Limb-girdle muscular dystrophy refers to a group of genetic disorders that cause progressive weakness and wasting of the skeletal muscles, predominantly around the shoulders and hips.
Signs and symptoms
Most patients present with a history of progressive, symmetric, proximal muscle weakness that starts in childhood to young adulthood. Pelvic muscle weakness is most often the first symptom. Other features may include the following:
Asymmetric or distal weakness (rare)
Respiratory failure
Cardiomyopathy, cardiac arrhythmias
Scapular winging
Calf hypertrophy
Contractures
See Clinical Presentation for more detail.
Diagnosis
Muscle biopsy and genetic testing are the most important tools used in the diagnostic evaluation of patients in whom limb-girdle muscular dystrophy (LGMD) is suspected.
Serum creatine kinase level is complementary, and may be significantly elevated in some forms of LGMD, especially the autosomal recessive LGMDs.
Magnetic resonance imaging (MRI) of muscles can help differentiate some forms of LGMD.
See Workup for more detail.
Management
Although causative gene mutations have been well characterized for LGMD, no specific treatment is available for any of the LGMD syndromes yet.
Supportive care is essential to preserve muscle function, maximize functional ability, and prolong life expectancy.
Use of passive stretching, bracing, and orthopedic procedures allow the patient to remain independent for as long as possible.
Orthopedic surgery may be needed to help correct or prevent contractures and scoliosis.
Walton and Nattrass first proposed limb-girdle muscular dystrophy (LGMD) as a nosological entity in 1954.[1] Their definition included the following characteristics:
Expression in either male or female sex
Onset usually in the late first or second decade of life (but also middle age)
Usually autosomal recessive and less frequently autosomal dominant
Primary involvement of shoulder or pelvic-girdle muscles with variable rates of progression
Variable rates of progression
Severe disability within 20–30 years
Muscular pseudohypertrophy, contractures uncommon
Their definition was primarily reliant on phenotypic appearance, and thus included a heterogenous groups of disorders, including some that were not truly LGMD.
In 1995, an alphanumeric system of LGMD classification was introduced. This assigned a number based on mode of inheritance (1: autosomal dominant; 2: autosomal recessive), and an alphabet based on the order of discovery of linkage to a specific, certain genetic locus or a new disease gene. At the time of this writing, more than 30 genetic subtypes of LGMD have been identified. As the list continued to expand, a lack of consensus on nomenclature was evident, once classification exceeds LGMD 2Z. As of 2017, there are 34 types of LGMD detailed in the OMIM database.
Notably, LGMD subtypes are phenotypically highly variable, limb-girdle weakness may not be the predominant presentation, and mutation in genes assigned to LGMD subtypes may cause allelic conditions with a different phenotype. For example, mutations in TTN gene may present with a wide range of phenotypes ranging from congenital myopathy to late-onset distal myopathy.[2]
The 229th ENMC international workshop has proposed that for a condition to be considered LGMD, the following conditions must be fulfilled:[3]
Condition must be described in at least two unrelated families
Affected individuals must have achieved independent walking
Evidence of elevated serum creatine kinase (CK) activity
Presence of degenerative changes on muscle imaging over the course of the disease
Presence of dystrophic changes on muscle histology; development of end-stage pathology for the most affected muscles, over time
Application of this definition has led to exclusion of 10 conditions from the previous LGMD umbrella, including myofibrillar myopathy (LGMD1E).[3] The new proposed LGMD subtype classification system follows the formula: “LGMD, inheritance (R [recessive] or D [dominant]), order of discovery (number), affected protein.” In the absence of an identified pathogenic gene, phenotypic presentations that fulfill the above definition criteria are referred to as "LGMD unclassified."
Table 1. Conditions that are no longer considered LGMD, as per the definition proposed by the 229th ENMC international workshop, 2017
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See Table
Table 2. New classification of LGMD with relevant affected protein
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See Table
The old classification system, with reference to new nomenclaure, is retained here for description.
Although not truly limb-girdle syndromes, diseases classified as myofibrillar myopathies share several phenotypic characteristics with the LGMDs. They are usually adult-onset diseases with slowly progressive weakness involving proximal (and distal) muscles. Many patients have respiratory failure, cardiomyopathy, and neuropathy. Some mutations can cause both a myofibrillar myopathy and a muscular dystrophy phenotype. X-linked limb girdle dystrophies (dystrophinopathies, Emery–Dreifuss, McLeods Syndrome, and vacuolar) are described elsewhere.
LGMD is caused by mutations in genes encoding for proteins constituting the sarcolemma, cytosolic contents, or nucleus of muscle cells (myocytes). Given the heterogenous nature of mutations, mechanism of myocyte damage and muscle fiber degeneration may variably include errors in protein complex formation, functional or structural errors in the contractile apparatus, sarcolemmal instability, enzymatic abnormalities, or errors in repair mechanisms. With accumulating damage, there is eventual deposition and replacement of muscle by fibrotic and adipose tissue. Although the primary defect in many LGMDs is known, the precise mechanism leading to the dystrophic phenotype has not always been elucidated. Specific protein function and abnormalities are discussed below with each LGMD.
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Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, dysferlin, and caveolin-....
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Schematic of the sarcomere with labeled molecular components that are known to cause limb-girdle muscular dystrophy or myofibrillar myopathy. Mutation....
There is considerable overlap of the LGMD phenotype with other hereditary myopathies. Often, mutations in the same gene lead to phenotypes variably characterized as LGMD or as congenital muscular dystrophy, myofibrillar myopathy, or less commonly as Emery-Dreifuss muscular dystrophy, congenital myasthenic syndrome, congential myopathy, or metabolic myopathy. Most of these are discussed in separate chapters, but mutations causing myofibrillar myopathy are discussed in this article. Of interest, several mutations that result in myofibrillar myopathy are in genes that code for Z-disk proteins.
LGMD subtypes based on pathophysiological mechanism:[4]
Autosomal recessive LGMDs (LGMDR) are more common than the autosomal dominant forms of the disease (LGMDD), which probably account for about 10% of all LGMDs. The pooled prevalence of LGMD syndromes has been estimated to be 1.63 per 100,000 (range 0.56–5.75).
Different populations often have different frequencies of the various LGMDs.
Several studies throughout the world have estimated the frequency of LGMDs based on immunochemical and genetic testing.[5, 6, 7, 8, 9] In many studies, LGMD2A is the most common, accounting for 8–26% of all LGMDs. In some populations, it may be the only LGMD present (Reunion Island, Basque Country) with very high prevalence rates (48–69 cases per million). LGMD2B is also relatively common, accounting for 3–19% of all LGMDs. LGMD2I is common in certain parts of Northern Europe (Denmark and parts of England), but worldwide frequencies outside this area account for 3–8% of all LGMDs.
The sarcoglycanopathies as a group (LGMD2C-LGMD2F) are a common cause of LGMDs, accounting for 3–18%, with a high percentage of severe cases. As with other LGMDs, different sarcoglycanopathies are overrepresented or underrepresented in different populations, with some populations having representative cases of all 4 sarcoglycanopathies and other populations having only 1 mutation type, which is probably related to founder effects and population inbreeding (consanguinity). LGMD2C is common in Tunisia; LGMD2D is common in Europe, the United States, and Brazil; and LGMD2E and LGMD2F are common in Brazil. Overall, LGMD2D (α-sarcoglycanopathy) is twice as common as LGMD2C (γ-sarcoglycanopathy) and LGMD2E (β-sarcoglycanopathy), and LGMD2F (δ-sarcoglycanopathy) is the rarest.
All the congenital muscular dystrophies can present with a LGMD phenotype, and OMIM recognizes 4 at this time (LGMD2I, LGMD2K, LGMD2M, LGMD2N).
Morbidity and mortality rates vary. In general, early onset forms tend to have a rapid course.
Patients with severe forms may become wheelchair bound in their early teens and die from respiratory complications in their late teens.
Patients with slowly progressive LGMD may retain independent ambulation into middle age. Some patients with confirmed mutations have had nearly normal strength.
LGMD is reported in races and countries throughout the world. It is the fourth most common muscular dystrophy after dystrophinopathies, myotonic dystrophies, and fascioscapulohumeral dystrophy.
Autosomal dominant and autosomal recessive forms of LGMD affect both sexes equally.
The age of onset varies among the different mutations. It also can vary amongst families and family members with the same mutation. Reported age of onset of LGMDs is between 1 and 50 years, although some patients may be asymptomatic. Myofibrillar myopathies can present in the first decade of life up until the 60s or 70s.
Clinical presentation is most often with progressive, symmetrical, predominantly proximal weakness. Distal predominant presentations may be seen in some LGMD types. Variable associated systemic features or other organ system involvement may be noted and is often useful in identification of LGMD type.
Autosomal recessive LGMD
All patients have a history of progressive, proximal muscle weakness. Described below are the major distinguishing characteristics.
LGMD2A (calpainopathy; LGMDR1 Calpain-3; 15q15)
LGMD2A is likely the most common autosomal recessive LGMD, accounting for up to 30% of all recessive cases. In some areas, including the Basque region of Spain (where a founder mutation is identified), LGMD2A accounts for almost 80% of all cases of LGMD. In other areas, it is quite rare; for example, it accounts for only 6% of LGMD cases in Denmark.
Recently patients carrying a single pathogenic variant in the CAPN3 have been reported, indicating a proportion of dominant inheritance.[10]
About two thirds of patients present at 8–15 years of age (range of 2–40 years).
The most typical presentation is of symmetrical weakness due to scapular-humeral-pelvic weakness, which may be similar to the presentation of facioscapulohumeral dystrophy, but without facial weakness. LGMD2I may also have a similar phenotype.
Muscle weakness is predominant in the axial muscles of trunk and proximal lower limb. Hip-girdle weakness is most prominent in the gluteus maximus and hip adductors. Along with abdominal weakness, this leads to a wide-based, lordotic gait.
Relatively spared muscles include flexor carpi, triceps surae, tibialis posterior and anterior and the sternocleidomastoid.
The combination of scapular winging, severe weakness of hip adductors and elbow flexors, normal respiratory function, and contractures has specificity for LGMD2A.[11] Contractures are usually mild and predominate in the Achilles tendon.
Atrophy is often prominent.
Progression tends to be slow, and wheelchair use begins 11–28 years after the onset of symptoms. Men may show earlier onset and faster progression than women.
The clinical course varies widely among and within families. Age of onset and age at loss of independent ambulation varies between different mutations.
Atypical presentations include a severe Duchenne-like course, exercise-induced stiffness and myalgia before the onset of weakness, and early and clinically significant contractures (especially of the ankles, elbow, and neck) similar to those of Emery-Dreifuss muscular dystrophy.
Presentation with asymptomatic hyperCKemia has been reporte in up to 10% of cases.
Facial and cardiac involvement have not been reported.
LGMD2B (dysferlinopathy; LGMDR22 Dysferlin; 2p13)
LGMD2B is also a common cause of autosomal recessive LGMD, accounting for about 20% of cases in the Brazilian population. However, in some populations (eg, Cajun, Arcadian groups), it accounts for about 40% of cases.
Several phenotypes can occur: Miyoshi myopathy, anterior tibial myopathy, LGMD, and an axial myopathy. A study from France showed 25% with Miyoshi myopathy, 25% with LGMD, and 35% with a combination.[12] Different phenotypes can occur in the same family.
With each phenotype, presentation usually occurs at 15–35 years, but it can be as early as 10 years. There are also rare cases of late presentation after age 70 years.
In the limb-girdle presentation, pelvic and femoral muscles are affected first, with the proximal portions of the arms becoming weak later.
With Miyoshi myopathy, the presentation includes gastrocnemius weakness and difficulty with toe walking. The forearm muscles are weak and atrophic, with sparing of intrinsic hand muscles. As the disease progresses, these 2 modes of presentation usually become indistinguishable.
The most common phenotype (35% of patients) has a mixed picture, with both proximal and distal weakness. Asymmetry may be present. The patient's gait is unique, with a waddling component combined with inability to raise his or her heels off the ground.
A few families have been reported with an anterior tibial myopathy.[13] Progressive weakness involves wrist and finger flexor weakness and biceps. Rare cases present with paraspinal (axial) myopathy.[14]
Interestingly, up to 50% of patients diagnosed with dysferlinopathy report a high degree of physical activity and good muscle prowess before the onset of symptoms.[15]
The disease slowly progresses, and patients are usually confined to a wheelchair 10–30 years after the onset of weakness.
Rare cases present with distal leg pain or swelling with or without weakness or with asymptomatic hyperCKemia.
Misdiagnosis as polymyositis can occur since inflammation can be present on muscle biopsy.
