eMedicine Specialties > Neurology > Neuromuscular Diseases

Limb-Girdle Muscular Dystrophy

Author: Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Contributor Information and Disclosures

Updated: Nov 28, 2007

Introduction

Background

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
• Involvement of shoulder or pelvic-girdle muscles with variable rates of progression
• Severe disability within 20-30 years
• Muscular pseudohypertrophy and/or contractures uncommon

This classification allowed for a wide range of phenotypic variability. Improved diagnostic methods have demonstrated that a large group of neuromuscular disorders, including some that were not truly LGMD, were included in this definition.

LGMD classification has been revolutionized with the advent of molecular genetics. A recent classification scheme, proposed during a workshop in 1995, is based on clinical and molecular characteristics. It divides cases into autosomal dominant (LGMD1) and autosomal recessive (LGMD2) syndromes. This list continues to expand, and, as of this writing, specific mutations are known for 3 autosomal dominant LGMDs and 12 autosomal recessive LGMDs.  

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.

Cardinal morphologic features on muscle biopsy are vacuolated muscle fibers and inclusions that were initially given different names in the 1970s. In 1980, desmin was noted to accumulate in the inclusions, and the name desmin storage myopathy was coined. However, in the mid 1990s, other proteins were also found to accumulate in the abnormal muscle fibers, and molecular genetic studies revealed several chromosomal loci. Since then, the relatively generic term myofibrillar myopathy has been adopted. These diseases are discussed here in part because mutations in 2 genes can present with either an LGMD or a myofibrillar myopathy phenotype.

Pathophysiology

Limb-girdle muscular dystrophy (LGMD) protein defects occur in several pathways involved in the biologic function of muscle and can be divided into groups based on cellular localization. These include proteins associated with the sarcolemma (see Media file 1), proteins associated with the contractile apparatus (see Media file 2), and various enzymes involved in muscle function. However, 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.

The cause of myofibrillar myopathies is unknown but is discussed below for each of the different mutations that have been associated with the disease. Of interest, several mutations that result in myofibrillar myopathy are in genes that code for Z-disk proteins.

Frequency

International

• Autosomal recessive LGMDs are more common than the autosomal dominant forms of the disease, which probably account for about 10% of all LGMDs. The overall frequency of all LGMD syndromes has been estimated to be 5-70 per 1 million population in several countries.
• Different populations often have different frequencies of the various LGMDs.
• A study involving 6 centers in the United States examined muscle biopsy results and performed Western blotting in 266 patients with a referral diagnosis of LGMD. Of these, 18% had dysferlinopathy, 15% had sarcoglycanopathy, 15% had alpha-dystroglycanopathy, 12% had calpainopathy, and 1.5% had caveolinopathy.²
• LGMD2A may be the most common LGMD in some populations, accounting for about 25% of all cases.
• LGMD2B may be the most common form in other populations, accounting for approximately 20% of all cases.
• As a group, the sarcoglycanopathies (LGMD2C-2F) account for about another 20-25% of all cases, but 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 with 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 (alpha-sarcoglycanopathy) is twice as common as LGMD2C (gamma-sarcoglycanopathy) and 2E (beta-sarcoglycanopathy), and LGMD2F (delta-sarcoglycanopathy) is the least common.
• LGMD2I due to a mutation in the fukutin-related protein gene (FKRP) is also relatively common. Recent studies show that patients with this mutation account for 6-38% of cases of LGMD, with a particularly high prevalence in parts of Northern Europe.
• The remaining autosomal recessive LGMDs are rare and are often observed in selected populations (eg, Hutterite population of Manitoba for LGMD2H).
• Myofibrillar myopathies are rare disorders. Their prevalence and incidence are unknown. The largest series was from the Mayo Clinic and consisted of 63 patients with myofibrillar myopathy who were examined between 1977 and 2003.

Mortality/Morbidity

• Morbidity and mortality rates vary. With early onset, the course is generally rapid.
• Patients can become wheelchair bound in their early teens and die from respiratory complications in their late teens.
• Patients with slowly progressive LGMD may be able to ambulate for more than 30 years after disease onset, and they may not become wheelchair bound until much later than their teens. Some patients with confirmed mutations have had nearly normal strength.

Race

LGMD is reported in races and countries throughout the world.

Sex

Autosomal dominant and autosomal recessive forms of LGMD affect both sexes equally.

