LGMDhttp://www.ncbi.nlm.nih.

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Limb-Girdle Muscular Dystrophy Overview

Synonym: LGMD Elena Pegoraro, MD, PhD and Eric P Hoffman, PhD. Author Information Initial Posting: June 8, 2000; Last Update: August 30, 2012. Go to:

Summary
Disease characteristics. Limb-girdle muscular dystrophy (LGMD) is a purely descriptive term, generally reserved for childhood- or adult-onset muscular dystrophies that are distinct from the much more common X-linked dystrophinopathies. LGMDs are typically nonsyndromic, with clinical involvement typically limited to skeletal muscle. Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal, and muscle degeneration/regeneration on muscle biopsy. Most individuals with LGMD show relative sparing of the bulbar muscles, although exceptions occur, depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes. Diagnosis/testing. The limb-girdle muscular dystrophies typically show degeneration/regeneration (dystrophic changes) on muscle biopsy, which is usually associated with elevated serum creatine kinase concentration. For any male or female suspected of having limb-girdle muscular dystrophy, it is necessary to first rule out an Xlinked dystrophinopathy. Biochemical testing (i.e., protein testing by immunostaining or immunblotting) performed on a muscle biopsy can establish the diagnosis of the following LGMD types: sarcoglycanopathy, calpainopathy, dysferlinopathy, and O-linked glycosylation defects (also known as dystroglycanopathy). In some cases, demonstration of complete or partial deficiencies for any particular protein can then be followed by mutation studies of the corresponding gene. Molecular genetic testing for most genes in which mutations have been identified to cause LGMD is available on a clinical basis. Genetic counseling. The term LGMD1 (including, e.g., LGMD1A, LGMD1B) refers to genetic types showing dominant inheritance, whereas LGMD2 refers to types with autosomal recessive inheritance. Mutations at more than 50 loci have been reported, making accurate diagnosis and genetic counseling a challenge. In most instances, the proband represents a simplex case, and the families can be counseled for recurrence risks associated with rare autosomal recessive conditions, which leaves a "significant" risk only for the sibs of the

proband. Prenatal diagnosis for many forms of limb-girdle muscular dystrophy is available for families in which the causative mutations have already been identified. Management. No definitive treatments for the limb-girdle muscular dystrophies exist. Management should be tailored as much as possible to each individual and each specific LGMD type. Management to prolong survival and improve quality of life includes weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and prevent contractures, use of mechanical aids to help ambulation and mobility, surgical intervention for orthopedic complications, use of respiratory aids when indicated, monitoring for cardiomyopathy in LGMD types with cardiac involvement, and social and emotional support and stimulation. Go to:

Definition
Limb-girdle muscular dystrophy (LGMD) is a purely descriptive term, generally reserved for childhood- or adult-onset muscular dystrophies that are distinct from the much more common X-linked dystrophinopathies, which include Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) (both affected males and symptomatic females). At one time, the term LGMD was reserved for individuals with onset of weakness in adolescence or adulthood. More severe childhood presentations were previously termed a "severe childhood autosomal recessive muscular dystrophy" (SCARMD); however, SCARMD is now considered a subset of LGMD. The term LGMD1 (including, e.g., LGMD1A, LGMD1B) refers to genetic types showing dominant inheritance, whereas LGMD2 refers to types with autosomal recessive inheritance. Mutations at more than 50 loci have been shown to cause LGMD.

Clinical Manifestations
Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. Proximal weakness refers to weakness of the muscles closer to the center of the body (including the shoulder, pelvic girdle, upper thighs, and upper arms). Distal weakness refers to weakness in muscles farther from the center of the body (including lower legs and feet, lower arms and hands). Onset, progression, and distribution of the weakness and wasting may vary considerably among individuals and genetic subtypes. LGMDs are typically nonsyndromic, with clinical involvement typically limited to skeletal muscle. While most individuals with LGMD show relative sparing of the bulbar muscles, exceptions occur, depending on the genetic subtype.

Establishing the Diagnosis

The clinical course of the limb-girdle muscular dystrophies is typically progressive, though some individuals may show mild symptoms and/or the disease may stabilize. Serum creatine kinase (CK) concentration is usually elevated.

Muscle biopsy typically shows degeneration/regeneration of muscle fibers ("dystrophic changes"). In some LGMDs (i.e., sarcoglycanopathy, calpainopathy, dysferlinopathy, and glycosylation defects, or dystroglycanopathy) the diagnosis can be established based on "biochemical testing," i.e., immunostaining/immunoblotting of a muscle biopsy to determine if specific proteins are present or absent. In some cases, molecular genetic testing can be used to identify the specific diseasecausing mutations. Inflammatory myopathy should be excluded during the diagnostic process.

Differential Diagnosis
The following disorders are included in the differential diagnosis of the limb-girdle muscular dystrophies:

The dystrophinopathies are caused by mutations in DMD. Duchenne muscular dystrophy (DMD) usually presents in early childhood and is rapidly progressive, with affected children being wheelchair-bound by age 12 years. Few survive beyond the third decade. Becker muscular dystrophy) (BMD) is characterized by later-onset skeletal muscle weakness. Affected individuals remain ambulatory into their 20s, but heart failure from dilated cardiomyopathy (DCM) is common. Inheritance is X-linked. DMD/BMD carriers are usually asymptomatic, but about 10% of them may present with muscle weakness or dilated cardiomyopathy. Any male or female suspected of having limb-girdle muscular dystrophy must first be evaluated for dystrophinopathy. o Males should be evaluated by molecular genetic testing of DMD and, when necessary, by dystrophin immunostaining or immunoblotting of a muscle biopsy. o Females should be evaluated by dystrophin immunostaining of a muscle biopsy or by molecular genetic testing of DMD. Note: In the past, when a female with muscular dystrophy was the only affected family member, a diagnosis of autosomal recessive LGMD was made; however, the affected female is nearly as likely to be a manifesting DMD carrier as to have some form of LGMD [Hoffman et al 1992, Hoffman et al 1996]. Facioscapulohumeral muscular dystrophy (FSHD) typically presents before age 20 years with marked weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. Severity is highly variable. Those individuals without significant facial weakness can closely resemble those with LGMD. Weakness is slowly progressive and approximately 20% of affected individuals require a wheelchair. Life expectancy is not shortened. A deletion of integral copies of a 3.3-kb DNA repeat motif termed D4Z4 is detected in about 95% of affected individuals. Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of (1) joint contractures that begin in early childhood; (2) slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution and later extending to the scapular and pelvic girdle muscles; and (3) cardiac involvement that may include palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. The X-linked form is caused by mutations in EMD, the gene encoding emerin; the dominant/recessive forms are caused by mutations in LMNA, the gene encoding lamin A/C.

Congenital muscular dystrophy (CMD) is a group of disorders in which weakness is present at birth. Affected infants typically appear "floppy" with low muscle tone and contractures. Diagnosis is based on (1) muscle biopsy, which typically shows a dystrophic or myopathic pattern, with or without fatty infiltration; (2) serum creatine kinase (CK) concentration, which is usually elevated; (3) immunostaining of muscle, which is abnormal in specific subtypes; and (4) brain MRI, which may show structural abnormalities indicative of syndromic congenital muscular dystrophy or abnormal white matter signal. Approximately 50% of CMD is caused by complete merosin deficiency; diagnosis is made by detection of complete merosin deficiency on immunostaining of muscle biopsy and abnormal white matter signal on MRI after age four months. The congenital muscular dystrophies are inherited in an autosomal recessive manner. Collagen type VI-related disorders are a continuum from Ullrich congenital muscular dystrophy to Bethlem myopathy. Bethlem myopathy is characterized by the combination of proximal muscle weakness and variable contractures, affecting most frequently the long finger flexors, elbows, and ankles. The onset of Bethlem myopathy ranges from prenatal to mid-adulthood. Prenatal onset is characterized by decreased fetal movements; neonatal onset by hypotonia or torticollis; early childhood onset by delayed motor milestones, muscle weakness, and contractures; and adult onset (4th to 6th decades) by proximal weakness and Achilles tendon or long finger flexor contractures. Because of slow but ongoing progression of the condition, more than two thirds of affected individuals older than age 50 years rely on supportive means for outdoor mobility. Respiratory muscle and diaphragmatic involvement is rare and seems to be related to severe weakness that occurs in later life. Bethlem myopathy is inherited in an autosomal dominant manner and Ullrich congenital muscular dystrophy usually in an autosomal recessive manner. Myositis (inflammatory myopathies) can share histopathologic features with the LGMDs. Inflammatory diseases typically show more acute onset and respond to immunosuppressive therapy; however, few types of LGMD also respond well to immunosuppressive therapy (i.e., prednisone). Clinical and histologic overlap between dysferlinopathy (LGMD2B) and inflammatory disease is considerable; individuals with myositis on muscle biopsy who do not respond to immunomodulation therapy can be considered for dysferlin testing.