Sarcoglycanopathies (LGMD2C–2F; LGMDR3–R6)
In general, sarcoglycanopathies tend to cause a severe Duchenne-like phenotype, but mild Becker-like phenotypes have been described. Overall, these diseases account for about 20–25% of all LGMDs, but they are overrepresented among severe cases. LGMD2D (α-sarcoglycan [adhalin]) accounts for 40% of the sarcoglycanopathies, LGMD2C and 2E (γ-sarcoglycan and β-sarcoglycan) each account for about 23% and LGMD2F (δ-sarcoglycan) accounts for 14% of cases in the Brazilian population.
Onset is usually at ages 6–8 years, but onset at or before 2 years and as late as the teens (or even adulthood) has been reported.
Some delay in motor milestones is not uncommon.
Weakness affects the hip and abdominal and shoulder musculature. Scapular winging is more common in LGMD2C-2F than in Duchenne muscular dystrophy.
Hypertrophy of the calf is common, and the tongue muscles may become enlarged.
Progression tends to be more rapid than that of other LGMDs, with loss of ambulation usually at 12–16 years but can be as early as 10 years. Patients with a late onset tend to have a more slowly progressive course.
Recently, patients with mild forms of alpha-sarcoglycanopathy have been identified using next-generation sequencing (NGS) targeted gene panels, indicating that milder forms may be underdiagnosed.[16]
Intelligence is normal.
Cardiomyopathy is reported in about 30% of cases and is most common with LGMD2E or 2F.
Progressive weakness leads to restrictive lung disease and hypoventilation and the need for ventilatory assistance.
Death can occur as early as in the second decade of life, although some patients live into adulthood without respiratory assistance.
LGMD2G (LGMDR7 Telethonin; 17q12)
LGMD2D is a rare cause of LGMD, with significant phenotypic variability between and within families.
The typical age of onset is the first to second decade of life. Presentation in infancy with a congenital muscular dystrophy phenotype has been described.[17]
Weakness is predominantly proximal, but one half of patients may present with foot drop and anterior compartment atrophy (leg), and nearly all eventually develop distal leg weakness. Gluteal and thigh atrophy may be prominent.[18]
Calf hypertrophy occurs in about 50%, but some patients have calf atrophy that may resemble Miyoshi myopathy (LGMD2B).
Wheelchair confinement occurs in the third to fourth decade.
Cardiomyopathy occurs in about 50%. Presentation with an isolated, dilated cardiomyopathy has been described.
LGMD2H (LGMDR8 TRIM32; 9q33)
LGMD2H has been observed mostly in the Hutterite people of Manitoba. A few non-Hutterites also have been shown to have LGMD2H and have a more variable phenotype.[19]
This disease is allelic with sarcotubular myopathy (see Congenital Myopathies).
Wide phenotype heterogeneity is reported.
Onset is usually in the second to third decades of life, with limb-girdle weakness and a waddling gait. The proximal arm muscles and the distal leg muscles are involved late.
Back pain and fatigue are common.
Progression is slow, with continued ambulation until around 50 years of age or later.
Other features can include neck flexor weakness, facial weakness, scapular winging, respiratory insufficiency, ankle contractures, and cramps.
Asymptomatic affected individuals with hyperCKemia have been reported.
LGMD2I may be a fairly common cause of autosomal recessive LGMD, causing 11% of all cases in Brazil and 38% of cases in Denmark.
The disease is allelic with congenital muscular dystrophy 1C (MDC 1C). (See Congenital Muscular Dystrophy.)
The presentation of patients with a mutation in fukutin-related protein (FKRP) gene can vary from severe congenital muscular dystrophy to mild, late-onset LGMD.
The LGMD phenotype is variable. Patients can have a severe Duchenne-like presentation with delay in motor milestones, hypotonia, and severe proximal weakness. Progression to wheelchair by the teenage years and restrictive respiratory failure (even when patients are ambulant) is common. Like in Duchenne muscular dystrophy, treatment with corticosteroids may improve strength. The most common presentation is with a Becker-like onset with normal early motor milestones. An adult-onset form occurs at 11–40 years of age and is slowly progressive.
While cognitive impairment is universal in patients with congenital muscular dystrophy due to mutations in FKRP, it is absent or only mild in patients with LGMD2I. Neuropsychological testing shows mild impairment in executive functions and visuospatial planning, without substantial impairment in global and logic IQ, suggesting involvement of frontal and posterior parietal lobes. MRI abnormalities are heterogenous and, when present, always mild, varying from normal-to-mild white matter abnormalities, ventriculomegaly, cerebellar atrophy, and enlarged subarachnoid space. No structural brain abnormalities are noted. There is no correlation between MRI findings and cognitive abnormalities or mutation type.[20]
In a large study in Denmark, 2 groups of patients could be delineated based on genotype-phenotype correlations. Of the 38 patients studied, 27 (71%) had a homozygous mutation (826C>A), while 11 (29%) had a compound heterozygous mutation.[21]
The patients with a homozygous mutation had a later onset (mean of 18 y) and slower progression than patients with a compound heterozygous mutation. Only 15% lost the ability to ambulate by their mid 40s. Presentation with exertional myoglobinuria, calf hypertrophy and cardiomyopathy were all more common than in patients with a compound heterozygous mutation.
The patients with a compound heterozygous mutation had an earlier onset (mean of 5 y) and more rapid progression. All lost the ability to ambulate by their mid 20s. Tongue hypertrophy, more severe respiratory failure, contractures, and spine abnormalities were more common than in patients with a homozygous mutation.
Another large series from Norway found 88 patients (of 326) from 69 families with a mutation in FKRP (prevalence of ≥1 case in 54,000).[22] Seventy-six of these patients were homozygous for the 826C>A mutation, with a generally milder phenotype and a significantly later onset (age 14 y) than the patients with a heterozygous mutation (age 6.1 y). Other common features included difficulty with walking, running, or climbing as the presenting complaint and progression to involve arm weakness. About 20% used a wheelchair and 20% needed ventilatory support at the time of evaluation, about 25 years after onset.
Myoglobinuria (27%) and myalgia or cramps (60%) are common,[23] as can be isolated hyperCKemia.[24]
Cardiac involvement can occur in up to 60% of patients with LGMD2I as measured by reduced left ventricular ejection fraction.[25] There is no clear correlation between severity of cardiac disease and severity of muscle disease. Severely abnormal ejection fraction can occur in about 10% of patients and may cause symptomatic congestive heart failure. Rhythm abnormalities are not present.
LGMD2J (LGMDR10 Titin; 2q24)
LGMD2J onset is at approximately 10–30 years, although one patient presented with weakness in infancy.[26] Proximal weakness progresses slowly, and tibialis anterior weakness may develop.
Wheelchair confinement usually occurs within 20 years, but some patients are ambulant past 60 years.
Occasional asymmetric presentation may be noted. Face is spared.
This disease is allelic, with the much more common presentation of tibial muscular dystrophy (TMD), sometimes called Finnish distal myopathy, the most common muscle disease in Finland. Some family members may have LGMD2J while others may have a TMD phenotype.
TMD presentation is usually in the fourth decade, with tibialis anterior weakness, which may be asymmetric. After many years, proximal weakness may develop. Less common manifestations include onset with proximal weakness, upper limb involvement, generalized weakness in childhood, persistent focal/asymmetric weakness, and mild bulbar/facial weakness.
The disease is also allelic with dilated cardiomyopathy 1G, autosomal recessive congenital myopathy with lethal cardiomyopathy, and hereditary myopathy with early respiratory involvement.
LGMD2K (MDDGC1; LGMDR11 POMT1; 9q34)
The disease is allelic with Walker-Warburg syndrome and mutations in POMT1 cause approximately 20% of Walker-Warburg syndrome cases. (See Congenital Muscular Dystrophy.)
The age of onset is 1–6 years; later onset may be noted.
LGMD2K is characterized by severe proximal muscle weakness with slow progression. Contractures and scoliosis may be present.
Clinical phenotype is inversely correlated with POMT1 activity.
Results of ophthalmologic and funduscopic examinations, including electroretinography, are normal.
Facial dysmorphic features and mental retardation may occur, though brain MRIs are normal in LGMD2K.
LGMD2L (LGMDR12 ANO5; 11p14)
LGMD2L was originally described in French-Canadian families[27, 28] but was later described in British, German, and Chinese patients as well.[29, 30]
Anoctaminopathy is one of the most common adult muscular dystrophies in Northern Europe.
Age of onset is usually between early 20s and 50 years (mean 34 years).
Females may show less severe phenotype.
Common presentation is with proximal shoulder and pelvic girdle weakness. Walking difficulties or standing on the toes is often the presenting complaint. There is often asymmetric quadriceps, hamstring, biceps, brachioradialis, or calf weakness and atrophy. Muscle pain is common. Scapular winging may occur in up to a third of patients.
Facial weakness, hand weakness, and contractures are uncommon.
Progression is slow, and walking is retained. Cardiac and respiratory function is normal.
Asymptomatic hyperCKemia may be noted.
This disease is allelic with distal myopathy MMD3, which presents with calf weakness. Proximal thigh, biceps, and proximal weakness may develop later and may be asymmetric. While patients can present with features more typcial of LGMD2L or MMD3, with progression, phenotypes overlap and merge into a more homogenous picture.MRI - predominant fatty degeneration of the gluteus minimus muscle and of the posterior segments of the thigh and calf muscles with sparing of the gracilis muscle.
LGMD2M (LGMDR13 Fukutin; 9q31)
The disease is allelic with Fukuyama congenital muscular dystrophy and most mutations in fukutin result in a severe phenotype.
Rare cases of LGMD2M have been described due to a mutation in the fukutin gene.[31, 32, 33]
Patients usually present with hypotonia or delayed motor milestones before age 2 years. Progression is moderate, with proximal greater than distal weakness affecting the legs more than the arms, but walking is maintained through the first decade. Joint contractures and calf hypertrophy may be present.
Other features include mild facial weakness, tongue hypertrophy, and contractures.
Some of these children have worsening weakness during febrile illnesses, and like boys with Duchenne muscular dystrophy, their weakness improves with steroids.
Most children had normal intelligence but a few had low IQs. Structural brain abnormalities in in the posterior fossa or cortex may be noted.
LGMD2N (LGMDR14 POMT2; 14q24)
The disease is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).
16 cases have been described with a LGMD phenotype.[34, 35]
Presenting symptoms include delayed motor milestones, difficulties in walking, exercise related muscle pain. Clinically, hip and knee flexors and extensors are maximally affected.
Cognitive impairment and learning difficulties are common. Structural brain abnormalities may be evident on MRI, and include ventricular enlargement, periventricular hyperintensities, and frontal.
On MRI, most affected muscles include hamstrings followed by paraspinal and gluteal muscles.
Calf hypertrophy and scapular winging have been noted.
Muscle biopsy may show inflammatory changes.
LGMD2O (LGMDR15 POMGnT1; 1p32)
This disease is allelic with muscle-eye-brain disease (see Congenital Muscular Dystrophy).
Rare cases are described with a LGMD phenotype. Calf hypertrophy has been noted
LGMD2P (LGMDR16 DAG1; 3p21)
Rare families have been reported with delayed walking, proximal more than distal weakness with slow progression, calf or thigh hypertrophy, occasional Achilles joint contracture, greatly elevated CK, and moderate-to-severe mental retardation.[36]
Brain MRI is normal
α -dystroglycan staining is reduced on muscle immunohistochemistry
LGMD2Q (LGMDR17 Plectin 1f; 8q24)
This disease is allelic with congenital muscular dystrophy with familial junctional epidermolysis bullosa (see Congenital Muscular Dystrophy).
Rare families have been reported with LGMD phenotype without skin manifestations.[37] Onset is in early childhood, with slow progression of proximal more that distal weakness.
Rare ocular involvement and hypertrophic gastrocnemius has been described.
LGMD2R (excluded from new classification)
Rare patients have been reported with a limb girdle phenotype.[38] Features include onset in the second or third decade with slowly progressive proximal and facial weakness. Scapular winging or respiratory involvement may be present. Scoliosis or scapular winging have been reported.
Cardiac symptoms are common, including conduction block and cardiomyopathy.
LGMD2S (LGMDR18 TRAPPC11; 4q35)
Rare patients have been reported with childhood onset of slowly progressive proximal weakness, which involves arms more than legs.[39] Facial weakness, scapular winging, and myalgias are occasionally noted.
There is mild-to-moderate intellectual disability and an infantile-onset hyperkinetic choreiform movement disorder.
Seizures, ataxia, and ocular abnormalities can occur.
LGMD2T (LGMDR19 GMPPB; 3p21)
Rare patients have been reported with a wide range of symptom onset (and severity) from birth to the mid 30s.[40, 41]
Proximal limb girdle weakness with slow progression is seen in all subjects. A preferential involvement of paraspinal and hamstring muscles may be noted.
Additional features can include cramps, calf hypertrophy, rhabdomyolysis, mild cognitive impairment, epilepsy, and cardiac conduction defects.