Age

• The age of onset varies among the different mutations.
• Age of onset can vary among families 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

History

Autosomal recessive limb-girdle muscular dystrophy (LGMD): All patients have a history of progressive, proximal muscle weakness. Described below are the major distinguishing characteristics. The Brazilian population has been particularly well studied, and much of the population data comes from this group.

• LGMD2A (calpainopathy)
• LGMD2A may be the most common autosomal recessive LGMD, accounting for about 30% of all cases in the Brazilian and other populations. 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.
• About two thirds of patients present at 8-15 years of age, with a range of 2-40 years.
• The most typical presentation is of weakness due to scapular-humeral-pelvic weakness that may be similar to the presentation of facioscapulohumeral dystrophy. LGMD2I may also have a similar phenotype.
• 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.
• Atrophy is often prominent.
• Progression tends to be slow, and wheelchair use begins 11-28 years after the onset of symptoms.
• The clinical course varies widely among and within families.
• Atypical presentations include a severe Duchenne-like course, exercise-induced stiffness and myalgia before the onset of weakness, 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 reported in about 10% of cases.
• Facial and cardiac involvement have not been reported.
• LGMD2B (dysferlinopathy)
• 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.
• Two main phenotypes can occur: a limb-girdle phenotype and a distal-myopathy phenotype (Miyoshi myopathy).
• With either phenotype, presentation usually occurs at 15-25 years, but it can be as early as 12 years.
• In the limb-girdle presentation, pelvic and femoral muscles are affected first, with the proximal portions of the arms becoming weak later. Gastrocnemius weakness and wasting may be prominent. The patient's gait is unique, with a waddling component combined with inability to raise his or her heels off the ground.
• 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.
• Late in the course of disease, the 2 modes of presentation usually become indistinguishable.
• Either phenotype can occur in the same family.
• 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 anterior leg weakness and foot drop or with asymptomatic hyperCKemia.
• Sarcoglycanopathies (LGMD2C-2F)
• 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 (alpha-sarcoglycan [adhalin]) accounts for 40% of the sarcoglycanopathies, LGMD2C and 2E (gamma-sarcoglycan and beta-sarcoglycan) each account for about 23% and LGMD2F (delta-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 slowly progressive course.
• 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 (telethoninopathy)
• To date, LGMD2D has been reported only in Brazilian patients, with great phenotypic variability between and within families.
• The age of onset is 2-15 years.
• Weakness is predominantly proximal, but one half of patients may present with foot drop, and nearly all eventually develop distal weakness.
• Calf hypertrophy occurs in about 50%.
• Wheelchair confinement occurs in the third to fourth decade.
• Mild cardiac involvement occurs in about 50%.
• LGMD2H (tripartite motif–containing gene 32 [TRIM32]–related dystrophy) 
• LGMD2H has been observed only in the Hutterite people of Manitoba .
• This disease is allelic with sarcotubular myopathy (see Congenital Myopathies).
• Most patients have a mild phenotype, with limb-girdle weakness and a waddling gait at presentation. The proximal arm muscles and the distal leg muscles are involved late.
• The age of onset is 8-27 years; some patients are asymptomatic in their third decade.
• Back pain and fatigue are common symptoms.
• Progression is slow, with continued ambulation until around 50 years of age or later.
• LGMD2I (fukutin-related proteinopathy) 
• LGMD2I may be a fairly common cause of autosomal recessive LGMD, causing 11% of all cases in Braziland 38% of cases in Denmark .
• The disease is allelic with congenital muscular dystrophy with secondary laminin alpha-2 deficiency (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. The most common presentation is likely a Becker-like onset with normal early motor milestones. An adult-onset form occurs at 11-40 years of age and is slowly progressive.
• 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 (826A>C) while 11 (29%) had a compound heterozygous mutation.³  
• 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.
• LGMD2J (titinopathy)
• LGMD2J has been described only in Finnish patients. Some family members have a typical limb girdle phenotype with severe proximal weakness (LGMD2J) while other family members have distal dominant weakness (Finnish [tibial] muscular dystrophy).
• The onset of the LGMD syndrome is at 10-30 years, with proximal weakness. Some patients later develop distal weakness.
• The disease slowly progresses, and wheelchair confinement usually occurs within 20 years, but some patients are ambulant past 60 years.
• No facial weakness or cardiac involvement is noted.
• LGMD2K
• LGMD2K has been described in Turkish and Italian families.
• The disease is allelic with Walker-Warburg syndrome. (See Congenital Muscular Dystrophy.)
• The age of onset is 1-6 years.
• LGMD2K is characterized by severe proximal muscle weakness with slow progression. Contractures may be present.
• Results of ophthalmologic and funduscopic examinations, including electroretinography, are normal.
• Facial dysmorphic features and mental retardation may occur, though brain MRIs are normal.
• LGMD2L
• LGMD2L has recently been proposed as the name for a LGMD syndrome described in 3 patients in 2 families with a mutation in the fukutin gene.⁴
• The disease is allelic with Fukuyama  congenital muscular dystrophy.
• Patients presented with hypotonia before age 1 year. Progression was moderate with proximal greater than distal weakness affecting the legs more than the arms. The affected children, now aged 7-9 years can still walk.
• Interestingly, these children have worsening weakness during febrile illnesses, and like boys with Duchenne muscular dystrophy, their weakness improves with steroids. 
• All children had normal intelligence and normal brain MRIs. 