Prevalence
Because of the heterogeneity of limb-girdle muscular dystrophy and the lack of diagnostic specificity, there are few reports on the prevalence of LGMD. Estimates of prevalence for all forms of LGMD range from one in 14,500 to one in 123,000 [van der Kooi et al 1996, Urtasun et al 1998]. The estimated prevalence of primary sarcoglycanopathies is approximately one in 178,000 [Fanin et al 1997]. According to this estimate, the carrier frequency can be estimated at 1:211; while Hackman et al [2005] estimate the carrier frequency of sarcogycanopathy at 1:150. Go to:

Causes
In this section, the type of limb-girdle muscular dystrophy is categorized by mode of inheritance and molecular genetics.

Autosomal Recessive Limb-Girdle Muscular Dystrophy

Molecular Genetics Table 1. Molecular Genetics of Autosomal Recessive Limb-Girdle Muscular Dystrophy (LGMD) % of Individuals with Disease Name Populations with AR LGMD (Synonym) Founder Mutations Alphasarcoglycanopathy None (LGMD2D) Beta-sarcoglycanopathy Amish (LGMD2E) Up to 68% of individuals with Gammachildhood onset and sarcoglycanopathy North Africans; ~10% with adult onset 2 (formerly SCARMD) Gypsies 4 (LGMD2C) 3 Delta-sarcoglycanopathy Brazilian 5 (LGMD2F) Amish, La Reunion Calpainopathy 6 ~10% Island, Basque (LGMD2A) (Spain), Turkish Dysferlinopathy ~5% Libyan Jewish (LGMD2B) 3% LGMD2G Italian (?) Manitoba Hutterites Unknown LGMD2H only LGMD2I 6% 7 Unknown (MDDGC5) 8 Unknown LGMD2J Finland LGMD2K Unknown Turkish (MDDGC1) 8 ~25% in the UK Northern LGMD2L population European 9, 10 LGMD2M Unknown Unknown (MDDGC4) 8 LGMD2N Unknown Unknown (MDDGC2) 8 LGMD2O Unknown Unknown (MDDGC3) 8 Unknown LGMD2Q Turkish Gene Symbol SGCA SGCB SGCG Locus 1 17q21.33 4q12 13q12.12

SGCD CAPN3 DYSF TCAP TRIM32 FKRP TTN POMT1 ANO5 FKTN POMT2

5q33.3 15q15.1 2p13.2 17q12 9q33.1 19q13.32 2q31.2 9q34.13 11p14.3 9q31.2 14q24.3

POMGNT1 1p34.1 PLEC 8q24.3

1. From omim.org 2. Vainzof et al [1999] 3. SCARMD = severe childhood autosomal recessive muscular dystrophy 4. Merlini et al [2000] 5. Nigro et al [1996], Vainzof et al [1999] 6. Ranges from 10% in the population of European descent [Chou et al 1999] to 80% in the Basque country [Urtasun et al 1998]. Actual frequency depends on the population. 7. Boito et al [2005] 8. MDDG (muscular dystrophy-dystroglycanopathy) [Amberger et al 2011] 9. Hicks et al [2011] 10. Penttil et al [2012] Sarcoglycanopathies, including -sarcoglycanopathy (LGMD2D) caused by mutation of SGCA; -sarcoglycanopathy (LGMD2E) caused by mutation of SGCB; -sarcoglycanopathy (LGMD2C) caused by mutation of SGCG; -sarcoglycanopathy (LGMD2F) caused by mutation ofSGCD. The four different sarcoglycan genes encode proteins that form a tetrameric complex at the muscle cell plasma membrane. This complex stabilizes the association of dystrophin with the dystroglycans and contributes to the stability of the plasma membrane cytoskeleton. The four sarcoglycan genes are related to each other structurally and functionally, but each has a distinct chromosome location (see Table 1). In outbred populations, the relative frequency of mutations in the four genes is alpha >> beta >> gamma >> delta in an 8:4:2:1 ratio [Duggan et al 1997a]. No common mutations have been identified in outbred populations except the p.Arg77Cys mutation, which accounts for up to one third of the mutated SGCA alleles [Hackman et al 2005]. Founder mutations have been observed in certain populations (Table 1). Calpainopathy (LGMD2A; caused by mutation of CAPN3). Calpain 3 is a calcium-sensitive protease involved in muscle remodeling. To date, more than 450 mutations in CAPN3 have been described. Dysferlinopathy (LGMD2B; DYSF). Dysferlin is a sarcolemmal protein that includes C2 domains thought to be important for calcium-mediated vesicle fusion with sarcolemma and membrane repair of skeletal muscle fibers [Bansal et al 2003, Han & Campbell 2007]. Although intra- and interfamilial clinical variability is significant, no specific genotypephenotype correlations have been established [Cagliani et al 2003]. LGMD2G (TCAP). Homozygosity for a TCAP mutation has been identified in four Brazilian families [Moreira et al 2000]. Affected individuals in one Italian family have been found to have compound heterozygous TCAP mutations.

LGMD2H (TRIM32). Mutations reported in TRIM32 include two missense mutations, one codon deletion, and two frameshift mutations [Frosk et al 2002, Saccone et al 2008, Cossee et al 2009]. The first-described TRIM32 mutation, p.Asp487Asn, is a founder mutation in the Hutterite population (of North America); one sib pair has been identified in a non-Hutterite family in Germany (the country of origin of the Hutterites). Sarcotubular myopathy (STM), also observed in the Hutterite population, is now known to be caused by the same mutation in TRIM32 [Schoser et al 2005, Borg et al 2009]. TRIM32 codes for an E3-Ub ligase responsible for post-translational regulation of protein levels [Frosk et al 2002]. O-linked glycosylation enzymes (dystroglycanopathies) including LGMD2I (caused by mutation of FKRP), LGMD2K (POMT1), LGMD2M (FKTN), LGMD2O (POMGNT1), LGMD2N (POMT2). These five different genes encode glycosyltransferases involved in the addition of carbohydrate residues to -dystroglycan and abnormal glycosylation of this molecule is a common finding in these forms of LGMD. Mutations of these genes have been associated with muscular dystrophies of variable severity ranging from congenital muscular dystrophies with various eye and brain involvement (see Congenital Muscular Dystrophy Overview) to milder forms with later onset (limb-girdle muscular dystrophies). Relatively few individuals with an LGMD phenotype and mutations in POMT1, FKTN, POMGNT1, or POMT2 have been reported [Balci et al 2005, Godfrey et al 2006, Biancheri et al 2007, Godfrey et al 2007, Clement et al 2008]. Reported affected individuals are compound heterozygous for missense or nonsense mutations. No common mutations have been reported except in LGMD2I. LGMD2I (FKRP). Individuals who are homozygous or compound heterozygous for missense mutations in FKRP have an LGMD phenotype. In contrast, individuals who are homozygous or compound heterozygous for nonsense mutations (complete loss of function) have a severe congenital muscular dystrophy (MDC1C) (see Congenital Muscular Dystrophy Overview). To date, two common mutations, 826C>A and 427C>A, have been observed in individuals with LGMD2I but not in those with MDC1C [Brockington et al 2001]. The identification of asymptomatic individuals who are homozygous for either of the common mutations and other asymptomatic individuals who are compound heterozygous for the common mutations suggests that other genes modify the disease presentation and/or age of onset [Boito et al 2005]. Note that the second mutation in compound heterozygotes may be any one of a number of missense, nonsense, deletion, and insertion mutations. Individuals homozygous for the 826C>A common mutation have a milder phenotype than those who are compound heterozygous [Brockington et al 2001, Mercuri et al 2003, Poppe et al 2003]. LGMD2L (ANO5). Anoctamin, encoded by ANO5, is a putative calcium-activated chloride channel possibly involved in membrane repair mechanism in muscular dystrophies. To date, a common mutation, one base-pair duplication c.191dupA (p.Asn64LysfsX15), has been reported both in the homozygous and heterozygous state; it is considered a founder mutation in northern Europe. ANO5 mutations identified to date include splice site, missense, and frame shift changes [Bolduc et al 2010, Hicks et al 2011, Penttil et al 2012]. See ANO5Related Muscle Diseases.