A more severe phenotype with congenital muscular dystrophy and associated brain and eye abnormalities has been described as in other muscular dystrophies with mutations in genes responsible for glycosylating α-dystroglycan. (see Congenital Muscular Dystrophy).
LGMD2U (LGMDR20 ISPD; 7p21)
Rare patients have been reported with childhood onset (1–12 years) of proximal weakness.[42, 43]
Progression is slow and ambulation is often lost in teenage years, although a few patients were walking in their 40s and 50s.
Cardiomyopathy may be present.
Cognition and MRI are normal in the majority.
Other features can include myoglobinuria, cramps, scapular winging, and calf hypertrophy.
A more severe phenotype with congenital muscular dystrophy and associated brain and eye abnormalities has been described as in other muscular dystrophies with mutations in genes responsible for glycosylating α-dystroglycan. (see Congenital Muscular Dystrophy). Phenotypic variability may be noted in the same family.
LGMD2V (excluded from new classification; see Type II Glycogen Storage Disease (Pompe Disease)
Late-onset Pompe disease may present as LGMD.
LGMD2W (excluded from new classification)
Single family described.
Childhood onset, severe weakness.
Other features include macroglossia and calf hypertrophy.
Cardiomyopathy developed in the 30s.
LGMD2X - Popeye domain–containing 1 (POPDC1); blood vessel epicardial substance (BVES) mutation (excluded from new classification)
One multigenerational family with 3 affected members is reported.[44]
Onset of slowly progressive proximal weakness in mid-adulthood.
Syncope due to AV-block in all family members may manifest before weakness.
LGMD2Y - Torsin A-interacting protein 1 (TOR1AIP1) (excluded from new classification)
One family described.
Onset in first decade.
Rigid spine and distal contractures.
Cardiomyopthy and respiratory failure.
LGMD2Z (LGMDR21 POGLUT1; 3q13)
Onset in the third decade with limb girdle weakness.
Progressive with scapular winging, wheelchair confinement, and respiratory insufficiency.
Childhood onset.
Progressive contractures.
Variable onset, early onset tends to be severe, late onset shows slow progression.
Neurological manifestations (epilepsy, leukoencephalopathy, globus pallidi signal changes, neuropathy).
Associated dilated cardiomyopathy.
Three Japanese patients described.
Early onset proximal weakness.
Calf hypertrophy.
Intellectual impairment.
Autosomal dominant LGMD
Autosomal dominant LGMD is less common than autosomal recessive LGMD, accounting for about 10% of all cases. In general, patients with autosomal dominant LGMD have a later onset and slower course than those of autosomal recessive LGMD. Creatine kinase (CK) elevations are also not as great in autosomal dominant LGMD as in autosomal recessive LGMD.
LGMD1A (myotilinopathy, also Myofibrillar myopathies; excluded from the new classification)
Onset varies from young adulthood to the mid-70s.
Presentation is often with distal weakness causing foot drop, but can also be distal and proximal or just proximal, but progresses to clinically significant proximal and distal weakness in all patients.
The progression is slow, with late loss of ambulation or, rarely, respiratory insufficiency.
Dysarthria and facial weakness may be present.
Cardiomyopathy or arrhythmia is noted in 50%.
Neuropathy noted in more than 50% may account for distal weakness.
LGMD1B (laminopathy, allelic with autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy; excluded from the new classification).
Onset can be from childhood (< 10 y) to mid-30s.
LGMD1B results in proximal weakness with slow progression.
Distal limb and facial weakness may be late manifestations.
Cardiac disease begins by the 30s–50s and affects two thirds of patients. Atrioventricular (AV) block progresses from first degree to complete. Dilated cardiomyopathy and ventricular arrhythmias may also be present.
LGMD1C (caveolinopathy; excluded from the new classification)
Predominant symptoms may be rippling-muscle disease, which presents as mechanical or activity-induced, electrically silent muscle contraction that moves laterally in wavelike fashion across the muscle. Myoedema, or mounding of the muscle after percussion, may be observed. Patients may also have proximal weakness, muscle hypertrophy, or myalgias.
Onset is usually in the first or second decade, but it may manifest into early adulthood. Presentation is usually with proximal weakness but can also be with distal weakness. Progression is slow to moderate and may be variable within families.
Rhabdomyolysis has been reported.[45]
Calf hypertrophy affects some patients.
Adults usually remain ambulant.
LGMD1D (DNAJB6 mutation; LGMDD1 DNAJB6; 7q36)
Nomenclature is confusing and some classify this as LGMD1E.
Usually adult onset with slow progression, although a few patients with childhood onset and respiratory involvement have been described.
Limb-girdle muscle weakness with waddling gait is common. Predominant distal weakness may occur.
The rectus femoris, sartorius, and the anterolateral group of lower leg and upper limb muscles are relatively preserved until the late stage.
Cardiac arrhythmia and cardiomyopathy are noted in all patients beginning 1–2 decades after weakness and may lead to sudden death.
LGMD1E (Desmin (DES) mutation[46] ; excluded from the new classification)
This was formerly reported as LGMD1D.
Several families have been reported with onset of weakness in their early 20s–60s.[47, 48] Most have proximal weakness, although distal weakness can predominate. Legs are usually affected more than arms.
Progression is slow, with most patients remaining ambulant into late life.
Dysphagia may be preset.
Serum CK is elevated.
No cardiomyopathy is noted.
LGMD1F (LGMDD2 TNPO3; 7q32)
One large family has been described.[49]
Onset is from the first year of life to the mid-50s.
Proximal weakness is noted early, with distal weakness as a late finding. Scapular winging may be noted.
Patients with a young onset may have rapid progression and require use of a wheelchair by their 20s–30s. They may also have facial and respiratory weakness and/or spinal deformity.
Onset in third to fourth decade.
Asymptomatic carriers reported.
Weakness may begin in proximal upper limbs or lower limbs.
Cataract.
Distal contractures.
LGMD1H (excluded from new classification)
Single family described.
Variable onset and severity.
Progressive proximal muscle weakness affecting both the upper and lower limbs.
Similar syndrome to LGMD2A (calpainopathy), but milder.
Later age of onset (mid-30s).
Milder weakness, but similar pattern (proximal leg [glutei/hamstring], paraspinal, medial gastrocnemius).
Myalgia in 50%.
CK may be markedly elevated.
Allelic with Bethlem myopathy, Ullrich Scleroatonic muscular dystrophy
Variable age of onset. Early onset may present with fetal hypotonia. Onset in seventh decade has been reported.
Spontaneous improvement may occur after birth and around puberty. Many become wheelchair bound by the seventh decade.
Distal or proximal contractures.
Muscle pain and cramps may be noted.
Respiratory and cardiac involvement may occur in minoritymuscle.
Hypertrophy is not reported.
Typical clinical features to distinguish the main LGMDs are often most helpful early in the disease.
LGMD1A: Dysarthria and swallowing difficulty are common. Distal weakness may be present.
LGMD1B: Frequent cardiac complications include cardiomyopathy and arrhythmia and there may be a family history of sudden cardiac death. Respiratory complications and contractures are common.
LGMD1C: Patients may present with myalgias, rippling muscles, or asymptomatic elevations of CK levels. Calf hypertrophy and toe walking may be prominent. Weakness is proximal and distal.
LGMD2A: Onset often in second decade of life. Patients have prominent atrophy of the periscapular muscles, biceps, gluteus maximus, thigh adductors, and hamstring muscles, with sparing of the hip abductors, sartorius, and gracilis. Presentation may be with toe walking. Contractures are common, in which case the disease needs to be differentiated from LGMD1B, Emery-Dreifuss muscular dystrophy, Bethlem myopathy, and laminin-α2 deficiency. This is a common cause of marked hyperCKemia or asymptomatic hyperCKemia.
LGMD2B: Patients may have early weakness and/or atrophy of the gastrocnemius (might be detected only on MRI), inability to walk on toes, waddling gait, atrophic distal biceps, and spared periscapular and deltoid muscles. Childhood onset is rare, with often sudden onset in the late teens or early 20s most common. CK can be markedly elevated. Misdiagnosis as polymyositis is not uncommon.
LGMD2C-2F: Patients may have Duchenne- and/or Becker-like weakness but with additional involvement of the periscapular muscles causing scapular winging. Muscle hypertrophy is common, especially of the calf and tongue muscles. Mental development is normal. Cardiomyopathy may be present in some. Respiratory complications are common. CK often markedly elevated. Contractures and scoliosis maybe present.
LGMD2G: Patients may have initial anterior tibial weakness causing foot drop or a typical LGMD phenotype.
LGMD2H: Patients may have a late onset, slow progression, and facial weakness. No cardiac symptoms are present, but mild ECG changes may be noted. This form is reported almost exclusively in the Hutterite population.
LGMD2I: This form has a widely variable spectrum with prominent muscle hypertrophy and cardiomyopathy (Duchenne-like). Respiratory complications are common. Patients may have prominent tongue hypertrophy and severe weakness and wasting of upper arms, neck flexors, and axial muscles; these features can help in distinguishing this disease from Duchenne muscular dystrophy.
LGMD2J: This is a severe LGMD described in the Finnish population. Distal muscles are affected as the disease progresses. No facial weakness is noted.
LGMD2K: This may present with global delay. Mental retardation and microcephaly may be present.
LGMD 2L: Adult onset common. Males more severely affected. Gastrocnemius atrophy and weakness is common. Asymmetry may be prominent. Gradual progression with myalgias and exercise intolerance. CK often markedly elevated.
LGMD2N: This may preset with global delay.
Specific clinical aspects of LGMD subtypes:[4]
Autosomal dominant LGMD: Rare, adolescent to late adult onset (LGMD 1B-1D may have childhood onset), mild weakness, normal to mildly elevated CK (except LGMD1C), rare exercise intolerance or rhabdomyolysis (except LGMD1C)
Autosomal recessive LGMD: Common, childhood to young adult onset, moderate to severe weakness, mild to highly elevated CK, common exercise intolerance or rhabdomyolysis
LGMDs with cardiac involvement: α-dystroglycanopathies, sarcoglycanopahies, myofibrillar myopathies, laminopathy (and other nuclear envelope proteins), LGMD1C (caveolinopathy), LGMDs with respiratory involvement: α-dystroglycanopathies, sarcoglycanopathies, myofibrillar myopathies, LGMD2V (acid maltase deficiency)
LGMDs with distal weakness (anterior compartment); myofibrillar myopathies
LGMDs with distal weakness (posterior compartment); LGMD2B (dysferlinopathy) LGMD2L (anoctaminopathy)
LGMDs with calf hypertrophy; α-dystroglycanopathies, sarcoglycanopathies, LGMD1C (caveolinopathy)
LGMDs with scapular winging: α-dystroglycanopathies, sarcoglycanopathies, LGMD2A (calpainopathy), myofibrillar myopathies, LGMD2B (dysferlinopathy), LGMD2L (anoctaminopathy), laminopathy (and other nuclear envelope proteins)
LGMDs with early/prominent contractures: laminopathy (and other nuclear envelope proteins, LGMD2A (calpainopathy), sarcoglycanopathies
LGMDs with onset in the first decade: LGMD2C-F, LGMD 2H, LGMD2J, LGMD2K, LGMD2M, LGMD2N, LGMD2O
LGMDs with onset in second decade: LGMD2A, LGMD2G, LGMD2I, LGMD1B, LGMD1C, LGMD1E, LGMD1F
LGMDs with onset in adulthood: LGMD2B, LGMD2L, LGMD1A, LGMD1D
LGMDs with eye involvement: α-dystroglycanopathies, HNRPDL
LGMD with liver involvement: TRAPPC11
KGMD with skin involvement: PLEC1
LGMDs with myotonic /discharges on Electromyography ( EMG) : LGMD1A, LGMD1D, LGMD1E
Myofibrillar myopathies (MFM)
Myofibrillar myopathies, (previously called desmin-storage myopathies because desmin was the first protein found and is the most consistent protein in the aggregates that are characteristic of these disorders) refers to a group of hereditary myopathies with homogeneous morphological features.
The relative frequency of mutations is unknown, but desminopathy is likely the most common and αβ-crystallinopathy is the least common. However, in more than half of patients with a myofibrillar myopathy, the causative gene mutation is unknown.
Age at onset varies from 7–77 years, with a mean of 54 years, except for patients with mutations in selenoprotein N who have onset at birth and the 1 described patient with a lamin A/C mutation who presented at age 3 years. Patients with desminopathy often present in early adulthood, while patients with myotilinopathy and filaminopathy often present after age 50 years.
Clinically, this group of disorders is heterogeneous, with slowly progressive weakness affecting the proximal and distal muscles in most patients, but about 25% present with distal predominant weakness (common in myotilinopathy), and 25% present with only proximal weakness (common in filaminopathy). They are included in this article because some mutations are in the same genes that cause LGMD phenotypes.