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)
• Onset varies from young adulthood to the mid 70s.
• Weakness can initially be proximal or distal but progresses to clinically significant proximal and distal weakness in all patients.
• The progression is slow, with late loss of ambulation. 
•  Dysarthria may be prominent.
• Cardiomyopathy is noted in 50%.
• Neuropathy noted in over 50% may account for distal weakness.
• LGMD1B (laminopathy, allelic with autosomal dominant Emery-Dreifuss muscular dystrophy). 
• Onset can be from childhood (<10 y) to the 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)
• Onset is usually in the first or second decade, but it may manifest at a later age with a distal myopathy or elevation of CK levels.
• Patients have mild-to-moderate proximal weakness with slow-to-moderate progression.
• Exercise-induced cramps may be present.
• Calf hypertrophy affects some patients.
• Adults usually remain ambulant.
• Patients may also present with elevated CK levels without weakness but with myalgia and cramps, distal weakness, hypertrophic cardiomyopathy, or rippling-muscle disease. The last condition is 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.
• LGMD1D (Online Mendelian Inheritance in Man [OMIM] %603511)
• Two families have been described. 
• Onset is in adulthood, with proximal weakness. 
• Progression is slow. 
• Dysarthria may be present.
• LGMD1E (Dilated cardiomyopathy with conduction defect and muscular dystrophy, OMIM %602067)
• One large family has been described. 
• Onset is in early adulthood, with proximal weakness. 
• Progression is slow. 
• Cardiac arrhythmia and cardiomyopathy are noted in all patients beginning 1-2 decades after weakness and may lead to sudden death.
• LGMD1F
• One large family has been described.
• Onset is from the first year of life to the mid 50s. 
• LGMD1F causes early proximal weakness with progression to distal weakness in most patients.  
• 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.  
• LGMD1G
• One family has been described.
• Onset is in the 30s-40s.
• LGMD1G causes slowly progressive proximal weakness.

Clinical features to distinguish the main LGMDs are often most helpful early in the disease.

• LGMD1A: Dysarthria is common.
• LGMD1B: Cardiac complications include cardiomyopathy and arrhythmia. Contractures are common.
• LGMD1C: Onset is usually in childhood, but patients may present with asymptomatic elevations of CK levels. Calf hypertrophy may be prominent.
• LGMD2A: Patients have prominent atrophy of the periscapular, biceps, gluteus maximus, thigh adductors, and hamstring muscles, with sparing of the hip abductors. Contractures are common, in which case the disease needs to be differentiated from Emery-Dreifuss muscular dystrophy, Bethlem myopathy, and laminin-alpha2 deficiency.
• 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. Onset is in the late teens or early 20s.
• 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. Mental development is normal. Cardiomyopathy may be present in some.
• 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, no cardiac symptoms, but mild ECG changes. This form is reported in the Hutterite population.
• LGMD2I: This form has a widely variable spectrum with prominent muscle hypertrophy and cardiomyopathy (Duchenne like). 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.