LGMD2J (TTN). In this disorder, all affected individuals characterized to date have a homozygous 11-bp deletion/insertion in the last exon (termed Mex6) of TTN. The deletion alters four amino acids and is close to the calpain-3 binding site. This mutation is common in the Finnish population. In the heterozygous state this mutation causes Udd distal myopathy [Hackman et al 2002]. LGMD2K (POMT1). LGMD2K is a form of LGMD2 with mild intellectual disability identified in five individuals from consanguineous families [Balci et al 2005] and in three additional patients [Godfrey et al 2007]. Mutations identified include three missense, one nonsense, and one frame-shift mutation in POMT1, the gene associated with WalkerWarburg syndrome (see Congenital Muscular Dystrophy Overview). The p.Ala200Pro mutation is an ancestral founder mutation in the Turkish population [Balci et al 2005]. LGMD2Q (PLEC). LGMD2Q is an early childhood-onset muscular dystrophy with progressive course and no skin involvement. The PLEC mutation identified in three families is a homozygous 9-bp deletion (c.1_9del) in exon 1f of the gene including the initiation codon. The c.1_9del is an ancestral founder mutation in a Turkish population from the Black Sea region [Gundesli et al 2010]. Plectin 1f is one of the particular scaffolds for costameric protein important for precise formation of myofiber structure [Gundesli et al 2010]. Other PLEC-associated phenotypes include epidermolysis bullosa simplex with late-onset progressive muscular dystrophy [Pulkkinen et al 1996] and myasthenic syndrome with lateonset myopathy [Banwell et al 1999]. Clinical Findings Table 2. Autosomal Recessive LGMD: Clinical Findings Presentation Other Findings Disease Name (Synonym) / Gene Weaknes Calf Contracture Symptoms Symbol s Muscle s/ Scoliosis Complete deficiency: Hypertroph Proximal Late Sarcoglycanopathie difficulty y s: run, walk LGMD2C / SGCG Partial LGMD2D / SGCA deficiency: LGMD2E / SGCB cramps, LGMD2F / SGCD exercise intolerance Proximal (normal Difficulty hip Calpainopathy run, walk, extensors (LGMD2A) / toe walk; Atrophy Early and CAPN3 stiff back adductors (rare) ), scapular winging Dysferlinopathy Inability to Distal Transient (LGMD2B) / tiptoe; and/or hypertroph Age Onset (Average)

Wheelchai r Bound

3-15 yrs (8.5 ~15 yrs yrs) Adolescent young adulthood

2-40 yrs (8- 11-28 yrs 15 yrs) after onset

17-23 yrs

pelvicfemoral difficulty DYSF (no y (rare) run, walk scapular winging) Proximal and distal Difficulty lower LGMD2G /TCAP run, walk; limb; foot drop proximal upper limb Facial weakness; Proximal waddling lower Muscle LGMD2H / TRIM3 Not reported gait, limb; wasting difficulty neck with stairs Proximal; Difficulty upper > Hypertroph LGMD2I / FKRP Rare, late run, walk lower y limb LGMD2J / TTN Proximal

9-15 yrs

~18 yrs after onset

1-9 yrs

Late in life

1.5-27 yrs (11.5 yrs) 5-25 yrs

23-26 yrs after onset Average 20 yrs after onset ~17 yrs (based on 1 individual; 4 remaining individuals , ages 7-17, still ambulatory )

Fatigability , difficulty Ankle climbing contractures stairs and present in 2 Mild running; Hypertroph of 5 LGMD2K / weakness; cognitive y of calves individuals; 1-3 yrs POMT1 proximal delay with and thighs elbow, spine, > distal limited and neck language contractures developme in 1 patient nt Adult onset (>20 yrs) of Proximal proximal pelvicQuadriceps lower and femoral , hamstring Contractures upper limbs Late teensLGMD2L / ANO5 or distal and biceps (wrist, finger, weakness 50s in the brachi TA) and/or lower atrophy difficulties limbs standing on toes LGMD2M / FKTN Early-onset Proximal; Hypertroph Not reported 4 mo - 4 yrs muscle lower > y of calves, weakness, upper thighs, and

Not reported

Not reported

difficulties climbing stairs, severe weakness limb after intercurrent illness -steroid responsive

triceps

Scapular winging and Slowness in LGMD2N / Hypertroph mild running and None POMT2 y of calves lordosis; getting up intellectual disability Difficulties Hypertroph raising y of calves from sitting and LGMD2O/ and Proximal quadriceps; Ankle POMGNT1 climbing > distal wasting of contractures stairs; hamstrings severe and myopia deltoids Delayed motor milestone, Muscle Multiple difficulties LGMD2Q / PLEC Proximal atrophy in contractures climbing 1 patient in 1 patient stairs, keeping up with peers

18 mo; 20 yrs (1 asymptomati patient) c at 5 yrs

12 yrs

19 yrs (1 patient)

2-3 yrs

24 yrs (1 patient)

Sarcoglycanopathies, including -sarcoglycanopathy, (LGMD2D); -sarcoglycanopathy, (LGMD2E); -sarcoglycanopathy, (LGMD2C); -sarcoglycanopathy (LGMD2F). Findings range from early childhood onset with severe progression (similar to Duchenne muscular dystrophy) to later onset with milder progression (similar to Becker muscular dystrophy) (see Table 2). Calf hypertrophy is common. Heart involvement is variable, but typically less severe than in the dystrophinopathies. Cardiomyopathy is common in beta-, delta-, and gamma-sarcoglycanopathy, but rare in alpha-sarcoglycanopathy [Melacini et al 1999, Fanin et al 2003, Kirschner & Lochmuller 2011]. Overall, about 30% of individuals have evidence of cardiomyopathy on ECG and echocardiogram. Significant discordance between siblings has been observed, including two siblings with SGCA mutations: one had onset at age 20 years and the other was asymptomatic at age 35 years [Angelini et al 1998]. Most individuals with severe, childhood-onset limb-girdle muscular dystrophy have mutations of SGCA, SGCB, SGCC, or SGCD [Duggan et al 1997a]. Thus, an individual with a clinical presentation and progression similar to Duchenne muscular dystrophy but with

normal dystrophin immunostaining in muscle is likely to have a primary sarcoglycanopathy. In contrast, only about 10% of individuals with limb-girdle muscular dystrophy with milder disease (onset in adolescence or adulthood) have a sarcoglycanopathy. Some individuals heterozygous for a mutation in SGCA have mild clinical symptoms including scapular winging and calf hypertrophy [Fischer et al 2003]. Genotype/phenotype correlations in large series have been published in multiple populations [Dincer et al 1997, Duggan et al 1997a, Duggan et al 1997b, Vainzof et al 1999, Merlini et al 2000]. Calpainopathy (LGMD2A; caused by mutation of CAPN3). Intra- and interfamilial clinical variability ranges from severe to mild. Three calpainopathy phenotypes have been identified based on the distribution of muscle weakness and age at onset:

Pelvifemoral LGMD (Leyden-Mbius) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle with onset before age 12 years or after age 30 years; Scapulohumeral LGMD (Erb) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle; and HyperCKemia, usually observed in children or young individuals, in which symptomatic individuals have only high serum CK concentrations.

Clinical findings include the tendency to walk on tiptoes, difficulty in running, scapular winging, waddling gait, and slight hyperlordosis. Early Achilles tendon shortening and scoliosis may be present. Dysferlinopathy (LGMD2B; caused by mutation of DYSF). The spectrum of muscle disease is characterized mainly by two phenotypes:

Limb-girdle muscular dystrophy syndrome (LGMD2B) with early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Respiratory and cardiac muscles are not involved. Miyoshi myopathy with muscle weakness and atrophy in young adults, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength, but the small muscles of the hands are spared.

Two other phenotypes are seen:

Distal anterior compartment myopathy (DMAT), which presents in the third decade with weakness of the anterior tibialis muscles. The disease is rapidly progressive resulting in severe proximal weakness of the lower limbs first, followed by the upper limbs [Illa et al 2001]. Dysferlinopathy with rigid spine, which presents with lower limb weakness and atrophy in addition to contractures of the neck, chest, hip, and knee [Nagashima et al 2004]

LGMD2G (caused by mutation of TCAP). Significant variability has been seen among the 14 individuals reported from four families. Some persons showed distal atrophy while others exhibited calf hypertrophy. All had significant proximal weakness. Cardiac involvement occurred in about half. Females appear to be less severely affected than males [Zatz et al 2003]. LGMD2H (TRIM32). Severity ranges from asymptomatic to severe proximal weakness. Facial weakness and a "flat smile" are common [Weiler et al 1998, Saccone et al 2008]. Affected individuals can remain ambulatory well into adulthood with some reports of ambulation (with difficulty) into the sixth decade [Weiler et al 1998, Saccone et al 2008]. Irreversible loss of motility after prolonged immobilization has been reported [Saccone et al 2008]. Sarcotubular myopathy (STM), caused by the same mutation in TRIM32, represents the severe end of the LGMD2H phenotype [Schoser et al 2005, Borg et al 2009]. LGMD2I (FKRP). The phenotype ranges from severe (similar to Duchenne muscular dystrophy) to mild with no clinically apparent skeletal muscle involvement [Brockington et al 2001, de Paula et al 2003, Mercuri et al 2003, Poppe et al 2003, Poppe et al 2004, Boito et al 2005, Muller et al 2005]. Cardiomyopathy without skeletal muscle involvement has been reported. When onset is in the first years of life, the ability to walk is lost about the beginning of the second decade. The milder end of the spectrum more closely resembles Becker muscular dystrophy, with later onset (age 6-23 years) and ambulation continuing into the third decade albeit with increasing difficulty. Cardiac involvement occurs in 10%-55% of affected individuals. Cardiomyopathy appears to present earlier in heterozygotes than homozygotes. Poppe et al [2004] identified respiratory involvement (i.e., a forced vital capacity lower than 75%) in about 50% of affected individuals. Memory impairment [Bourteel et al 2009] and mild impairment in executive function and visuo-spatial planning without substantial impairment in global and logic IQ have been reported [Bourteel et al 2009, Palmieri et al 2011]. Brain MRI studies showed a small number of patients with focal abnormal cortical signals consistent with dysplasia, subcortical atrophy, and frontal cortical atrophy with periventricular nonspecific white matter signal [Bourteel et al 2009, Palmieri et al 2011]. LGMD2J (TTN). This disorder is the severe (homozygous state) form of the milder tibial muscular dystrophy (TMD). Individuals with LGMD2J have a severe progressive proximal weakness with onset ranging from the first decade to the early 30s. In about half of all reported cases, weakness ultimately involved the distal muscles and individuals required the use of a wheelchair; in other cases ambulation was preserved. Joint contractures have not been associated with LGMD2J [Udd et al 1991]. LGMD2K (POMT1). Affected individuals exhibit mild proximal weakness with significant developmental delay. Individuals retain the ability to walk for at least 15 years after disease onset. Microcephaly without structural brain abnormalities, and intellectual disability with low IQ are reported in all patients [Balci et al 2005, Godfrey et al 2007, Lommel et al 2010]. All individuals had CK levels 10-40 times the normal range [Balci et al 2005, Godfrey et al 2007, Lommel et al 2010]. LGMD2L (ANO5). Affected individuals present with two distinct phenotypes:

Late onset proximal pelvic girdle muscle weakness with (often asymmetric) atrophy of the quadriceps femoris and biceps brachii Later-onset mild asymmetric calf hypertrophy or early calf weakness without atrophy associated with difficulties walking on tiptoes

As disease progresses the phenotypes overlap and merge into a homogeneous clinical entity [Hicks et al 2011], characterized by severe hip and thigh weakness with distal involvement. Muscle wasting affects quadriceps, hamstrings, and the medial gastrocnemius. Knee hyperextension is a common finding. In later stages of the disease mild weakness and wasting of the upper limbs is observed. Cardiac and respiratory involvement is not observed. See ANO5-Related Muscle Diseases. LGMD2M (FKTN). Affected individuals present with mild to moderate proximal muscle weakness in the lower and upper limbs. Weakness was more distal in the upper limb in one individual involving wrist and finger extensor and wrist flexors [Godfrey et al 2006]. Muscle hypertrophy was common. All patients reported are cognitively normal and have normal brain MRI [Godfrey et al 2006, Godfrey et al 2007, Puckett et al 2009]. Of interest, three individuals showed severe weakness after intercurrent illness with a remarkable response to steroid therapy [Godfrey et al 2006]. Minimal proximal weakness, normal intellect, and severe dilated cardiomyopathy have been reported in six Japanese patients [Murakami et al 2006]. LGMD2N (POMT2). Two affected individuals with discordant phenotypes have been reported. One affected female was asymptomatic at age five, but neurologic exam showed scapular winging, calf hypertrophy, and slowness in running and getting up. She had normal intellect [Biancheri et al 2007]. The second reported individual had developmental delay but remain ambulant at age 20. Muscle hypertrophy was present. She showed intellectual disability and right bundle branch block [Godfrey et al 2007]. LGMD2O (POMGNT1). One affected female has been reported. Her early motor milestones were normal. Progressive muscle weakness was first reported at age 12 years and progressed to the loss of ambulation at age 19 years. Weakness was more proximal than distal, with the neck, hip girdle, and shoulder abductor muscles particularly affected. There was hypertrophy of the calves and quadriceps, wasting of the hamstring and deltoid muscles, and ankle contractures. The woman had severe myopia and was cognitively normal [Clement et al 2008]. Another patient reported by Godfrey [Godfrey et al 2007] had a discordant, milder, phenotype. This individual presented in the second decade with mild proximal weakness and had normal intellectual function. LGMD2Q (PLEC). Six individuals have been reported. Onset was in early childhood and was slowly progressive until the late teenage years, with rapid progression thereafter. Delay in motor milestones was a common presenting symptom. Muscle weakness was proximal and progressive. Loss of ambulation in the late 20s has been observed. Multiple contractures and muscle atrophy were reported in one individual. No cardiac or respiratory involvement was reported and intelligence was normal. No affected individuals had any evidence of a skin disorder [Gundesli et al 2010].

Autosomal Dominant Limb-Girdle Muscular Dystrophy

Most of the autosomal dominant limb-girdle muscular dystrophy loci have been described in single extended pedigrees [Speer et al 1999] (see Table 3 and Table 4). These disorders are considered rare. Molecular Genetics Table 3. Molecular Genetics of Autosomal Dominant LGMD Disease Name LGMD1A (Myotilinopathy) LGMD1B LGMD1C (Caveolinopathy) LGMD1D LGMD1E LGMD1F LGMD1G LGMD1H Gene Symbol (Locus Name 1) Chromosomal Locus MYOT 5q31.2 LMNA 1q22 CAV3 3p25.3 DES 2q35 DNAJB6 7q36.3 Unknown 7q32.1-q32.2 Unknown 4q21 Unknowm 3p25.1-p23

1. Locus name given if gene symbol is unknown Myotilinopathy (LGMD1A caused by mutation of MYOT). Four missense mutations p.Thr57Ile and p.Ser55Phe [Hauser et al 2000, Hauser et al 2002], p.Arg450Lys [Shalaby et al 2009], and p.Arg6His [Reilich et al 2011] have been described in four families in MYOT encoding the myotilin protein. Mutations in MYOT have been also reported in myofibrillar myopathy [Selcen & Engel 2004] and in spheroid body myopathy [Foroud et al 2005]. Myotilin is a sarcomeric protein that binds to alpha-actinin and is associated with the Z-line. The normal function of myotilin is to stabilize assembled actin bundles and to facilitate normal myofibril organization. The abnormal protein results in Z-line streaming and myofibril aggregation compromising the structure of the sarcomere [Salmikangas et al 2003]. LGMD1B (LMNA). Mutations in LMNA result in at least eleven allelic conditions including LGMD1B, autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy, Dunnigan-type familial partial lipodystrophy (FPLD), mandibuloacral dysplasia, Hutchinson-Gilford progeria syndrome, and Charcot-Marie-Tooth type 2B1. Although missense mutations in LMNA were believed to be the sole cause of LGMD1B, Todorova et al [2003] found that synonymous changes in LMNA can result in splice site mutations that also cause LGMD1B. To date all LMNA mutations resulting in LGMD1B have been found in exons 1 to 11 [Mercuri et al 2005]. LGMD1C (caveolinopathy; CAV3). CAV3 encodes caveolin-3, a protein involved in membrane trafficking in the myofiber. Cavelin-3 functions as part of the T-tubule system in skeletal muscle during development but not after maturation; conversely, caveolin-3 is always expressed in smooth muscle [Woodman et al 2004]. Mutations in CAV3 were first identified in a few Italian families [Minetti et al 1998]. (See Caveolinopathies.) LGMD1D. A single family showing an autosomal dominant limb-girdle phenotype was genetically mapped, although subsequent refinements of pedigree details altered locus assignment because age-dependent penetrance changed the phenotypic status of critical family members [Greenberg et al 2012]. An intron splice donor site mutation (IVS+3A>G) in

the desmin gene (DES) was identified in the family [Greenberg et al 2012]. Most desmin mutations result in other phenotypes, such as Dilated Cardiomyopathy, and Myofibrillar Myopathy. LGMD1E. DNAJB6 is a member of the HSP/DNAJ family of molecular co-chaperones involved in protecting proteins from irreversible aggregation during protein synthesis or cellular stress. Mutations in DNAJB6 have been identified in two families with AD-LGMD with skeletal muscle vacuoles [Harms et al 2012]. LGMD1F. Mapped in a large Spanish family, the gene has not yet been identified [Palenzuela et al 2003]. LGMD1G. Mapped in one Brazilian-European family, the gene has not yet been identified. LGMD1H. Mapped in one Italian family, the gene has not yet been identified [Bisceglia et al 2010]. Clinical Findings Table 4. Autosomal Dominant LGMD: Clinical Findings Name Late Findings Signs Tight Achilles tendons Nasal, dysarthric Myotilinopathy speech 18-40 years Proximal weakness Distal weakness (LGMD1A) (50%);respiratory insufficiency and dysphagia Mild contractures Birth to of elbows adulthood; Arrhythmia and Proximal lower LGMD1B ~1/2 with other cardiac limb weakness childhood complications (25onset 45 years) Sudden death Cramping Mild-moderate Caveolinopathy ~5 years proximal weakness Calf hypertrophy (LGMD1C) Rippling muscle disease Cardiac conduction All individuals LGMD1D <25 yrs defect, proximal remain ambulatory muscle weakness Proximal or distal weakness in the Mild heel contractures Wheelchair bound LGMD1E 18-40 years lower limbs in 1 patient at age 45-62 years progressing to the unaffected regions Presentation Onset (Average) Symptoms

LGMD1F LGMD1G LGMD1H

Proximal lower and Serum CK (normal to upper limb Distal weakness 20x normal) weakness Progressive limitation Proximal lower Proximal upper 30-47 years of finger and toe limb weakness limb weakness flexion Muscle hypotrophy of 16-50 years Proximal lower limb girdle muscles (39) limb weakness with calf hypertrophy 1-58 years