Muscle MRI may help to distinguish distinct subtypes.[50] In patients with desminopathy, the semitendinosus was as least equally affected as the biceps femoris and the peroneal muscles were never less involved than the tibialis anterior. In patients with myotilinopathy, the adductor magnus was more affected than the gracilis and the sartorius was as least equally affected as the semitendinosus. In patients with filaminopathy, the biceps femoris and semitendinosus were at least equally affected as the sartorius, the medial gastrocnemius was more affected than the lateral gastrocnemius and the semimembranosus was more affected than the adductor magnus.
Rare findings include the following:
Facial weakness
Asymmetric weakness
Severe atrophy
Respiratory failure, which may be severe or at presentation
Contractures
Distal sensory deficits (neuropathy diagnosed in about 20%)
Cardiac disease (especially common in desmopathy) may be present either as cardiomyopathy or arrhythmias and conduction block, and is present in about 50%.
Specific mutations include the following:
Desminopathy (MFM1): Onset is generally in the 20s or 30s with slow progression. Patients often present with distal weakness that progresses proximally, but limb-girdle, scapuloperoneal, and distal weakness combined with proximal weakness have all been described. Inter- and intrafamilial variability exists. Those with autosomal recessive disease may have an early onset. Cardiac disease (cardiomyopathy or atrioventricular conduction abnormalities) occurs in about 60% and may follow or precede myopathy, may be isolated, and may be severe. Respiratory failure may be severe and may be present at presentation. Facial and bulbar weakness may occur late. About 75% of patients eventually need assistance with ambulation.
αβ-crystallinopathy (MFM2): Onset varies from early to mid adulthood. Patients present with proximal more often than distal weakness. They may also present with respiratory failure. Patients may have neuropathy, cardiac failure, conduction abnormality, and congenital posterior polar cataracts.
Myotilinopathy (MFM3): The first mutations described were in 2 patients with an LGMD phenotype (see LGMD1A). Since then, several patients have been found with a myofibrillar myopathy. Onset is usually in mid-to-late adulthood. Most patients present with distal greater than proximal weakness, often with early foot drop. Neuropathy occurs in about 50%. Cardiomyopathy affects about 50%. Dysarthria, joint contractures and myalgias are present in about 33%. One family with spheroid body myopathy, a congenital myopathy, has been found with a mutation in the myotilin gene.
Z-band alternatively spliced PDZ motif-containing protein (ZASPopathy) (MFM4): Onset is at age 44-73 years, and patients most often present with distal more than proximal weakness, though proximal weakness can occur alone. Cardiac disease occurs in about 25% of patients and may be the presenting or predominant feature. Neuropathy affects approximately 45% of patients. Mutations are allelic with Markesbery distal myopathy, and dilated cardiomyopathy +/- isolated noncompaction of left ventricular myocardium.
Filamin C (γ-filamin) myopathy (MFM5): Age at onset is 24-57 years, with proximal greater than distal weakness. Respiratory failure occurs in about 50% of patients. Neuropathy affects about 40%. Cardiac disease may be present in up to 33%.
BCL2-associated athanogene 3 (BAG3) myopathy (MFM6): Age of onset is from childhood to early teens with proximal and distal weakness with progression that often causes respiratory failure and wheelchair dependency.[51, 52] Other features include contractures, scoliosis, and rigid spine. Peripheral neuropathy may be present. Cardiomyopathy is common and often severe, requiring transplantation in some patients.
Selenoprotein N myopathy: Selenoprotein N mutations were originally found in patients with congenital muscular dystrophy with rigid spine syndrome or minicore congenital myopathy. A study has shown that some patients with Mallory-body desmin-related myopathy also have a mutation in the selenoprotein N gene. Onset is at birth with hypotonia as well as axial and proximal weakness. Contractures and scoliosis are common and cardiac disease may occur. Death or the need for ventilatory support occurs before adulthood due to progressive respiratory failure.
Laminopathy: Besides presenting with a limb girdle phenotype (see LGMD1B), a case was described with a myofibrillar myopathy. The patient presented at age 3 years with difficulty running and at age 5 years was noted to have limb-girdle weakness.
LGMD2A is caused by mutations in the calpain-3 gene (CAPN3) that encodes a Ca2+-dependent nonlysosomal cysteine protease. The calpain-3 isoform is a homodimer that is abundant in skeletal muscle. More than 450 distinct pathological mutations have been identified so far. Many types of mutations have been found including nonsense mutations leading to stop codons, missense mutations often leading to decreased catalytic activity of calpain-3, splice site mutations, and small deletions or insertions.
In general, null mutations give rise to phenotypes more severe than those due to missense mutations.
CAPN3 (p94) is a member of the calpain family of intracellular, soluble cysteine proteases, most of which have calcium-dependent activation (CAPN3 is not calcium-activated). It is expressed almost exclusively in muscle and is anchored by titin at the M-line and N2 line (within the I-band of the sarcomere).
CAPN3 is involved in cleavage and/or breakdown of several proteins, particularly those involved in assembly and scaffolding of myofibrillar proteins including titin, vinculin, C-terminal binding protein 1, and filamin C.
CAPN3 also has thiol-dependent proteolytic activity directed against the skeletal muscle ryanodine receptor (RyR). RyR is a Ca2+-release channel, and lack of regulation of RyR by CAPN3 may play a role in skeletal muscle dysfunction.
Mutations in the CAPN3 gene can lead directly to loss of proteolytic activity or to secondary loss of activity due to its loss of anchorage with titin. The loss of proteolytic activity may lead to reduced cleavage of cytoskeletal and myofibrillar proteins, decreased ubiquitination, and proteasome-mediated degradation, accumulation of damaged proteins that then accumulate within muscle.
How the absence of CAPN3 triggers an initial event that leads to metabolic reprogramming in the muscle is not entirely understood at this time. There is evidence that the metabolic adjustment triggered by the absence of CAPN3 in muscle results in an aberrant regeneration; AMPK pathway activation has been shown to play an essential role.[53]
Dysregulation of Ca2+ metabolism has also been implicated to play an important role in the pathogenesis of LGMD2A.[54]
Biopsy pathology is typically dystrophic, sometimes characterized by frequent lobulated fibers.
Of patients with LGMD2A, 20%–30% exhibit normal CAPN3 protein levels as measured by Western blotting.[55]
On muscle biopsy, CAPN3 can be visualized by using Western blots but not muscle immunohistochemistry. Correlation between the degree of deficiency and the clinical phenotype can be total, partial, or (in rare cases) nonexistent. Expression of dystrophin and the sarcoglycans is normal. Expression of dysferlin can be reduced.
LGMD2B is caused by mutations on chromosome 2 in the dysferlin gene.
More than 300 mutations have been identified, most commonly missense, nonsense, small deletions, and splice-site mutations.
The type of mutation is not correlated with the phenotype, ie, LGMD versus Miyoshi distal myopathy. Both phenotypes have been described in the same family with identical mutations.
Dysferlin protein is a large membrane protein with sequence analogy to the nematode protein fer-1, and is a member of the ferlin family of proteins, which are all involved in calcium-dependent membrane fusion. Dysferlin protein has been localized to the sarcolemma, the T-tubule system, and cytoplasmic vacuoles.[56] Dysferlin is thought to be involved in the docking and fusion of intracellular vesicles to the sarcolemma during injury-induced membrane repair by interacting with other dysferlin molecules and other proteins. Some of these proteins include annexins A1 and A2 (phospholipid binding proteins), caveolin-3 (LGMD1C), calpain-3 (LGMD2A), the dihydropyridine receptor within the T-tubule system, and AHNAK (desmoyokin, a protein involved in cell membrane differentiation and repair). Dysfunction of dysferlin may lead to impaired muscle membrane repair as well as delayed myoblast fusion and maturation.
Ultrastructural studies have shown small sarcolemmal defects, replacement of the plasma membrane by multiple layers of vesicles, and small subsarcolemmal vacuoles, all suggesting that dysferlin is likely required for maintaining the structural integrity of the muscle fiber plasma membrane, and plasma membrane injury is an early event in the pathogenesis of dysferlinopathy.
LGMD2C–2F are caused by mutations in the sarcoglycan genes.
LGMD2C is caused by a mutation on chromosome 13 in the γ-sarcoglycan gene.
LGMD2D is caused by a mutation on chromosome 17 in the α-sarcoglycan (adhalin) gene.
LGMD2E is caused by a mutation on chromosome 4 in the β-sarcoglycan gene.
LGMD2F is caused by a mutation on chromosome 5 in the δ-sarcoglycan gene.
Missense and nonsense mutations are the most common for all the sarcoglycanopathies, though with γ-sarcoglycanopathies (LGMD2C), small or large deletions are also common.
Sarcoglycan protein complex is a transmembrane complex that is part of the large dystrophin glycoprotein complex. The core of the complex is made up of the β and δ subunits with weaker binding of the α and γ subunits. This complex likely does not bind directly to dystrophin, but binds to the dystroglycan complex which in turn binds to dystrophin. The sarcoglycan complex also binds strongly to sarcospan as well as to α-dystrobrevin and filamin.
The function of the sarcoglycan complex is unknown, but it likely stabilizes the dystrophin glycoprotein complex. In the absence of the sarcoglycan complex, binding of dystrophin to β-dystroglycan and binding of β-dystroglycan to α-dystroglycan are weakened.
The sarcoglycan complex may also play a role in cell signaling based on the following evidence. It may act as a receptor since it has cysteine bonds, common in other receptors, although no substrate has been identified. ATPase activity occurs in α-sarcoglycan. The sarcoglycan complex binds α-dystrobrevin, which in turn binds to syntrophin, which binds nNOS and voltage-gated sodium channels.
Muscle biopsy usually shows a dystrophic pattern of muscle-fiber necrosis and regeneration similar to that observed in Duchenne muscular dystrophy.
On immunohistochemistry, dystrophin staining is often slightly reduced, but may be normal (whereas sarcoglycan expression may be mildly reduced in Duchenne-Becker muscular dystrophy). α-sarcoglycan mutations cause absent or reduced α-sarcoglycan staining with preservation of staining for γ-sarcoglycan. Minimal or no staining occurs for β and δ-sarcoglycan. This is the only mutation for which the amount of residual staining (for α-sarcoglycan) and the clinical phenotype are correlated. β- and δ-sarcoglycan mutations usually cause absent staining of the entire sarcoglycan complex.
LGMD2G is caused by mutations on chromosome 17 in the telethonin gene.
Null mutations have been described in only a few families with a wide range of phenotypic variability.
Allelic with hereditary cardiomyopathy (CMD 1N & CMH25)
Telethonin protein (titin-cap protein) is a sarcomeric protein present in the Z disk that binds to titin and several other Z-disk proteins, and is thought to be important in sarcomere assembly. While LGMD2G patients with null mutations do not appear to have a primary defect in myofibril assembly, knock down of titin-cap protein results in decreased expression of several myogenic regulatory factors suggesting that titin-cap protein may function to permit signaling between the contractile apparatus and genes involved in muscle development or maintenance.[57]
Immunofluorescence and Western blot assays may show a telethonin deficiency. Full sequencing testing may be cost-effective in all cases, as the gene is composed only of two small exons.
LGMD2H is caused by mutations on chromosome 9 in TRIM32 (tripartite-motif containing gene 32).
Most patients have the D487N mutation. Different mutations in TRIM32 have also been found, but all mutations cluster in the NHL domain of TRIM32 protein.
Mutations in TRIM32 can also cause sarcotubular myopathy (see Congenital Myopathies) and Bardet-Biedl syndrome.
TRIM32 protein is an E3-ubiquitin ligase that transfers activated ubiquitin residues onto a target protein, tagging the protein for degradation in the proteosome.
All mutations in the NHL domain result in loss of the self-interacting ability of TRIM32 protein , as well as the loss of interaction of TRIM32 protein with E2N, a muscle-specific protein involved in the ubiquitination process .[19] While the disease mechanism is unknown, it is speculated that disruption in the ubiquitination process may lead to protein accumulation and subsequent cell stress and dysfunction.
On muscle biopsy, no protein accumulations or inclusions have been identified.
LGMD2I (MDDGC5) is caused by mutations on chromosome 19 in the FKRP gene.
Missense point mutations are the most common mutation. A homozygous Leu276Ileu mutation (826A>C) is particularly common and is present in about 90% of patients. The disease severity correlates with the mutation in the second allele; patients with a homozygous mutation are less severely affected. The most severe phenotype occurs when patients have compound heterozygous mutations for 2 other missense mutations or 1 missense and 1 nonsense mutation. This form is allelic with congenital muscular dystrophy 1C. (See Congenital Muscular Dystrophy.)
