risk for musculoskeletal spine deformities, including kyphosis or scoliosis [1]. Patients who develop spine deformities should be referred to an orthopedic specialist for evaluation and surgery, if needed, to maintain optimal posture, mobility, and cardiopulmonary function.

Investigational therapies — Gene replacement, editing, and modulation; myoblast transplantation; and small molecule therapies are under study for the treatment of various LGMD subtypes. However, only limited data are available, and the effectiveness and safety of these interventions remains to be determined [1].

PROGNOSIS — The prognosis of LGMD is variable. In most autosomal recessive cases of LGMD, weakness occurs early and leads to significant disability during childhood [122]. In other cases, particularly those inherited in an autosomal dominant fashion, the weakness may not be apparent until early or even late in adult life. The course is usually one of slowly progressive, mostly symmetric weakness, with the exception of a few types with rapid progression or asymmetric weakness [1]. The prognosis for the more common individual subtypes of LGMD is discussed above. (See 'Clinical features and genetics' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Muscular dystrophy (The Basics)")

Beyond the Basics topics (see "Patient education: Overview of muscular dystrophies (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Limb-girdle muscular dystrophy (LGMD) includes a number of disorders with heterogeneous etiologies. It is defined as a genetically inherited condition that primarily affects skeletal muscles and presents with progressive, predominantly proximal muscle weakness due to a loss of muscle fibers. (See 'Definition and nomenclature' above.)

LGMDs are inherited in an autosomal recessive or autosomal dominant pattern. In a new classification system (table 1), the LGMD abbreviation is retained, but the mode of inheritance is designated by the letter "D" for dominant and "R" for recessive, the order of discovery is designated by a number, and the affected protein is listed. Thus, the format is "LGMD, inheritance (R or D), order of discovery (number), affected protein" [4]. (See 'New classification' above.)

Together, the group of disorders that constitute LGMD are the fourth most common genetic cause of muscle weakness, with an estimated minimum prevalence between 10 and 23 per 100,000. The age of onset of LGMD varies from early childhood to adulthood. (See 'Epidemiology' above.)

Weakness in LGMD may affect the shoulder girdle (scapulohumeral type), the pelvic girdle (pelvifemoral type), or both. Facial weakness is usually mild and, in some cases, totally absent. Extraocular muscles are completely spared in the LGMDs. Distal muscle strength is usually preserved, even at the late stage of the disease. Intellect is usually normal. (See 'General features' above.)

Many of the subtypes of LGMD have distinguishing though nonspecific clinical characteristics. They are discussed above. (See 'Clinical features and genetics' above.)

For patients suspected of having LGMD, we suggest genetic testing prior to obtaining a muscle biopsy. Broad genetic testing should be obtained with an LGMD or neuromuscular gene panel, which analyzes multiple genes associated with LGMDs and other muscular dystrophies/myopathies. A muscle biopsy is appropriate if genetic and protein testing for LGMD is uninformative or unavailable. Muscle biopsy can also be used for muscle RNA sequencing if genetic testing results are negative or ambiguous. (See 'Evaluation and diagnosis' above.)

A number of conditions characterized by proximal-predominant muscle weakness are more prevalent than LGMD and should be excluded early in the evaluation. The list includes the dystrophinopathies (Duchenne and Becker muscular dystrophy), acquired muscle disorders such as toxic, endocrine, and autoimmune myopathies, and nonmuscle disorders such as myasthenia gravis and spinal muscular atrophy. Pompe disease should also be excluded because it is treatable. (See 'Differential diagnosis' above.)

The management of LGMD is supportive; no disease-modifying treatments are available. Goals of therapy include maintaining mobility and functional independence, managing associated complications, and maximizing quality of life. Multidisciplinary treatment involving physical and occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics is recommended to provide optimal care. (See 'Management' above.)

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Topic 6190 Version 42.0

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