Myotilinopathy (LGMD1A). Findings in three families (North American with German and Argentinean ancestry and Turkish) and in one Japanese individual have been reported [Hauser et al 2000, Hauser et al 2002, Shalaby et al 2009, Reilich et al 2011]. In addition to the findings described in Table 4, reduced knee and elbow tendon reflexes are common. Nerve conduction studies are normal [Gilchrist et al 1988]. LGMD1B. Muscle weakness and cardiac involvement are present by the third decade. Left ventricular hypertrophy and atrioventricular conduction defect are common and can progress to second-degree heart block requiring a pacemaker; rarely, dilated cardiomyopathy is present. The onset of skeletal muscle weakness prior to cardiac involvement distinguishes LGMD1B from allelic LMNA disorders; the absence of elbow contractures distinguishes LGMD1B from Emery-Dreifuss muscular dystrophy (EDMD) [Mercuri et al 2005]. Caveolinopathy (LGMD1C). Mutations in CAV3 are associated with five distinct phenotypes that all demonstrate intrafamilial variability: (1) LGMD1C; (2) rippling muscle disease; (3) hyperCKemia; (4) familial hypertrophic cardiomyopathy; and (4) distal myopathy [Cagliani et al 2003, Fee et al 2004, Hayashi et al 2004, Woodman et al 2004]. Onset ranges from early childhood (first decade) to late adulthood. Those with childhood onset typically show a Gower sign, calf hypertrophy, and mild to moderate proximal weakness. Cardiac involvement is common [Hayashi et al 2004]. LGMD1D. In the only family reported cardiac conduction defects (heart block, ventricular tachycardia, paroxysmal atrial fibrillation, right bundle branch block), dilated cardiomyopathy, and/or muscle weakness were usually present. Conduction defects precede congestive heart failure. Onset is in early adulthood. LGMD1E. Two families have been reported. In one family, onset was in the fourth decade with a progressive proximal muscle weakness predominant in the lower limbs with a relative sparing of quadriceps compared to hamstrings. In the second reported family, onset was variable between 18 and 35 years with weakness in the distal lower extremities presenting with tripping. Weakness progressed to include the hands and proximal legs, with loss of ambulation after disease duration of 20-30 years [Harms et al 2012]. LGMD1F. One large Spanish family has been reported. Pelvic girdle weakness presented earlier than shoulder girdle weakness. Distal weakness occurred late. A juvenile-onset form and an adult-onset form were observed; the more rapid progression seen in the juvenile-onset form is thought to result from anticipation. A subset of individuals with the juvenile-onset form show scapular winging and facial muscle weakness. No calf hypertrophy, eye involvement, or intellectual impairment has been observed [Gamez et al 2001].

LGMD1G. While symptoms are slowly progressive, all but one individual were still ambulatory ten years after diagnosis. No other joint limitation, aside that noted in Table 4, was observed [Starling et al 2004]. LGMD1H. One large Italian family has been reported. Variable expression in terms of age at onset and disease severity was observed within the family. Patients either presented in the fourth-fifth decade of life with a slowly progressive muscle weakness in both upper and lower limb, or in the second-third decade with calf hypertrophy and/or muscle weakness and occasionally high CK and/or lactate serum level. Subsarcolemmal accumulation of mitochondria and multiple mitochondrial DNA deletion have been observed on muscle biopsy [Bisceglia et al 2010]. Go to:

Evaluation Strategy
Establishing the type of LGMD can be useful in discussions of the clinical course of the disease and for genetic counseling purposes. Establishing the specific type of LGMD in a given individual usually involves obtaining the medical history and family history, performing a physical examination, and laboratory testing (see Table 5) including serum CK concentration and muscle biopsy for histologic examination and protein testing [Pogue et al 2001]. Note: (1) Only dysferlin immunoblotting of muscle is currently thought to be specific and sensitive. (2) Results of immunostaining of muscle should be confirmed with molecular genetic testing when it is available. Use of molecular genetic testing to establish the specific type of LGMD is problematic:

Many genes are involved. Mutations in no one gene account for the majority of cases. Few clinical or laboratory findings help identify the associated gene for a given individual. The lack of common mutations prevents efficient screening by genotype. About 50% of currently identified LGMD would have no molecular diagnosis, even if all 20 currently known genes were fully sequenced.

For these reasons, clinicians may consider use of limb-girdle muscular dystrophy multi-gene panels that include a number of genes associated with LGMD. See . Note: Panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation(s) in any given individual with LGMD also varies. Table 5. Testing Used to Establish LGMD Type Test Availability Serum CK Muscle Protein Muscle Biopsy Molecula Protein Concentratio (Biochemical) Histology r Genetic (Biochemical) n Testing 1, 2 Testing Testing

Type

Autosomal recessive Alphasarcoglycanopath y Betasarcoglycanopath Mildly to y greatly Gammaelevated sarcoglycanopath y Deltasarcoglycanopath y

Clinical Clinical Clinical Clinical Clinical (immunohistochemistry)

Myopathic changes

Reduced or complete absence of sarcoglycan antibodies 3

Calpainopathy

Fiber degeneration and Often 5-80x regeneration, normal, but central nuclei, can be normal fiber size variation, endomysial fibrosis Often >100x normal Significant inflammation sometimes observed 5

Absence of calpain-3 on immunoblotting Clinical , loss of calpain-3 autolytic activity 4 Absence or partial deficiency of dysferlin by immunoblot 6

Clinical (immunoblottin g and histochemistry)

4

Dysferlinopathy

Clinical

Clinical (immunohistochemistry and immunoblot) Not available

Myopathic changes with Absence of Telethoninopathy 3-17x normal rimmed telethonin vacuoles Fiber size variation with degeneration and LGMD2H 4-30x normal NA regeneration, internal nuclei and endomysial fibrosis Muscle fiber Variably size variation decreased with type 1 glycosylated Normal to fiber alphaLGMD2I greatly predominance dystroglycan; elevated and necrotic slight reduction and of laminin regenerating alpha 2 5 fibers LGMD2J Greatly Myopathic Almost

Clinical

Clinical

Not available

Clinical

Clinical (immunohistochemistry and immunoblotting of glycosylated alphadystroglycan) 4 Not available

Clinical

elevated

changes

complete absence of calpain-3 Clinical (immunohistochemistry and immunoblotting of glycosylated alphadystroglycan) 4 Not available Clinical (immunohistochemistry and immunoblotting of glycosylated alphadystroglyan) 4 Not available

LGMD2K

LGMD2L LGMD2M LGMD2N LGMD2O

Mild fibrosis; fiber size variation; regenerating Decreased and necrotic glycosylated 20-40x normal fibers; alphahypertrophic dystroglycan fibers with multiple central nuclei Myopathic or Greatly dystrophic NA elevated changes Muscular Decreased dystrophy often glycosylated 4-50x normal with alphainflammatory dystroglycan infiltrates Greatly elevated Dystrophic or Decreased myopathic plectin changes Normal myotilin on immunohistochemistry; reduced laminin 1 Myopathic changes Variable fiber size with central nuclei and fiber size variation NA

Clinical

Clinical Clinical Clinical Clinical

LGMD2Q

Clinical

Autosomal dominant Normal or mildly elevated Normal or mildly elevated Clinical

LGMD1A

Not available

LGMD1B

Clinical

Not available

LGMD1D

2-4x normal

LGMD1E

1-4x normal

Myopathic changes with endomysial DNAJB6 fibrosis and positive rimmed inclusions vacuoles; scattered COXnegative fibers Variable fiber NA size; increased endomysial connective

Not available

Clinical Not available

tissue Caveolin-3 reduced on immunofluorescence and western blotting; Clinical dysferlin reduced on immunohistochemistry and normal on western blot 7

Caveolinopathy

4-25x normal

Myopathic changes

Clinical (immunohistochemistry and immunoblotting )

Variable fiber size with Normal to 20x LGMD1F increased NA Not available normal connective tissue Normal Fiber size immunostaining variation with for dystrophin, Normal to 9x LGMD1G necrotic fibers sarcoglycans, Not available normal and rimmed calpain-3, vacuoles telethonin, and dysferlin Myopathic changes and subsarcolemma Normal to 10x LGMD1H l mitochondria NA Not available normal accumulation; rarely, raggedred fibers Clinical Limb-girdle muscular dystrophy multi-gene panels 8 Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratorysubmitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. 1. Muscle protein (biochemical) testing: - Immunochemistry = exposing sections of tissue to an antibody to determine if a specific protein is present or absent. Immunohistochemistry does not quantify the amount of the protein.