• Myofibrillar myopathies, also called desmin-storage myopathies (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 initial morphological change in MFM is disintegration of the Z-disk, and then of the myofibrils, followed by abnormal ectopic accumulation of multiple proteins. 
• 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.
• 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, and 25% present with only proximal weakness. They are included in this article because some mutations are in the same genes that cause LGMD phenotypes.
• 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 may be present either as cardiomyopathy or arrhythmias and conduction block is present in about 50%.
• Specific mutations
• Desminopathy: 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 occurs in about 60% and may follow or precede myopathy, or it may be isolated. 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.
• Alpha-β -crystallinopathy: 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, or conduction abnormality. Other mutations can cause dominant congenital posterior polar cataract.
• Myotilinopathy: 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. 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.
• Filamin C (gamma-filamin) myopathy: Age at onset is 37-57 years, with proximal greater than distal weakness. Respiratory failure occurs in about 50% of patients. Neuropathy affects about 40%. Cardiac disease may be present.
• Z-band alternatively spliced PDZ motif-containing protein (ZASPopathy): 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.   
• 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 recent case was described with a myofibrillar myopathy. The patient presented at age 3 with difficulty running and at age 5 was noted to have limb-girdle weakness.
  

Physical

See History.

Causes

Autosomal recessive LGMD

• LGMD2A is caused by mutations on chromosome 15 in the calpain-3 gene.
  • More than 280 different, mostly private, mutations have been identified throughout the calpain-3 gene. With the exception of founder effects in isolated populations, no predominant mutations exist. All 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 and frameshift mutations, and large deletions or insertions.
  • In general, null mutations give rise to phenotypes more severe than those due to missense mutations.
  • Calpain-3 (p94) is a member of the calpain family of intracellular, soluble cysteine proteases that all have calcium-dependent activation. It is expressed almost exclusively in muscle and is likely anchored by titin.
  • The mechanisms involved in the pathogenesis of LGMD2A are unknown. Calpain-3 is a protease with many substrates that likely is involved in many physiological processes within muscle. It has been proposed to be involved in apoptosis, muscle cell differentiation, sarcomere formation, muscle remodeling, and regulation of the cytoskeleton. One hypothesis suggests that mutations in the calpain-3 gene lead either 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 turnover of muscle proteins, and an accumulation of damaged proteins that then accumulate within muscle. This leads to a cell stress response and cell toxicity and ultimately to a dystrophic phenotype.
  • On muscle biopsy, calpain-3 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 50 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. 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), and the dihydropyridine receptor within the T-tubule system.
  • Muscle biopsy may show reduced or absent immunohistochemical staining for dysferlin (also observed on Western blotting). Absent staining is only relatively specific for LGMD2B because reduced staining can be seen in other diseases such as LGMD2A. Staining for dystrophin and sarcoglycans is normal. On Western blotting, calpain-3 staining is reduced.
  • 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 gamma-sarcoglycan gene.
  • LGMD2D is caused by a mutation on chromosome 17 in the alpha-sarcoglycan (adhalin) gene.
  • LGMD2E is caused by a mutation on chromosome 4 in the beta-sarcoglycan gene.
  • LGMD2F is caused by a mutation on chromosome 5 in the delta-sarcoglycan gene.
  • Sarcoglycanopathies have a worldwide distribution. Where no founder effect is present, LGMD2D (alpha-sarcoglycanopathy) is the most common form, accounting for about 50% of cases. Missense and nonsense mutations are the most common for all the sarcoglycanopathies, though with gamma-sarcoglycanopathies (LGMD2C), small or large deletions are also common.
  • The genotype-phenotype correlation is often unclear. In general, nonsense or truncating mutations tend to increase the severity of disease. Interfamilial and intrafamilial variability with LGMD2C, 2D, and 2E is marked. Most mild cases are due to alpha-sarcoglycan mutations (LGMD2D). Patients with LGMD2E and LGMD2C tend to have severe phenotypes, but mild cases can also occur. Patients with the rare delta-sarcoglycan mutation (LGMD2F) tend to have a severe phenotype.
  • 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 beta and delta subunits with weaker binding of the alpha and gamma 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 alpha-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 beta-dystroglycan and binding of beta-dystroglycan to alpha-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 alpha-sarcoglycan. The sarcoglycan complex binds alpha-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). Alpha-sarcoglycan mutations cause absent or reduced alpha-sarcoglycan staining with preservation of staining for gamma-sarcoglycan. Minimal or no staining occurs for beta and delta-sarcoglycan. This is the only mutation for which the amount of residual staining (for alpha-sarcoglycan) and the clinical phenotype are correlated. Gamma-sarcoglycan mutations cause absent or reduced gamma-sarcoglycan staining with trace amounts of alpha, beta, and delta-sarcoglycan staining. Beta- and delta-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 4 Brazilian families with a wide range of phenotypic variability.
  • Telethonin protein (titin-cap protein) is a sarcomeric protein present in the Z disk that binds to titin and several other Z-disk proteins. Telethonin protein may help to maintain the integrity of the sarcomere. However, in patients with LGMD2G, in whom telethonin is absent from muscle, sarcomeric integrity is maintained.
• LGMD2H is caused by mutations on chromosome 9 in the TRIM32 gene.
  • To date, all patients have been Hutterites from Manitoba with the same Asp487Asn homozygous point mutation; this is the same mutation as that found in sarcotubular myopathy.
  • TRIM32 protein is an E3-ubiquitin ligase that transfers activated ubiquitin residues onto a target protein, tagging the protein for degradation in the proteosome.
  • On muscle biopsy, no protein accumulations or inclusions have been identified.
• LGMD2I 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 with secondary laminin-alpha2 deficiency (MDC 1C). (See Congenital Muscular Dystrophy.)
  • FKRP protein is a putative glycotransferase based on its sequence homology to fukutin. It is thought, but not formally demonstrated, to be involved in O-linked glycosylation of alpha-dystroglycan.
  • In muscle biopsy, antibodies to the glycosylated portion of alpha-dystroglycan show reduced staining (and decreased mass on Western blots). Antibodies to laminin-alpha2 may show reduced staining; however, in mild cases, this is often evident only on Western blots.
• LGMD2J is caused by mutations on chromosome 2 in the titin gene.
  • Finnish patients who are homozygous for titin mutations develop LGMD2J, while patients with a heterozygous mutation develop Finnish (tibial) muscular dystrophy.
  • Titin protein is the largest protein found in humans. It is a sarcomeric protein that spans the entire sarcomere from the M line to the Z disk. Titin binds many other sarcomeric proteins and plays a mechanical role in muscle contraction, keeping the contractile elements of skeletal muscle in place and providing elasticity to the sarcomere. 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.
• LGMD2K 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 alpha-dystroglycan.
  • Muscle biopsy shows decreased staining for alpha-dystroglycan.
• LGMD2L is caused by mutations on chromosome 9 in the fukutin POMT1 gene.
  • LGMD2L 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.
  • Muscle biopsy shows decreased staining for alpha-dystroglycan.