FKRP protein is a putative glycotransferase based on its sequence homology to fukutin. FKRP deficiency causes hypoglycosylation of α-dystroglycan, a component of the dystrophin-associated glycoprotein complex. α-dystroglycan hypoglycosylation is associated with loss of interaction with laminin α2, which in turn results in laminin α2 depletion.[58]
In muscle biopsy, antibodies to the glycosylated portion of α-dystroglycan show reduced staining (and decreased mass on Western blots). Antibodies to laminin-α2 may show reduced staining; however, in mild cases, this is often evident only on Western blots. No consistent relationship is noted between clinical function and the degree of morphological pathology.
LGMD2J is caused by mutations on chromosome 2 in the titin gene.
The most common mutation is an 11-base pair deletion-insertion mutation in the terminal exon. Finnish patients who are homozygous for this titin mutation develop autosomal recessive LGMD2J, while patients with a heterozygous mutation develop autosomal dominant Finnish (tibial) muscular dystrophy.
Titin protein is the largest protein found in humans. It is important for sarcomeric organization, stretch response, and sarcomerogenesis in myofibrils. It also likely plays a role in the assembly of contractile elements, regulation of the size of the Z disk, and in cell signaling pathways.
Titin binds caplain-3 in muscle, which may stabilize it from autolytic degradation. Muscle biopsy in patients with LGMD2J shows secondary deficiency of calpain-3. No signal is obtained using autoantibodies to the C-terminus region of titin near the common mutation site. This C-terminus region is important for calpain-3 binding and cell signaling pathways. Muscle biopsy in LGMD2J shows loss of calpain-3.
Allelic with hereditary cardiomyopathy syndromes (CMD 1G, CMH 9, EOMFC [early onset myopathy with fatal cardiomyopathy]).
LGMD2K (MDDGC1) is caused by mutations on chromosome 9 in the protein O-mannosyltransferase 1 (POMT1) gene.
LGMD2K is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).
POMT1 protein is an O-mannosyltransferase that glycosylates α-dystroglycan and disease is likely related to reduced or abnormal glycosylation of α-dystroglycan. POMT enzymatic activity is inversely correlated with severity of clinical phenotype such that patients with a LGMD phenotype have mildly reduced activity and patients with a Walker-Warburg syndrome phenotype have severely reduced activity.[59]
Muscle biopsy shows decreased staining for α-dystroglycan.
LGMD2L is caused by a mutation on chromosome 11 in the ANO5 gene.
ANO5 encodes a member of the Anoctamin family, comprised of at least 10 proteins all with 8 transmembrane domains. The function of Anoctamin 5 is unknown, but other anoctamins have been recognized to code for calcium-activated chloride channels.[28]
The c.191dupA mutation may be a founder mutation, accounting for the high prevalence in families of northern European descent.[29]
In some biopsies in patients with Anoctamin 5 mutation, there is evidence of sarcolemmal membrane lesions and defective membrane repair. It is hypothesized that similar to mutations in dysferlin, mutations in anoctamin 5 may lead to LGMD due to defects in membrane repair.
LGMD2M (MDDGC4) is caused by mutations on chromosome 9 in the fukutin gene.
LGMD2M is allelic with Fukuyama congenital muscular dystrophy.
Fukutin is a putative glycosyltransferase and has sequence homologies to a bacterial glycosyltransferase, but its exact role and enzymatic substrate have not been determined. However, like other glycotransferases, disease is likely related to reduced or abnormal glycosylation of α-dystroglycan.
Muscle biopsy shows decreased staining for α-dystroglycan.
LGMD2N (MDDGC2) is caused by mutations on chromosome 14 in the POMT2 gene.
LGMD2N is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).
POMT2 is an O-mannosyl transferase and is required to form a complex with POMT1 for enzyme activity. Similar to mutations in POMT1, disease is likely related to defective glycosylation of α-dystroglycan.
LGMD2O (MDDGC3) is caused by mutations on chromosome 1 in the POMGnT1 gene.
LGMD2O is allelic with muscle-eye-brain disease (see Congenital Muscular Dystrophy).
POMGnT1 is the glycosyltransferase O-mannose β-1,2-N-acetylglucosaminyl-transferase. It catalyzes the transfer of N -acetylglucosamine to the O-linked mannose of glycoproteins, including α-dystroglycan. Like other glycosyltransferase mutations disease is probably related to defective glycosylation of α-dystroglycan.
LGMD2P (MDDGC7) is caused by mutations on chromosome 3 in the DAG1 gene.[36]
DAG1 codes for α -dystroglycan, which is known to be modified by several glycotransfersases and mutations in several of these genes are causes of LGMD or congenital muscular dystrophy.
In these patients, there is a missense mutation in the DAG1 gene itself.
A mouse model of this mutation mimics the human disease. The mutation was shown to impair the receptor function of α -dystroglycan by inhibiting post-translational modification by LARGE disease (see Congenital Muscular Dystrophy).
LGMD2Q is caused by mutations on chromosome 8 in the plectin (PLEC1) gene.[37]
Plectin is present in muscle sarcolemma and is thought to be important as a linker of various cytoskeletal proteins, thereby maintaining cell integrity.
Eight plectin isoforms have been identified. In these families, there was a mutation in the initiation codon for isoform 1f. Plectin expression was reduced in muscle and there was almost no expression of plectin 1f mRNA.
Allelic with epidermolysis bullosa simplex syndromes (see Epidermolysis Bullosa).
LGMD2R is caused by a mutation on chromosome 2 in the DES gene.
This disease is allelic LGMD1D and with myofibrillar myopathy 1 (see below).
Desmin is important in linking myofibrils to the sarcolemma, nucleus, and mitochondria.
In these patients, desmin staining in muscle was normal.[38] However, ultrastructural abnormalities typical for myofibrillar myopathies such as disruption of myofibrillar organization, formation of myofibrillar degradation products, and aggregation of membranous organelles were not present.
LGMD2S is caused by a mutation on chromosome 4 in the TRAPPC11 gene.
The TRAPP complex is involved in membrane trafficking.
Mutations impair the binding of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus.[39] There was delayed exit of proteins from the Golgi to the cell surface, and in particular alterations of the lysosomal glycoproteins lysosome-associated membrane protein1 (LAMP1) and LAMP2 support a defect in the transport of secretory proteins as a pathologic mechanism.
LGMD2T (MDDGA14) is caused by a mutation on chromosome 3 in the GMPPB gene.
LGMD2T is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).
GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate[40, 41] . GDP-mannose is required for O-mannosylation of proteins and like other glycosyltransferase mutations disease is probably related to defective glycosylation of α-dystroglycan.
Muscle biopsy of affected patients shows reduced glycosylation of α-dystroglycan.
LGMD2U (MDDGA7) is caused by a mutation on chromosome 7 in the ISPD gene
LGMD2U is allelic with Walker-Warburg syndrome (see Congenital Muscular Dystrophy).
ISPD belongs to the glycosyltransferase-A family (as does LARGE) and is required for efficient O-mannosylation of alpha-dystroglycan.[42, 43]
Muscle biopsy of affected patietns shows reduced glycosylation of α-dystroglycan.
LGMD2V is caused by a mutation on chromosome 17 in the GAA gene (see Genetics of Glycogen-Storage Disease Type II (Pompe Disease) & Type II Glycogen Storage Disease (Pompe Disease)
LGMD2V is allelic with Late-onset Pompe disease (glycogen storage disease type 2)
α-1.4 glucosidase is a lysosomal enzyme that hydrolyzes α-1.4 linkages on carbohydrates. A mutation causes glycogen accumulation in most tissues.
LGMD2W is caused by a mutation on chromosome 2 in the LIMS2 gene
LIMS2 is a component of a complex that mediates multiple protein-protein interactions at adhesion sites between cells and the extracellular matrix and is critical for muscle attachment[60] . This complex also functions as a signaling mediator that transmits mechanical signals.
LIMS2 localizes to sarcomeric Z-disks and costameres in heart and skeletal muscle.
Patients have reduced staining for pinch2 (alternative name) at Z-disc.
LGMD2X is caused by a mutation on chromosome 6 in the POPDC1 (BVES) gene
POPDC1 belongs to a group of membrane proteins (popeye domain-containing proteins) that are abundantly expressed in skeletal muscle and heart[44] .
These proteins bind cAMP and TREK1 (human potassium channel KCNK2) and may have regulatory roles in action potential generation.
In zebrafish, expression of the homologous mutation caused heart and skeletal muscle phenotypes that resembled those observed in patients.
Autosomal dominant LGMD
LGMD1A is caused by mutations on chromosome 5 in the myotilin gene.
Several different missense mutations have been identified.
The term myotilinopathy has been coined because of the overlapping features in patients described as having a LGMD or myofibrillar myopathy and a mutation in the myotilin gene. Furthermore, a large family described as having spheroid body myopathy (see Congenital Myopathies) was recently found to have a mutation in the myotilin gene.
Myotilin protein is associated with the Z disk and is expressed in skeletal muscle and, to a lesser extent, cardiac muscle. Myotilin protein binds to α-actinin, filamin C, and actin, and it is likely important in stabilizing and anchoring thin filaments to the Z disk during myofibrillogenesis.
Muscle biopsy shows muscle fiber degeneration/necrosis and nonhyaline or hyaline inclusions that stain positively for multiple proteins (a feature similar to that of other myofibrillar myopathies). Myotilin, dystrophin, neural-cell adhesion molecule (NCAM), desmin, plectin, gelsolin, ubiquitin, and prion protein all are found in the inclusions. Other consistent findings are rimmed or nonrimmed vacuoles, autophagic vacuoles, cytoplasmic or spheroid bodies, and mild evidence of denervation. On electron microscopy, there is Z-disk streaming and sarcomeric disruption.
LGMD1B is caused by mutations on chromosome 1 in the lamin A/C gene.
Missense and deletion mutations have been reported.
Mutations in lamin A/C can also cause Emery-Dreifuss muscular dystrophy, quadriceps myopathy, congenital muscular dystrophy with rigid spine, autosomal dominant dilated cardiomyopathy with AV block (or CMD1A, see the Neuromuscular Disease Center), Familial partial lipodystrophy (Köbberling-Dunnigan syndrome), Charcot-Marie Tooth type 2A, mandibuloacral dysplasia, and premature aging syndromes (Hutchinson-Gilford progeria, atypical Werner syndrome).
No clear genotype-phenotype correlation distinguishes the disorders listed above. Different phenotypes can occur in the same family. One individual can have more than 1 phenotype.
Lamin A/C is an intermediate filament in the inner nuclear membrane and nucleoplasm of almost all cells. Multiple functions are described, but the pathophysiologic basis for LGMD1B is unknown. Lamin A/C provides mechanical strength to the nucleus; helps to determine nuclear shape; anchors and spaces nuclear pore complexes; is essential for DNA replication and mRNA transcription; and binds to structural components (emerin, nesprin), chromatin components (histone), signal transduction molecules (protein kinase C), and several genetic regulatory molecules.
LGMD1C is caused by mutations on chromosome 3 in the caveolin-3 gene.
Most are autosomal dominant missense or deletion mutations in the scaffolding region, but a family with autosomal recessive disease has been described. The same mutation can cause different phenotypes (LGMD1C, elevated CK levels, rippling-muscle disease, distal myopathy, hypertrophic cardiomyopathy), even in the same family.
Caveolins are transmembrane proteins that are the principal component of caveolae. Caveolae are 30- to 60-nm invaginations in cell membranes that can bind several components of signal-transduction pathways and may act as a scaffold, placing members of the pathway in close proximity.
Caveolin-3 is a muscle-specific caveolin that is localized to the sarcolemma. It interacts with G proteins, a variety of signaling molecules, dystrophin, dystrophin associated proteins, phosphofructokinase, dysferlin, and nitric oxide synthase (nNOS).
All mutations in caveolin-3 decrease sarcolemmal immunostaining, suggesting that the mutation is due to a loss of function. A dominant negative effect has been noted in which an aberrant protein product forms aggregates that sequester the normal caveolin-3 in the Golgi apparatus. Other effects due to improper caveolin-3 oligomerization and membrane localization result in derangements of the T tubule system, alterations in the sarcolemmal membrane, and the formation of subsarcolemmal vesicles.
Muscle biopsy shows reduced or absent immunochemical staining for caveolin-3 at the sarcolemma, and this can be used as a screening test before searching for caveolin-3 mutations. In addition, immunochemical staining for dysferlin (caveolin-3 interactions) at the sarcolemma is reduced and the number of caveolae on electron microscopy is also reduced.
LGMD1D (note that some references call this LGMD1E) is caused by a mutation on chromosome 6 in the DES gene.[46] See below for myofibrillar myopathy MFM1.
LGMD1E (note that some references call this LGMD1D) is caused by a mutation on chromosome 7 in the DNAJB6 gene (DNAJ/HSP40 Homolog, subfamily B, Member 6).