- Immunostaining = use of a dye to detect the antibody - Immunofluorescence = use of a fluorescent dye to detect the antibody - Immunoblot (or western blot) = removing a specific protein from a tissue of interest to quantify the size and amount of the protein Note: Not all protein tests are available for each of the conditions in Table 5, nor are all protein tests as effective in diagnosing each form of LGMD (e.g., immunoblot for dysferlin is both sensitive and specific for diagnosing LGMD2B, whereas immunostaining for dysferlin is sensitive but not specific). 2. Most protein tests are not specific for proteins altered by a mutation in a particular gene, but the results can help focus molecular genetic testing. 3. Because of the interdependent nature of the sarcoglycan complex, deficiency of any of the four sarcoglycan proteins on immunostaining can be representative of a mutation in any of the four sarcoglycan genes. Sensitivity and specificity for the sarcoglycanopathies is high, although specificity for the particular form of sarcoglycanopathy is low. 4. Specificity is low. 5. May lead to misclassification as autoimmune disease 6. Immunostaining for dysferlin is much less specific than immunoblotting. Immunoblotting of muscle or white blood cells is highly specific for mutations in DYSF. 7. Protein quantification is unreliable; diagnosis relies on molecular genetic testing [Woodman et al 2004]. 8. The genes included and the methods used in multi-gene panels vary by laboratory. Sarcoglycanopathy. Mutation in any one of the sarcoglycan genes leads to secondary deficiency of all the sarcoglycan proteins detected by immunostaining of muscle. For example, immunostaining of muscle from individuals with mutations in the gene encoding alpha-sarcoglycan show marked deficiency or absence of alpha-, beta-, gamma-, and deltasarcoglycan. Typically a single sarcoglycan antibody (alpha-sarcoglycan) is used to classify an individual as having complete or partial sarcoglycan deficiency. Using antibodies against all four sarcoglycan proteins may identify a sarcoglycan deficiency more precisely; however, no immunostaining pattern is specific enough to identify which of the four genes encoding the sarcoglycan proteins is most likely to be mutated. Heterozygotes for a mutation in SGCA, the gene encoding alpha-sarcoglycan, have normal levels of alpha-, beta-, gamma-, and delta-sarcoglycan on immunostaining of muscle, despite mild clinical features [Fischer et al 2003]. Because individuals with dystrophinopathy have deficient sarcoglycan proteins detected on immunostaining of muscle, both dystrophin immunostaining and sarcoglycan

immunostaining must be performed on the same sample. The finding of normal dystrophin immunostaining and complete deficiency of any of the sarcoglycans suggests that mutations in one of the genes encoding the sarcoglycan proteins may be causative. Data suggest that immunostaining of frozen muscle is relatively sensitive for detecting primary sarcoglycanopathy; however, it is not specific. Calpainopathy. Deficiency of calpain-3 on immunostaining of muscle biopsy is observed in calpainopathy and also as a secondary effect in many types of LGMD. Because sensitivity and specificity for both immunostaining and western blot analysis are reduced, protein analysis needs to be interpreted with caution and diagnosis needs to be confirmed with molecular genetic testing. Dysferlinopathy. Immunostaining of muscle usually reveals complete absence of dysferlin, although partial deficiency has also been observed. LGMD2I, LGMD2K, LGMD2M, LGMD2O, LGMD2N. Immunostaining of muscle reveals significant reduction in the amount of glycosylated alpha dystroglycan with antibodies recognizing glycosylated epitopes of alpha dystroglycan. There is a good correlation between the reduced alpha dystroglycan staining and clinical course in individuals with mutations in POMT1, POMT2 and POMGNT1, but this is not always the case in FKTN and FKRP mutations [Jimenez-Mallebrera et al 2009]. Go to:

Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Mode of Inheritance
Limb-girdle muscular dystrophy may be transmitted in an autosomal recessive manner or less commonly in an autosomal dominant manner. Difficulties in accurate diagnosis and determination of inheritance in an individual family make genetic counseling particularly complicated.

Risk to Family Members Autosomal Recessive Limb-Girdle Muscular Dystrophy

Parents of a proband

The parents are obligate heterozygotes and therefore carry a single copy of a diseasecausing mutation.

Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Clinical severity and disease phenotype often differ among individuals with the same mutations; thus, age of onset and/or disease progression in affected sibs cannot be predicted.

Offspring of a proband

All offspring are obligate carriers. In inbred populations with an autosomal recessive disorder, risks to the offspring of a proband should be calculated based on the carrier frequency in the population.

Other family members of a proband. Each sib of an obligate carrier is at a 50% risk of being a carrier.

Carrier Detection
Carrier detection using molecular genetic techniques is available on a clinical basis for some types of limb-girdle muscular dystrophy once the mutations have been identified in the proband.

Risk to Family Members Autosomal Dominant Limb-Girdle Muscular Dystrophy

Parents of a proband

Most individuals diagnosed as having autosomal dominant limb-girdle muscular dystrophy have an affected parent, although symptoms may be variable among family members. Occasionally the family history is negative. It should be emphasized that an individual with no family history of LGMD may have a de novo dominant mutation. The frequency of de novo mutations causing any of the types of limb-girdle muscular dystrophy is unknown. Note: Although most individuals diagnosed with autosomal dominant limb-girdle muscular dystrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

The risk to sibs depends on the genetic status of the proband's parents. If one of the proband's parents has a mutant allele, the risk to the sibs of inheriting the mutant allele is 50%. Clinical severity and disease phenotype often differ among individuals with the same mutation; thus, age of onset and/or disease progression cannot be predicted. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband

Individuals with autosomal dominant limb-girdle muscular dystrophy have a 50% chance of transmitting the mutant allele to each child. Clinical severity and disease phenotype often differ among individuals with the same mutation; thus, age of onset and/or disease progression cannot be predicted.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Uncertainties regarding the specificity of protein-based testing of individual muscle biopsies make accurate genetic counseling difficult when based purely on protein testing of muscle biopsy. Often the mode of inheritance cannot be determined. In most instances, the families can be counseled for recurrence risks associated with rare autosomal recessive conditions, which leaves a "significant" risk only for the sibs of the proband. Because many of the LGMDs show a later onset, the parents of the proband may have completed their family by the time that the diagnosis is established. Family planning

The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing
Prenatal diagnosis for pregnancies at increased risk is possible for some types of limb-girdle muscular dystrophy by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at

about ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) have been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see . Note: It is the policy of GeneReviews to include in GeneReviews chapters any clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s). Go to:

Management
Treatment of Manifestations
No definitive treatments for the limb-girdle muscular dystrophies exist. Management should be tailored as much as possible to each individual and each specific LGMD type. A general approach to appropriate management can prolong survival and improve quality of life. This general approach is based on the typical progression and complications of individuals with LGMD as described by McDonald et al [1995] and Bushby [1999].

Weight control to avoid obesity Physical therapy and stretching exercises to promote mobility and prevent contractures Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis Use of respiratory aids when indicated Referral to a cardiologist for standard supportive treatment of cardiomyopathy Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders [Eggers & Zatz 1998] Genetics consultation

Surveillance

Monitoring for orthopedic complications such as foot deformity and scoliosis Monitoring of respiratory function Monitoring for evidence of cardiomyopathy in those LGMD types known to have cardiac involvement

Agents/Circumstances to Avoid

Weight should be controlled to avoid obesity.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory. See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. Go to:

Resources
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.ED. Go to:

References
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page

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Suggested Reading
1. Bushby KM. The limb-girdle muscular dystrophies - multiple genes, multiple

mechanisms. Hum Mol Genet. 1999;8:187582. [PubMed] 2. Messina DN, Speer MC, Pericak-Vance MA, McNally EM. Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Am J Hum Genet. 1997;61:90917. [PMC free article] [PubMed] Go to:

Chapter Notes
Author History
Erynn Gordon, MS, CGC; Children's National Medical Center (2003-2012) Eric P Hoffman, PhD (2000-present) Elena Pegoraro, MD, PhD (2000-present) Cheryl Scacheri, MS; GeneDx, Inc (2000-2003)

Revision History

30 August 2012 (me) Comprehensive update posted live 23 July 2009 (cd) Revision: clinical testing available for LGMD1A, telethoninopathy, LGMD2H, and LGMD 2J 8 June 2007 (cd) Revision: clinical testing available for caveolinopathies 8 February 2006 (cd) Revision: clinical testing available for LGMD2K 3 February 2006 (me) Comprehensive update posted to live Web site 14 October 2004 (eh) Revision: Differential Diagnosis

26 July 2004 (eh) Revision: prenatal testing for LGMD1B; changes to Bethlem myopathy 11 February 2004 (eh) Revision: sequence analysis for LMNA clinically available 14 November 2003 (eh) Revision: molecular genetic testing clinically available 14 August 2003 (me) Comprehensive update posted to live Web site 31 January 2001 (eh) Author revisions 8 November 2000 (eh) Author revisions 8 June 2000 (tk, pb) Overview posted to live Web site 20 April 2000 (eh) Original submission