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 alpha-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 and 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, Z-disk streaming, and mild evidence of denervation.
• 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, myofibrillar myopathy, autosomal dominant dilated cardiomyopathy with AV block (or CMDI1A, see the Neuromuscular Disease Center), Familial partial lipodystrophy (Köbberling-Dunnigan syndrome) (see the Neuromuscular Disease Center), 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 any associated disease is unknown. The filament 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 has been linked to chromosome arm 7q.
• LGMD1E (dilated cardiomyopathy with conduction defect and muscular dystrophy) has been linked to chromosomal region 6q23.
• LGMD1F has been linked to chromosomal bands 7q32.1-32.2.
• LGMD1G has been linked to chromosomal region 4p21.

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.
• Desminopathy 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 alpha-helical rod domain, which is critically important for filament assembly. Different mutations cause highly 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.
• Alpha-β -crystallinopathy is caused by a mutation on chromosome 11 on the alpha-β -crystallin gene. Three mutations, all autosomal dominant, have been identified. 
  
  Alpha-β -crystallin protein is a small heat-shock protein that forms homo-oligomeric or hetero-oligomeric complexes with alpha-β -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 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 alpha-actinin, F-actin and filamin C and likely plays a role in cross-linking actin filaments and in control of sarcomere assembly.
• Filamin C myopathy 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.
• ZASP (Z-band alternatively spliced PDZ-containing protein) myopathy is caused by mutations on chromosome 10 in the ZASP gene. 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 alpha-actinin in the Z disk, and supports Z-disk structure during contraction. 
• 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
  • 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. Focal muscle fiber degeneration often occurs. 
  • Electron microscopy: 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 or Z-disk streaming. The normal myofibrillar architecture is replaced by fragments of thick and thin filaments and Z-disk material. Abnormal sarcomeric proteins and other organelles are degraded in autophagic vacuoles.
  • Immunohistochemical staining: Many proteins can be localized to over 50% of abnormal fibers noted on light microscopy: desmin, alpha-β -crystallin, myotilin, dystrophin, beta-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 alpha 1-antichymotrypsin, gelsolin, ubiquitin, synemin, and nestin.

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