It is a member of the HSP40 family, a class of co-chaperones with a J domain.[47, 48] These co-chaperones interact with chaperones of the HSP70 family to protect client proteins from irreversible aggregation during protein synthesis or times of cellular stress.
Mutations have a dominant toxic effect, increasing the half-life of cytoplasmic isoform of DNAJB6 and reducing its protective antiaggregation effect.
It interacts with BAG3 (See below myofibrillar myopathy MFM6).
LGMD1F is caused by a mutation on chromosome 7 in the transportin 3 (TNPO3) gene.[61]
Transportin 3 is a member of the importinb super-family that imports proteins into the nucleus, including serine/arginine-rich proteins that control mRNA splicing.
Muscle biopsy shows variable muscle fiber degeneration, desmin expression in muscle fibers, rimmed vacuoles, and abnormal nuclear morphology.
LGMD1G is caused by a mutation on chromosome 4 in the hetrogenous nuclear ribonucleoprotein D-like (HNRPDL) gene.[62]
HNPRDL is a member of the hetrogenous ribonucleoprotein family whose members participate in mRNA biogenesis and metabolism including the splicing of specific exons in pre-mRNA transcripts of muscle related genes. .
LGMD1H is caused by a mutation on chromosome 3 at the 3p25.1-p23 locus; the protein has not yet been identified.
LGMD1I is caused by in-frame deletion on c.643_663del21 in calpain-3 gene.
LGMDD5 is caused by mutations in α1, α2, or α3 subunits of collagen type VI.
Allelic disorders include bethlem myopathy, myosclerosis, early-onset dystonia and Ullrich Scleroatonic muscular dystrophy.
Collagen VI may play a role in anchoring basement menbranes and stabilizing cells in the extracellular matrix, via interactions with proteoglycans, integrins, and other proteins.
Mutations may result in lower protein level, misfolded protein, or defective assembly.
Myofibrillar myopathies
Many patients with a clinical and histologic phenotype of myofibrillar myopathy have no known mutation. Myofibrillar myopathy syndromes related to know genetic mutations are described below.
Most mutations are in proteins of the Z-disk or with attachments to the Z-disk. Most are proposed to cause disease by means of a dominant negative effect due to combined wild-type and mutant protein. The pathogenesis of disease is likely due to disrupted Z-disk function, which includes: (1) an attachment site and mechanical link of actin and titin filaments, (2) transmission of force along the myofibril, and (3) an attachment site for intermediate filaments (desmin) that link adjacent sarcomeres with each other and with other cellular organelles.
The common morphologic features of myofibrillar myopathies includes myobrillar disorganization at the Z-disk (Z-disk streaming) followed by accumulation of myofibrillar degradation products and aggregation of many proteins. These proteins include not only cytoskeletal and myofibrillar proteins and intermediate filaments, but also proteins of the ubiquitin-proteasome system, nuclear proteins, chaperones, Alzheimer disease-related proteins, oxidative stress proteins, kinases, and neuronal proteins.[63] A proposed molecular pathogenesis includes aggregation of mutant proteins followed by aggregation of other proteins including those of the ubiquitin-proteasome system, which is the main pathway for nonlysosomal protein degradation. Abnormal proteasome function results and may then lead to autophagocytosis, hyaline inclusion body formation, and inflammation, all pathologic hallmarks of the disease.
Desminopathy (MFM1) is caused by mutations on chromosome 2 in the desmin gene and can be either autosomal dominant or autosomal recessive. More than 20 mutations (most nonsense or missense and autosomal dominant) have been identified. Most mutations are located in the α-helical rod domain, which is critically important for filament assembly. Different mutations cause variable phenotypes and also disrupt desmin filaments at various stages of assembly. Pathogenesis is likely due to loss of desmin function or a dominant negative effect related to the accumulation of mutant desmin into toxic aggregates that disrupt cell function and eventually cause cell death.
Desmin protein is an intermediate filament (IF) protein. In muscle, it is located at the periphery of the Z-disk, under the sarcolemma, and at myotendinous junctions. In cardiac muscle, it is at intercalated disks and Purkinje fibers. Two desmin molecules align head to tail to form a dimer, 2 dimers form a tetramer, 2 tetramers form a protofilament, 2 protofilaments form a protofibril, and 2-6 protofibrils form an IF. IFs can heterodimerize with other IFs or IF-associated proteins. Desmin binds to ankyrin, spectrin, synemin, syncoilin, plectin, and nebulin. IFs form a heteropolymeric lattice to organize the myofibrils and link them to nuclei, mitochondria, and the sarcolemma.
αβ-crystallinopathy (MFM2) is caused by a mutation on chromosome 11 on the αβ-crystallin gene. Mutations have all been autosomal dominant.
αβ-crystallin protein is a small heat-shock protein that forms homo-oligomeric or hetero-oligomeric complexes with αβ-crystallin or other heat-shock proteins. Expression in skeletal and cardiac muscles and in the lens is high. In muscle, the protein is localized to the Z-disk. It binds to unfolded and denatured proteins to suppress nonspecific aggregation, and it protects actin, desmin, tubulin, and a variety of soluble enzymes from stress-induced damage. Mutant proteins are expressed and likely impair this chaperone function by means of dominant negative effect.
Myotilinopathy (MFM3) is caused by mutations on chromosome 5 in the myotilin gene (see LGMD1A). More than 15 families have been described with autosomal dominant or sporadic mutations. The serine-rich exon 2 is a hot spot for mutations. Myotilin protein is expressed in skeletal and cardiac muscle and in peripheral nerves. In muscle, it is expressed at the Z-disk. The protein binds to α-actinin, F-actin and filamin C and likely plays a role in cross-linking actin filaments and is in control of sarcomere assembly.
ZASP (Z-band alternatively spliced PDZ-containing protein) myopathy (MFM4) is caused by mutations on chromosome 10 in the ZASP gene, and is allelic with Markesbery distal myopathy and a form of hereditary dilated cardiomyopathy. In the largest series to date, 3 mutations have been identified in 11 patients with autosomal dominant or sporadic inheritance. ZASP may be a common cause of myofibrillar myopathy (about 15% of patients). ZASP protein is expressed in cardiac and skeletal muscle, binds to α-actinin in the Z-disk, and supports Z-disk structure during contraction.
Filamin C myopathy (MFM5) has been described in 1 German family with an autosomal dominant truncating mutation on chromosome 7 in the filamin C gene. Filamin C protein is expressed in skeletal and cardiac muscle. It is a Z-disk protein that binds actin, sarcoglycans, myotilin, myozenin, and many other proteins. It functions in actin reorganization, signal transduction, and maintenance of membrane integrity during force application.
BCL2-associated athanogene 3 myopathy (MFM6) is caused by a mutation on the BAG3 gene and has been described in a few patients.[51, 52] The BAG family of proteins bind to HSP70/HSC70 (heat shock proteins that act as chaperones to assist with protein folding and prevent protein aggregation) and are thought to inhibit the activity of these HSPs, thereby promoting protein release. Bag-3 localizes to and co-chaperones the Z disk in skeletal and cardiac muscle. Muscle pathology showed abnormal aggregation of desmin and Bag-3, Z-disc disintegration, and nuclear apoptosis.
Selenoprotein N related myopathy is caused by mutations on chromosome 1 in the selenoprotein N gene. These patients were originally described as having Mallory-body desmin-related myopathy. The term selenoprotein-related myopathy has been proposed to encompass patients with Mallory-body desmin-related myopathy, rigid spine syndrome, and minimulticore disease who have mutations in selenoprotein N. Selenoprotein N is a ubiquitously expressed glycoprotein that localizes to the endoplasmic reticulum and has an unknown function. Increased levels are present in myoblasts, with lower levels in myotubes or mature muscle fibers suggesting a role in early muscle development or in muscle cell proliferation or regeneration.
Laminopathy: Mutations in lamin A/C cause a wide variety of neuromuscular and more complex phenotypes. The pathogenesis is unknown (see LGMD1B).
Muscle biopsy of myofibrillar myopathies
See the list below.
Light microscopy: Trichrome-stained tissue shows single or multiple areas of blue-red amorphous material described as hyaline structures, cytoplasmic bodies, or inclusions. Abnormal hyaline structures are congophilic and contain many degraded proteins. Oxidative enzymes and ATPase activity is absent in the areas containing inclusions. Rimmed or nonrimmed vacuoles are present in most biopsies. Focal muscle fiber degeneration or inflammation can occur.
Electron microscopy: Z-disk streaming is an early feature. The main ultrastructural feature of all myofibrillar myopathies is disintegration of the Z disk and replacement of normal structures by homogenous irregular masses of electron dense material and granulofilamentous material. The normal myofibrillar architecture is replaced by fragments of thick and thin filaments and Z-disk material. Autophagic vacuoles contain abnormal sarcomeric proteins and other organelles.
Immunohistochemical staining: Many proteins can be localized to over 50% of abnormal fibers noted on light microscopy: desmin, αβ-crystallin, myotilin, dystrophin, β-amyloid precursor protein, neural cell adhesion molecule, actin, cell division cycle kinase 2, plectin, and prion protein. Several other proteins are noted in less than 50% of abnormal fibers including α1-antichymotrypsin, gelsolin, ubiquitin, synemin, and nestin.
Autosomal recessive limb-girdle muscular dystrophies (LGMDs) often cause extremely high CK levels. The sarcoglycanopathies (LGMD2C-2F) and LGMD2B markedly elevate CK levels by 10-150 times normal. The other autosomal recessive LGMDs usually cause CK elevations that are 3-80 times normal.
Autosomal dominant LGMD1C can result in high CK elevations of 5-25 times normal. All other autosomal dominant LGMDs result in CK levels between normal and 15 times normal.
Myofibrillar myopathies have CK levels ranging from normal to 7 times normal.
Consider other myopathies that markedly elevate CK levels: dystrophinopathies, dermatomyositis and/or polymyositis, hypothyroid myopathy, rhabdomyolysis, and acid maltase deficiency.
A guideline for the diagnosis and management of patients with limb-girdle or distal muscular dystrophies, issued by the American Academy of Neurology and the American Association of Neuromuscular & Electrodiagnostic Medicine, calls for referral of patients suspected of having MD to a specialist center for evaluation and genetic testing. The guideline provides algorithms for diagnosis based on the clinical phenotype, including pattern of muscle involvement, inheritance pattern, age of onset, and associated manifestations (e.g. contractures, cardiomyopathy, respiratory failure). If initial targeted genetic testing (either single gene or a panel of LGMDs) is negative, a muslce biopsy showld be obtained to look at the immunohistochemical staining patterns using antibodies directed at known disease associated proteins (e.g. dystrophin, sarcoglycans, merosin, α-dystroglycan, dysferlin, cveloin-3, etc) and to look for distinguishing features (e.g. rimmed vacuoles, myofibrillar myopathy). If subsequent targeted genetic testing remains negative then whole exome sequncing should be performed.[64, 65]
Next‐generation sequencing (NGS)‐based gene‐panel testing, using targeted NGS panel, is now available for the diagnosis of LGMD. Whole genome sequencing has additional benefits of identifying novel pathogenic mutations and putative phenotype-influencing variants, as well as identifying potential digenic or multigenic contribution to LGMD especially in patients with atypical presentations and /or progression.[66, 67]
In a large cohort of LGMD families[68] 35% were diagnosed based on protein-based testing (muslce biopsy) followed by targeted candidate gene testing. Of the remaining patients, 60 families underwent whole exome sequencing, pathogenic mutations in known myopathy genes were identified in 45% of the families. Interestingly, about half of the identified genes were not LGMD genes, highlighting the clinical overlap between LGMD and other myopathies. Common causes of phenotypic overlap included genes causing collagen myopathy, metabolic myopathies and congenital myopathies.
Magnetic resonance imaging (MRI) can help differentiate forms of LGMD. Hyperintense signal change on T1 scans is seen in more severely affected muscles. An MRI study of 20 patients with LGMD showed the following:
Patients with LGMD2A show prominent involvement of thigh adductors, hamstrings, and medial head of the gastrocnemius, with sparing of the sartorius. Serial imaging shows stronger deterioration in the soleus muscle, vastus intermedius, and biceps femoris.[69]
Patients with LGMD2B can have a variable MRI picture. The adductor magnus, quadriceps, and calf muscles are predominantly involved, with relative sparing of the Sartorius and gracilis muscles.[70] Involvement of gastrocnemius predominates in Miyoshi myopathy, and involvement of glutei and anterior and posterior thigh muscle is prominent in patients with a LGMD phenotype. Tibialis anterior and axial abnormalities are described in patients with anterior tibial myopathy and axial myopathy, respectively.