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Ringkasan Penyakit karakteristik. Limb-korset distrofi otot (LGMD) adalah istilah murni deskriptif, umumnya dicadangkan untuk dystrophies anak-atau orang dewasaonset otot yang berbeda dari X-linked dystrophinopathies jauh lebih umum. LGMDs biasanya nonsyndromic, dengan keterlibatan klinis biasanya terbatas pada otot rangka. Individu dengan LGMD umumnya menunjukkan kelemahan dan wasting terbatas pada otot-otot tungkai, lebih besar daripada distal proksimal, dan degenerasi otot / regenerasi pada biopsi otot. Kebanyakan individu dengan relatif menunjukkan hemat LGMD dari otot-otot bulbar, meskipun pengecualian terjadi, tergantung pada subtipe genetik. Onset, kemajuan, dan distribusi kelemahan dan membuang-buang bervariasi antara individu-individu dan subtipe genetik. Diagnosis / pengujian. Ekstremitas-korset dystrophies otot biasanya menunjukkan degenerasi / regenerasi (perubahan dystrophic) pada biopsi otot, yang biasanya dikaitkan dengan konsentrasi creatine kinase peningkatan serum. Untuk setiap pria atau wanita yang diduga ekstremitas-korset distrofi otot, maka perlu aturan pertama keluar sebuah dystrophinopathy X-linked. Pengujian Biokimia (yaitu, protein pengujian dengan immunostaining atau immunblotting) dilakukan pada otot biopsi dapat menentukan diagnosis jenis LGMD berikut: cacat glikosilasi sarcoglycanopathy, calpainopathy, dysferlinopathy, dan O-linked (juga dikenal sebagai dystroglycanopathy). Dalam beberapa kasus, demonstrasi kekurangan lengkap atau parsial untuk setiap protein tertentu kemudian dapat diikuti oleh penelitian mutasi gen yang sesuai. Tes genetik molekuler untuk gen kebanyakan di mana mutasi telah diidentifikasi untuk menyebabkan LGMD tersedia secara klinis. Genetik konseling. The LGMD1 panjang (termasuk, misalnya, LGMD1A, LGMD1B) mengacu pada jenis genetik menunjukkan warisan dominan, sedangkan LGMD2 mengacu pada jenis dengan warisan resesif autosomal. Mutasi di lebih dari 50 lokus telah dilaporkan, membuat diagnosis yang akurat dan konseling genetik tantangan. Dalam kebanyakan kasus, proband mewakili kasus simplex, dan keluarga dapat diberi konseling untuk risiko kekambuhan dikaitkan dengan langka kondisi resesif autosomal, yang meninggalkan "signifikan" risiko hanya untuk saudara kandung dari proband tersebut. Diagnosis prenatal untuk berbagai bentuk ekstremitas-korset distrofi otot tersedia bagi keluarga di mana mutasi penyebab telah diidentifikasi. Manajemen. Tidak ada pengobatan definitif untuk ekstremitas-korset dystrophies otot ada. Manajemen harus disesuaikan sebanyak mungkin untuk setiap individu dan setiap jenis LGMD tertentu. Manajemen untuk memperpanjang kelangsungan hidup dan meningkatkan kualitas hidup meliputi pengendalian berat badan untuk menghindari obesitas latihan, terapi fisik dan peregangan untuk meningkatkan mobilitas dan mencegah kontraktur, penggunaan alat bantu mekanik untuk membantu ambulasi dan mobilitas, intervensi bedah ortopedi untuk komplikasi, penggunaan alat bantu pernapasan bila diindikasikan , pemantauan untuk kardiomiopati dalam jenis LGMD dengan keterlibatan jantung, dan dukungan sosial dan emosional dan stimulasi. Pergi ke: Definisi

Limb-korset distrofi otot (LGMD) adalah istilah murni deskriptif, umumnya dicadangkan untuk dystrophies anak-atau orang dewasa-onset otot yang berbeda dari dystrophinopathies terkait-X jauh lebih umum, yang meliputi distrofi otot Duchenne (DMD) dan distrofi otot Becker (BMD) (baik laki-laki dan perempuan yang terkena gejala). Pada suatu waktu, LGMD istilah disediakan untuk individu dengan timbulnya kelemahan pada masa remaja atau dewasa. Presentasi anak lebih parah yang sebelumnya disebut sebagai "masa kanak-kanak distrofi otot autosomal resesif yang parah" (SCARMD), namun, SCARMD sekarang dianggap sebagai subset dari LGMD. The LGMD1 panjang (termasuk, misalnya, LGMD1A, LGMD1B) mengacu pada jenis genetik menunjukkan warisan dominan, sedangkan LGMD2 mengacu pada jenis dengan warisan resesif autosomal. Mutasi di lebih dari 50 lokus telah terbukti menyebabkan LGMD. Manifestasi Klinis Individu dengan LGMD umumnya menunjukkan kelemahan dan wasting terbatas pada otot-otot tungkai, lebih besar daripada distal proksimal. Kelemahan proksimal mengacu pada kelemahan otot lebih dekat ke pusat tubuh (termasuk bahu, korset panggul, paha atas, dan lengan atas). Kelemahan distal mengacu pada kelemahan otot jauh dari pusat tubuh (termasuk kaki bawah dan kaki, lengan bawah dan tangan). Onset, kemajuan, dan distribusi dari kelemahan dan wasting dapat bervariasi antara individu-individu dan subtipe genetik. LGMDs biasanya nonsyndromic, dengan keterlibatan klinis biasanya terbatas pada otot rangka. Sementara sebagian besar individu dengan relatif menunjukkan hemat LGMD dari otot-otot bulbar, pengecualian terjadi, tergantung pada subtipe genetik. Membangun Diagnosis Kursus klinis dari ekstremitas-korset dystrophies otot biasanya progresif, meskipun beberapa orang mungkin menunjukkan gejala ringan dan / atau penyakit dapat menstabilkan. kreatin kinase Serum (CK) konsentrasi biasanya ditinggikan. Otot biopsi biasanya menunjukkan degenerasi / regenerasi serabut otot ("perubahan dystrophic"). Dalam beberapa LGMDs (yaitu, sarcoglycanopathy, calpainopathy, dysferlinopathy, dan cacat glikosilasi, atau dystroglycanopathy) diagnosis dapat dibentuk berdasarkan "uji biokimia," yaitu, immunostaining / imunoblotting otot biopsi untuk menentukan apakah protein tertentu hadir atau tidak hadir . Dalam beberapa kasus, pengujian genetika molekuler dapat digunakan untuk mengidentifikasi penyebab penyakit mutasi spesifik. miopati inflamasi harus dikeluarkan selama proses diagnostik. Differential Diagnosis Gangguan berikut termasuk dalam diagnosis diferensial dari ekstremitas-korset dystrophies otot: Para dystrophinopathies disebabkan oleh mutasi pada DMD. Duchenne distrofi otot (DMD) biasanya menyajikan pada anak usia dini dan cepat progresif, dengan anak-anak yang terkena dampak yang duduk di kursi roda pada usia 12 tahun. Beberapa bertahan lebih dari satu dekade ketiga. Distrofi otot Becker) (BMD) ditandai dengan onset kemudian-kelemahan otot rangka. Individu yang

terkena tetap rawat jalan ke 20-an mereka, tapi gagal jantung dari kardiomiopati dilatasi (DCM) adalah umum. Warisan adalah X-linked. DMD / BMD pembawa biasanya tanpa gejala, tetapi sekitar 10% dari mereka mungkin hadir dengan kelemahan otot atau cardiomyopathy membesar. Setiap diduga laki-laki atau perempuan memiliki ekstremitas-korset distrofi otot pertama harus dievaluasi untuk dystrophinopathy. Pria o harus diuji secara genetik molekuler DMD dan, bila perlu, oleh distrofin immunostaining atau imunoblotting otot biopsi. Wanita o harus dievaluasi oleh immunostaining distrofin dari otot biopsi atau dengan pengujian genetika molekuler DMD. Catatan: Di masa lalu, ketika seorang wanita dengan distrofi otot adalah anggota keluarga hanya terkena, diagnosis LGMD resesif autosomal dibuat, namun, perempuan yang terkena hampir mungkin untuk menjadi pembawa DMD mewujudkan sebagai memiliki beberapa bentuk LGMD [Hoffman et al 1992, Hoffman et al 1996]. distrofi otot facioscapulohumeral (FSHD) biasanya menyajikan sebelum usia 20 tahun dengan kelemahan ditandai otot-otot wajah dan stabilisator dari skapula atau dorsiflexors kaki. Keparahan sangat bervariasi. Orang-orang tanpa kelemahan wajah signifikan erat dapat menyerupai dengan LGMD. Kelemahan bersifat progresif lambat dan sekitar 20% dari individu yang terkena memerlukan kursi roda. Harapan hidup tidak dipersingkat. Sebuah penghapusan salinan integral dari motif ulangi 3.3-kb DNA disebut D4Z4 terdeteksi di sekitar 95% dari individu yang terkena. Emery-Dreifuss distrofi otot (EDMD) ditandai oleh tiga serangkai klinis (1) kontraktur bersama yang dimulai pada anak usia dini, (2) progresif lambat kelemahan otot dan membuang-buang awalnya dalam distribusi humeroperoneal dan kemudian memperluas ke scapular dan panggul korset otot, dan (3) keterlibatan jantung yang mungkin termasuk palpitasi, presyncope dan sinkop, toleransi latihan miskin, dan gagal jantung kongestif. Bentuk X-linked disebabkan oleh mutasi pada EMD, gen emerin encoding; dominan / resesif bentuk yang disebabkan oleh mutasi pada LMNA, pengkodean gen Lamin A / C. distrofi otot kongenital (CMD) adalah sekelompok gangguan di mana kelemahan hadir pada saat lahir. Terkena bayi biasanya muncul "floppy" dengan nada otot rendah dan kontraktur. Diagnosa didasarkan pada (1) biopsi otot, yang biasanya menunjukkan pola dystrophic atau miopati, dengan atau tanpa infiltrasi lemak, (2) creatine kinase serum (CK) konsentrasi, yang biasanya ditinggikan, (3) immunostaining otot, yang abnormal pada subtipe tertentu, dan (4) MRI otak, yang bisa menunjukkan kelainan struktural menunjukkan distrofi otot sindrom bawaan atau sinyal materi putih abnormal. Sekitar 50% dari CMD disebabkan oleh defisiensi merosin lengkap, diagnosis dibuat dengan deteksi defisiensi merosin lengkap immunostaining dari biopsi otot dan sinyal materi putih abnormal pada MRI setelah usia empat bulan. Para dystrophies otot bawaan diwariskan secara autosomal resesif. Kolagen tipe VI-terkait gangguan adalah sebuah kontinum dari distrofi otot bawaan Ullrich untuk miopati Bethlem. Bethlem miopati dicirikan oleh kombinasi kelemahan otot proksimal dan kontraktur variabel, yang mempengaruhi paling sering fleksor jari panjang, siku, dan pergelangan kaki. Terjadinya berkisar miopati Bethlem dari pralahir untuk pertengahan dewasa. Onset Prenatal