Patients with sarcoglycanopathies do not show any major differences regarding pattern of muscle involvement, as seen on MRI. Adductor and glutei muscles seem to be the first affected, with a proximodistal gradient evident in the vastus lateralis. Adductor longus may show some areas of sparing, with a complete or relative sparing of tibialis posterior and flexor digitorum longus. Less consistently, a relative hypertrophy of either sartorius or gracilis may be seen.[71]
Patients with LGMD2D and with Becker muscular dystrophy had more severe MRI changes in the anterior thigh compartment than in the posterior thigh.
Muscle tissue in patients with LGMD2I who have the founder mutation c.545A>G in FKRP shows a distinctive concentric pattern of fatty infiltration and edema on MRI, most pronounced in the vastus intermedius and vastus medialis muscles around the distal femoral diaphysis.[72]
Needle electromyography (EMG) and nerve conduction studies (NCSs)
Order EMG and NCSs in all patients with suspected LGMD to confirm the myopathic nature of the disease.
NCS results are normal in LGMD.
EMG shows early recruitment and the typical small-amplitude, narrow-duration, polyphasic motor-unit potentials that are seen in muscular diseases.
Abnormal spontaneous activity in the form of fibrillations and positive sharp waves is not prominent but has been described in a few cases of LGMD. When present, it should raise the clinician's suspicion for an inflammatory myopathy, such as polymyositis.
Myotonic or pseudomyotonic discharges may occasionally be noted in LGMD1A, LGMD1D, and LGMD1E.
Electrocardiography
Cardiac involvement is common in the autosomal dominant syndromes of LGMD1A and 1B (50%–65%). Cardiomyopathy and cardiac arrhythmias in LGMD1B may cause clinically significant morbidity. In patients with LGMD1E (dilated cardiomyopathy with conduction defect and muscular dystrophy), cardiomyopathy and arrhythmias are nearly always present.
In the autosomal recessive LGMD syndromes, cardiomyopathy is uncommon except in LGMD2G and 2I, where as many as 30%–50% of patients can have mild-to-moderate cardiomyopathy. In the sarcoglycanopathies (most often LGMD2E and 2F), cardiomyopathy is occasionally problematic.
In myofibrillar myopathies, cardiac disease is common, occurring in more than 50% of cases. Presentation can be with cardiomyopathy or cardiac conduction disturbances.
Annual screening with ECG (and possibly echocardiography if the patient is symptomatic) is important for quick diagnosis and follow-up in cases of LGMD and myofibrillar myopathy with cardiac disease.
Muscle biopsy is the most important diagnostic evaluation of patients in whom LGMD is suspected.
In most cases of LGMD, routine histochemical studies show typical dystrophic features, including various degrees of muscle-fiber degeneration and regeneration, variation in fiber size with small round fibers, and endomysial fibrosis.
Details of routine muscle histochemistry include the following:
In LGMD1A the muscle biopsy may show rimmed vacuoles.
In LGMD1C the muscle biopsy may show only mild myopathic features.
In LGMD2B the biopsy may show perimysial and perivascular T-cell infiltrates and upregulation of major histocompatibility complex (MHC-1), and may be mistaken for polymyositis.
In LGMD2G there may be rimmed vacuoles.
In LGMD2H the biopsy may show features of sarcotubular myopathy (see Congenital myopathy).
In LGMD2J the muscle biopsy may be myopathic with rimmed vacuoles.
Immunohistochemical findings are as follows:
Dystrophin testing is usually the first step in dystrophic biopsy performed by using antibodies against the N-terminus, rod, and C-terminus. A minor reduction in dystrophin staining can be seen in sarcoglycanopathies. Conversely, a minor reduction in sarcoglycan staining may occur in dystrophinopathies.
All sarcoglycan antibodies should be tested next. While the pattern of sarcoglycan deficiency can be quite variable in sarcoglycanopathies, some generalizations can be made.[73] If α-sarcoglycan and γ-sarcoglycan are both absent, there is frequently a mutation in α-sarcoglycan (LGMD2D). Patients with a γ-sarcoglycan mutation (LGMD2C) have complete absence of γ-sarcoglycan. Patients with reduced levels of γ-sarcoglycan usually have a mutation in α-sarcoglycan (LGMD2D) or less commonly of β-sarcoglycan (LGMD2E).
Antibodies to dysferlin and calpain-3 are also important in evaluating LGMDs. Patients with LGMD2A have reduced staining for calpain-3 by Western blot. Reduction or loss of staining for the 60kD band is more sensitive and specific than loss of staining for the 30kD band. Loss of staining for both bands occurs in about 25% of cases and is highly specific for a calpain-3 mutation. About 25% of patients with a mutation may have a normal Western blot. Patients with LGMD2A may have reduction in immunohistochemical staining for dysferlin. Staining for dystrophin and the sarcoglycans is normal. Calpain-3 staining may be reduced in other disorders including LGMD1C, LGMD2B, LGMD2I, LGMDJ, and dystrophinopathies.
Patients with LGMD2B have reduced or absent immunohistochemical staining for dysferlin as well as absent or reduced Western blot staining. Absence of staining is highly specific for a mutation in the dysferlin gene, but there is no correlation between the level of staining and the severity of disease. However, a mutation in dysferlin was always found in patients with reduction in Western blot staining to less than 20% of normal.[74] Calpain-3 staining may also be reduced. Dystrophin and sarcoglycan staining is normal.
Patients with LGMDI, LGMD2K and LGMD2M all have reduced staining for glycosylated α-dystroglycan. There may also be a reduction in staining for laminin-α2.
Patients with LGMD1A often have increased staining for myotilin, desmin, and for other proteins typically found in myofibrillar myopathies (see below).
Patients with LGMD1C have reduced staining for caveolin-3 by immunohistochemistry and Western blot. There may also be reduced staining for dysferlin on immunohistochemistry.
Myofibrillar myopathies
General features include myopathic changes as well as the presence of hyaline/cytoplasmic bodies.
Immunohistochemistry shows aggregates containing desmin as well as numerous other proteins (myotilin, laminin-B, ubiquitin, αβ-crystallin, β-amyloid, dystrophin).
Examples of histologic findings are depicted in the images below.
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Top: Photomicrograph shows normal alpha-sarcoglycan staining of a myopathic biopsy specimen. Note dark staining around the rims of the muscle fibers. ....
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Gomori trichrome–stained section in patient with myofibrillar myopathy. Note the abnormal accumulations of blue-red material in several muscle fibers.....
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Immunohistochemical staining by using an anti-desmin antibody in a patient with a myofibrillar myopathy. Courtesy of Alan Pestronk.
No specific treatment is available for any of the LGMD syndromes, though aggressive supportive care is essential. The AAN developed guidelines for treatment of LGMDs.[65]
Cardiac involvement
Many LGMDs have associated cardiac disease. Newly diagnosed patients with LGMDs known to have cardiac involvement (LGMD1A, LGMD1B, LGMD1C, LGMD1E, LGMD2C-F, LGMD2G, LGMD2I, LGMD2M, LGMD2N, LGMD2R, LGMD2T, LGMD2U, LGMD2W, LGMD2X) should have early referral to a cardiologist. Cardiology referral should also be made for undiagnosed patients with LGMD.
Testing should include EKG and echocardiography. If these are abnormal or if cardiac symptoms develop, other tests may be needed including cardiac MRI, Holter monitoring, and event monitoring. Cardiac arrhythmias can be a major cause of morbidity and mortality (sudden cardiac death) and placement of a pacemaker can be a life-saving procedure.
Respiratory failure
Many LGMDs may have early respiratory involvement (LGMD1A, LGMD1B, LGMD1D, LGMD1E, LGMD1F, LGMD2B, LGMD2C-F, LGMD2G, LGMD2I, LGMD2J, LGMD2K, LGMD2M, LGMD2N, LGMD2O, LGMD2R, LGMD2T, LGMD2U, LGMD2V, LGMD2W).
Pulmonary function testing should be done in the neurology clinic or through referral to a pulmonologist in most LGMD patients at time of presentation or when symptomatic.
Patients with excessive daytime sleepiness, frequent arousals, morning headache, or with shortness of breath or abnormal pulmonary function tests should be referred to a pulmonary or sleep medicine clinic for consideration of non-invasive ventilation.
Early intervention to treat respiratory insufficiency with non-invasive ventilation can help improve function and prolong the patient's life expectancy.
Dysphagia and nutrition
Patients with dysphagia, aspiration, or weight loss should be evaluated with a modified barium swallow by a speech pathologist.
Nutritional supplementation or enteral feeding (gastrostomoy tube) may be needed to maintain optimal nutrition and reduce the risk of aspiration pneumonia.
Spinal deformities
Skeletal abnormalities, such as scoliosis and contractures can result in discomfort and impairment of gait or activities of daily living.
Neurologists should monitor for these and refer appropriate patients to a physical therapist, orthotist, or orthopedic surgeon
Passive stretching, bracing, and orthopedic procedures can help to allow the patient to remain independent for as long as possible.
As for other hereditary myopathies, a team approach, including a neurologist, pulmonologist, cardiologist, orthopedic surgeon, physiatrist, physical/occupational/speech therapist, nutritionist, orthotist, and counselors, ensures the best therapeutic program.
Exercise can help to counteract the loss of muscle tissue and strength in LGMD. Though there is no certain evidences about the type, frequency, or intensity, a training with moderate (less than 70% of predicted maximal aerobic capacity) aerobic exercise seems to be useful and safe in muscular dystrophies.[75]
Gene therapy using vectors based on the adeno-associated virus may become a viable treatment option in the future. Preliminary data using adeno-associated virus to deliver full-length α-sarcoglycan to the extensor digitorum brevis muscle in patients with LGMD2D resulted in 6 months of sustained α-sarcoglycan gene expression in 2 of 3 patients.[76] Muscle fiber size increased, and, in the patients with sustained expression, there were no neutralizing antibodies or T-cell immunity to adeno-associated virus.
A phase 1 trial of a neutralizing antibody against myostatin provided evidence of safety and tolerability.[77]
Guidelines issued by the American Academy of Neurology and the American Association of Neuromuscular & Electrodiagnostic Medicine call for referral of patients suspected of having MD to a specialist center for evaluation and genetic testing. Patients at high risk for cardiac complications should be given a cardiology evaluation, even if asymptomatic and those at known risk for respiratory failure should receive periodic pulmonary function testing.[64, 65]
Additional consultation with the following may prove helpful:
In general patients with LGMD lead a sedentary lifestyle due to their weakness. The effect of endurance training has been only rarely studied.
A study of endurance training on patients with LGMD2I and mild weakness was carried out. The patients cycled for 30 minute training sessions progressing up to a maximum of 5 sessions per week over 12 weeks at 65% of their maximum oxygen uptake. Training significantly improved work capacity, paralleled by self-reported improvements. Creatine kinase levels did not increase significantly, and muscle morphology was unaffected. The authors concluded that moderate-intensity endurance training is a safe method to increase exercise performance and daily function in patients with LGMD2I.
However, this was a small study, performed in only one form of LGMD, has not been replicated and lasted only 12 weeks. The long-term repercussions of endurance training in LGMD are not known and caution should be used in recommending endurance training for patients with LGMD.
In 2014, guidelines for the diagnosis and management of patients with limb-girdle or distal muscular dystrophies were issued by the American Academy of Neurology (AAN) and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). The guidelines were endorsed by the American Academy of Physical Medicine and Rehabilitation, the Child Neurology Society, the Jain Foundation, and the Muscular Dystrophy Association.[78]
The guideline provides algorithms for diagnosis, with the clinical picture, ethnicity, family history, and cardiac and respiratory symptoms all considered in deciding whether genetic testing for muscular dystrophy (MD) is appropriate and which of the many individual tests to select. The guidelines call for referral of patients suspected of having MD to a specialist center for evaluation and genetic testing. The key recommendations are listed below.
Clinicians should use a clinical approach to guide genetic diagnosis based on the clinical phenotype, including the following (level B):
Pattern of muscle involvement
Inheritance pattern
Age at onset
Associated manifestations (eg, early contractures, cardiac or respiratory involvement)
In patients with suspected MD in whom initial clinically directed genetic testing does not provide a diagnosis, clinicians may obtain genetic consultation or perform any of the following to identify the genetic abnormality (level C):
Parallel sequencing of targeted exomes
Whole-exome sequencing
Whole-genome screening
Next-generation sequencing
Other referral and assessment recommendations include the following:
Clinicians should refer newly diagnosed patients for cardiology evaluation, even if they are asymptomatic, to guide appropriate management; the evaluation should include an electrocardiogram (ECG) and structural evaluation (echocardiography or cardiac magnetic resonance imaging [MRI]) (level B)
If cardiology evaluation yields abnormal results, or if the patient has episodes of syncope, near-syncope, or palpitations, clinicians should order rhythm evaluation (eg, Holter monitor or event monitor) to guide appropriate management (level B)
Refer patients with palpitations, symptomatic or asymptomatic tachycardia or arrhythmias, or signs and symptoms of cardiac failure for cardiology evaluation (level B)
Referral of patients with LGMD2A, LGMD2B, and LGMD2L for cardiac evaluation is not obligatory unless they develop overt cardiac signs or symptoms (level B)
Refer patients with dysphagia, frequent aspiration, or weight loss for swallowing evaluation or gastroenterology evaluation to assess and manage swallowing function and aspiration risk, to teach patients techniques for safe and effective swallowing (eg, chin tuck maneuver, altered food consistencies), and to consider placement of a gastrostomy/jejunostomy tube for nutritional support (level B)
Refer for pulmonary function testing (PFT; spirometry and maximal inspiratory/expiratory force in the upright and, if normal, supine positions) or referral for pulmonary evaluation (to identify and treat respiratory insufficiency) at the time of diagnosis, or if the patient develops pulmonary symptoms (level B)
In patients with a known high risk of respiratory failure (eg, those with LGMD2I or MFM), obtain periodic pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright position and, if normal, in the supine position) or evaluation by a pulmonologist to identify and treat respiratory insufficiency (level B)
Referral of patients with LGMD2B and LGMD2L for pulmonary evaluation is not obligatory unless they are symptomatic (level C)
Refer patients with excessive daytime somnolence, nonrestorative sleep (eg, frequent nocturnal arousals, morning headaches, excessive daytime fatigue), or respiratory insufficiency based on PFTs for pulmonary or sleep medicine consultation for consideration of noninvasive ventilation to improve quality of life (level B)
Monitor patients for the development of spinal deformities to prevent resultant complications and preserve function (level B)
Refer patients with musculoskeletal spine deformities to an orthopedic spine surgeon for monitoring and surgical intervention if it is deemed necessary in order to maintain normal posture, assist mobility, maintain cardiopulmonary function, and optimize quality of life (level B)
Refer patients to a clinic that has access to multiple specialties (eg, physical therapy, occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics) designed specifically to care for patients with MD and other neuromuscular disorders in order to provide efficient and effective long-term care (level B)
Clinicians should recommend that patients have periodic assessments by a physical and occupational therapist for symptomatic and preventive screening (level B)
While respecting and protecting patient autonomy, clinicians should proactively anticipate and facilitate patient and family decision-making as the disease progresses, including decisions regarding loss of mobility, need for assistance with activities of daily living, medical complications, and end-of-life care (level B)
Prescribe physical and occupational therapy, as well as bracing and assistive devices that are adapted specifically to the patient's deficiencies and contractures, in order to preserve mobility and function and prevent contractures (level B)
Advise patients that aerobic exercise combined with a supervised submaximal strength training program is probably safe (level C)
Advise patients that gentle, low-impact aerobic exercise (swimming, stationary bicycling) improves cardiovascular performance, increases muscle efficiency, and lessens fatigue (level C)
Counsel patients to hydrate adequately, not to exercise to exhaustion, and to avoid supramaximal, high-intensity exercise (level C)
Educate patients who are participating in an exercise program about the warning signs of overwork weakness and myoglobinuria, which include feeling weaker rather than stronger within 30 minutes after exercise, excessive muscle soreness 24–48 hours after exercise, severe muscle cramping, heaviness in the extremities, and prolonged shortness of breath (level B)
Clinicians should not offer patients gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine the efficacy and safety of the treatment (level R)
What is limb-girdle muscular dystrophy (LGMD)?What are the signs and symptoms of limb-girdle muscular dystrophy (LGMD)?How is limb-girdle muscular dystrophy (LGMD) diagnosed?What is the approach to treatment of limb-girdle muscular dystrophy (LGMD)?How was limb-girdle muscular dystrophy (LGMD) initially defined?What was the alphanumeric classification of limb-girdle muscular dystrophy (LGMD)?What is the 229th ENMC international workshop definition of limb-girdle muscular dystrophy (LGMD)?Which conditions are no longer considered subtypes of limb-girdle muscular dystrophy (LGMD)?How is limb-girdle muscular dystrophy (LGMD) currently classified?What is the pathophysiology of limb-girdle muscular dystrophy (LGMD)What is the prevalence of limb-girdle muscular dystrophy (LGMD)What is the morbidity and mortality associated with limb-girdle muscular dystrophy (LGMD)What are the racial predilections of limb-girdle muscular dystrophy (LGMD)What are the sexual predilections of limb-girdle muscular dystrophy (LGMD)At what age is limb-girdle muscular dystrophy (LGMD) typically diagnosed?What is the prognosis of limb-girdle muscular dystrophy (LGMD)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2B (LGMD2B)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2C-2F (LGMD2C-2F)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2G (LGMD2G)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2H (LGMD2H)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2I (LGMD2I)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2J (LGMD2J)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2K (LGMD2K)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2L (LGMD2L)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2M (LGMD2M)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2N (LGMD2N)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2O (LGMD2O)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2P (LGMD2P)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2Q (LGMD2Q)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2R (LGMD2R)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2S (LGMD2S)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2T (LGMD2T)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2U (LGMD2U)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2V (LGMD2V)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2W (LGMD2W)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2X (LGMD2X)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2Y (LGMD2Y)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2Z (LGMD2Z)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy R22 (LGMDR22)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy R23 (LGMDR23)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy R24 (LGMDR24)?Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1A (LGMD1A)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1B (LGMD1B)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1C (LGMD1C)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1D (LGMD1D)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1E (LGMD1E)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1F (LGMD1F)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1G (LGMD1G)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1H (LGMD1H)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy 1I (LGMD1I)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy D5 (LGMDD5)Which clinical history findings are characteristic of limb-girdle muscular dystrophy (LGMD)?Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2A (LGMD2A)Which clinical history findings are characteristic of autosomal-dominant limb-girdle muscular dystrophy (LGMD)?Which clinical history findings help to differentiate among limb-girdle muscular dystrophy (LGMD) types?Which clinical history findings are characteristic of myofibrillar myopathies?What causes limb-girdle muscular dystrophy (LGMD)?What causes myofibrillar myopathies?What are the differential diagnoses for Limb-Girdle Muscular Dystrophy?What is the role of lab tests in the workup of limb-girdle muscular dystrophy (LGMD)?What is the role of MRI in the workup of limb-girdle muscular dystrophy (LGMD)?What are the roles of EMG and NCS in the workup of limb-girdle muscular dystrophy (LGMD)?What is the role of EEG in the workup of limb-girdle muscular dystrophy (LGMD)?What is the role of muscle biopsy in the workup of limb-girdle muscular dystrophy (LGMD)?Which histologic findings are characteristic of limb-girdle muscular dystrophy (LGMD)?How is limb-girdle muscular dystrophy (LGMD) treated?How are cardiac diseases treated in limb-girdle muscular dystrophy (LGMD)?How is respiratory failure treated in limb-girdle muscular dystrophy (LGMD)?How is dysphagia treated in limb-girdle muscular dystrophy (LGMD)?How are the skeletomuscular manifestations of limb-girdle muscular dystrophy (LGMD) treated?What is the role of surgery in the treatment of limb-girdle muscular dystrophy (LGMD)?Which specialist consultations are beneficial to patients with limb-girdle muscular dystrophy (LGMD)?Which activity modifications are used in the treatment of limb-girdle muscular dystrophy (LGMD)?What are the AAN and AANEM guidelines for the diagnosis and treatment of limb-girdle muscular dystrophy (LGMD)?What is included in the long-term monitoring of limb-girdle muscular dystrophy (LGMD)?When is inpatient care indicated for the treatment of limb-girdle muscular dystrophy (LGMD)?What are the possible complications of limb-girdle muscular dystrophy (LGMD)?What is the prognosis of limb-girdle muscular dystrophy (LGMD)?What is included in patient education about limb-girdle muscular dystrophy (LGMD)?
Monica Saini, MBBS, MD, Senior Resident Physician, Neurology, National Neuroscience Institute, Singapore; Clinical Tutor, National University of Singapore
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Nicholas Lorenzo, MD, MHA, CPE, Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc; Chief Strategy Officer, Discourse LLC
Disclosure: Nothing to disclose.
Additional Contributors
Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital
Disclosure: Nothing to disclose.
Raj D Sheth, MD, Chief, Division of Pediatric Neurology, Nemours Children's Clinic; Professor of Neurology, Mayo Clinic Alix School of Medicine; Professor of Pediatrics, University of Florida College of Medicine
Disclosure: AAN reviewer, ACNS Ed board, Infantile spasms consultant for: AAN; ACNS; Mackilrodt.
Hughes S. Guideline to Aid Muscular Dystrophy Diagnosis, Management. Medscape Medical News. Available at http://www.medscape.com/viewarticle/833400. Accessed: October 19, 2014.
Naravanaswami P., et al. . Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies: 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 Oct. 14;83(16):1453-63.
Bönnemann CG, Bushby K. The limb-girdle muscular dystrophies. Engel AG, Franzini-Armstrong C. Myology. 3rd ed. New York, NY: McGraw Hill; 2004. 1077-1121.
Neuromuscular Disease Center. Dilated cardiomyopathy. St Louis, Mo: Washington University. Available at https://neuromuscular.wustl.edu/. Accessed: January 12, 2006.
Neuromuscular Disease Center. Large or prominent muscles. Familial partial lipodystrophy (Kobberling-Dunnigan syndrome). St Louis, Mo: Washington University. Available at https://neuromuscular.wustl.edu/. Accessed: September 19, 2005.
Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, dysferlin, and caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan can result in limb-girdle muscular dystrophy syndrome. Reprinted with permission from Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. In: Neuromuscular Disorders. Vol. 15. Cohn RD. Elsevier; 2005: 207-17. 7, 20
Schematic of the sarcomere with labeled molecular components that are known to cause limb-girdle muscular dystrophy or myofibrillar myopathy. Mutations in actin and nebulin cause the congenital myopathy nemaline rod myopathy, and the mutations in myosin cause familial hypertrophic cardiomyopathy. Image courtesy of Dr F. Schoeni-Affoher, University of Friberg, Switzerland.
Top: Photomicrograph shows normal alpha-sarcoglycan staining of a myopathic biopsy specimen. Note dark staining around the rims of the muscle fibers. Bottom: Alpha-sarcoglycan stain of a muscle biopsy specimen from a patient with alpha-sarcoglycan deficiency. Note the absence of staining at the rims of the muscle fibers. Patterns of staining similar to these are observed in all the sarcoglycanopathies, dysferlinopathy, calpainopathy and limb-girdle muscular dystrophy type 2I (LGMD2I, Fukutin-related proteinopathy). However, staining may be variably reduced or absent.
Gomori trichrome–stained section in patient with myofibrillar myopathy. Note the abnormal accumulations of blue-red material in several muscle fibers.
Immunohistochemical staining by using an anti-desmin antibody in a patient with a myofibrillar myopathy. Courtesy of Alan Pestronk.
Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, dysferlin, and caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan can result in limb-girdle muscular dystrophy syndrome. Reprinted with permission from Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. In: Neuromuscular Disorders. Vol. 15. Cohn RD. Elsevier; 2005: 207-17. 7, 20
Schematic of the sarcomere with labeled molecular components that are known to cause limb-girdle muscular dystrophy or myofibrillar myopathy. Mutations in actin and nebulin cause the congenital myopathy nemaline rod myopathy, and the mutations in myosin cause familial hypertrophic cardiomyopathy. Image courtesy of Dr F. Schoeni-Affoher, University of Friberg, Switzerland.
Top: Photomicrograph shows normal alpha-sarcoglycan staining of a myopathic biopsy specimen. Note dark staining around the rims of the muscle fibers. Bottom: Alpha-sarcoglycan stain of a muscle biopsy specimen from a patient with alpha-sarcoglycan deficiency. Note the absence of staining at the rims of the muscle fibers. Patterns of staining similar to these are observed in all the sarcoglycanopathies, dysferlinopathy, calpainopathy and limb-girdle muscular dystrophy type 2I (LGMD2I, Fukutin-related proteinopathy). However, staining may be variably reduced or absent.
Gomori trichrome–stained section in patient with myofibrillar myopathy. Note the abnormal accumulations of blue-red material in several muscle fibers.
Immunohistochemical staining by using an anti-desmin antibody in a patient with a myofibrillar myopathy. Courtesy of Alan Pestronk.
Previous name
Gene
Reason for exclusion
Proposed new name
LGMD1A
Myot
Distal weakness
Myofibrillar myopathy
LGMD1B
LMNA
High risk of cardiac arrhythmias; EDMD phenotype
Emery–Dreifuss muscular dystrophy (EDMD)
LGMD1C
CAV3
Main clinical features rippling muscle disease and myalgia
Rippling muscle disease
LGMD1E
DES
Primarily false linkage; distal weakness and cardiomyopathy
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