ditandai dengan penurunan gerakan janin, neonatal onset oleh hypotonia atau tortikolis, onset anak usia dini oleh tonggak motorik tertunda, kelemahan otot, dan kontraktur, dan onset dewasa (4 untuk dekade 6) oleh kelemahan proksimal dan tendon Achilles atau kontraktur jari panjang fleksor . Karena perkembangan lambat tapi berlangsung dari kondisi, lebih dari dua pertiga dari individu yang terkena lebih tua dari usia 50 tahun mengandalkan sarana pendukung untuk mobilitas luar ruangan. Otot pernafasan dan keterlibatan diafragma adalah langka dan tampaknya berhubungan dengan kelemahan yang parah yang terjadi di kemudian hari. Bethlem miopati diwariskan secara autosomal dominan dan distrofi otot bawaan Ullrich biasanya secara resesif autosomal. Myositis (myopathies inflamasi) dapat berbagi fitur histopatologi dengan LGMDs. Penyakit inflamasi biasanya menunjukkan onset lebih akut dan menanggapi terapi imunosupresif, namun, beberapa jenis LGMD juga merespon dengan baik untuk terapi imunosupresif (misalnya, prednison). Tumpang tindih klinis dan histologis antara dysferlinopathy (LGMD2B) dan penyakit inflamasi cukup besar, individu dengan miositis pada otot biopsi yang tidak merespon terapi immunomodulation dapat dipertimbangkan untuk pengujian dysferlin. Kelaziman Karena heterogenitas ekstremitas-korset distrofi otot dan kurangnya spesifisitas diagnostik, ada beberapa laporan tentang prevalensi LGMD. Perkiraan prevalensi untuk semua bentuk rentang LGMD dari satu di 14.500 untuk satu 123.000 [van der Kooi et al 1996, Urtasun et al 1998]. Estimasi prevalensi sarcoglycanopathies primer sekitar satu dari 178.000 [Fanin et al 1997]. Menurut perkiraan ini, frekuensi pembawa dapat diperkirakan 1:211, sedangkan Hackman dkk [2005] memperkirakan frekuensi pembawa sarcogycanopathy di 1:150. Pergi ke: Penyebab Pada bagian ini, jenis ekstremitas-korset distrofi otot dikategorikan oleh modus warisan dan genetika molekular. Autosomal resesif Dystrophy Limb-Girdle Muscular Molekuler Genetika Tabel 1. Genetika Molekuler dari Dystrophy Resesif Autosomal Limb-Girdle Muscular (LGMD) % Dari Individu dengan Nama Penyakit LGMD AR (Sinonim) Populasi dengan Simbol Gene Mutasi Pendiri Locus 1 Hingga 68% dari individu dengan onset masa kanak-kanak dan ~ 10% dengan onset dewasa 2 Alpha-sarcoglycanopathy (LGMD2D) Tidak ada SGCA 17q21.33 Beta-sarcoglycanopathy (LGMD2E) Amish SGCB 4q12 Gamma-sarcoglycanopathy (sebelumnya SCARMD) (LGMD2C) 3 Afrika Utara, Gipsi 4 SGCG 13q12.12 Delta-sarcoglycanopathy (LGMD2F) Brazilian 5 SGCD 5q33.3 ~ 10% 6 Calpainopathy (LGMD2A) Amish, La Reunion Island, Basque (Spanyol), Turki CAPN3 15q15.1

~ 5% Dysferlinopathy (LGMD2B) Yahudi DYSF Libya 2p13.2 3% LGMD2G Italia (?) TCAP 17q12 Diketahui LGMD2H Manitoba Hutterit hanya TRIM32 9q33.1 6% 7 LGMD2I (MDDGC5) 8 FKRP diketahui 19q13.32 Diketahui LGMD2J Finlandia TTN 2q31.2 Diketahui LGMD2K (MDDGC1) 8 Turkish POMT1 9q34.13 ~ 25% di Inggris populasi LGMD2L Eropa Utara 9, 10 ANO5 11p14.3 Diketahui LGMD2M (MDDGC4) 8 FKTN diketahui 9q31.2 Diketahui LGMD2N (MDDGC2) 8 Tidak diketahui POMT2 14q24.3 Diketahui LGMD2O (MDDGC3) 8 Tidak diketahui POMGNT1 1p34.1 Diketahui LGMD2Q Turki PLEC 8q24.3 1. Dari omim.org 2. Vainzof et al [1999] 3. SCARMD = anak distrofi otot autosomal resesif yang parah 4. Merlini et al [2000] 5. Nigro et al [1996], Vainzof et al [1999] 6. Berkisar dari 10% pada populasi keturunan Eropa [Chou et al 1999] menjadi 80% di negara Basque [Urtasun et al 1998]. Frekuensi yang sebenarnya tergantung pada populasi. 7. Boito et al [2005] 8. MDDG (otot distrofi-dystroglycanopathy) [Amberger et al 2011] 9. Hicks et al [2011] 10. Penttil et al [2012] Sarcoglycanopathies, termasuk -sarcoglycanopathy (LGMD2D) yang disebabkan oleh mutasi SGCA, -sarcoglycanopathy (LGMD2E) yang disebabkan oleh mutasi SGCB, -sarcoglycanopathy (LGMD2C) yang disebabkan oleh mutasi SGCG, sarcoglycanopathy (LGMD2F) yang disebabkan oleh mutasi ofSGCD. Empat gen yang berbeda sarcoglycan menyandi protein yang membentuk kompleks tetrameric pada membran plasma sel otot. Kompleks ini menstabilkan asosiasi distrofin dengan dystroglycans dan memberikan kontribusi bagi stabilitas sitoskeleton membran plasma. Keempat sarcoglycan gen terkait satu sama lain secara struktural dan fungsional, tetapi masing-masing memiliki lokasi kromosom yang berbeda (lihat Tabel 1). Dalam populasi outbred, frekuensi relatif dari mutasi pada gen keempat adalah alpha beta >> >> gamma >> delta dalam rasio 8:4:2:1 [Duggan et al 1997a]. Tidak ada mutasi umum telah diidentifikasi pada populasi outbred kecuali mutasi p.Arg77Cys, yang menyumbang hingga sepertiga dari alel bermutasi SGCA [Hackman et al 2005]. Pendiri mutasi telah diamati dalam populasi tertentu (Tabel 1). Calpainopathy (LGMD2A, yang disebabkan oleh mutasi CAPN3). Calpain 3 adalah

kalsium-sensitif protease yang terlibat dalam renovasi otot. Sampai saat ini, lebih dari 450 mutasi pada CAPN3 telah dijelaskan. Dysferlinopathy (LGMD2B, DYSF). Dysferlin adalah protein sarcolemmal yang mencakup domain C2 dianggap penting untuk kalsium-dimediasi fusi vesikel dengan sarcolemma dan perbaikan membran serat otot rangka [Bansal et al 2003, Han & Campbell 2007]. Meskipun intra-dan variabilitas klinis interfamilial adalah signifikan, tidak ada genotipe-fenotip korelasi yang spesifik telah dibentuk [Cagliani et al 2003]. LGMD2G (TCAP). Homozigositas untuk mutasi TCAP telah diidentifikasi dalam empat keluarga Brasil [Moreira et al 2000]. Individu yang terkena dalam satu keluarga Italia telah ditemukan memiliki senyawa mutasi heterozigot TCAP. LGMD2H (TRIM32). Mutasi dilaporkan dalam TRIM32 termasuk mutasi missense dua, salah satu penghapusan kodon, dan dua mutasi frameshift [Frosk et al 2002, Saccone et al 2008, Cossee et al 2009]. Yang pertama-dijelaskan TRIM32 mutasi, p.Asp487Asn, adalah mutasi pendiri dalam populasi Hutterite (Amerika Utara), satu sib pasangan telah diidentifikasi dalam keluarga non-Hutterite di Jerman (negara asal Hutterit). Sarcotubular miopati (STM), juga diamati pada populasi Hutterite, kini diketahui disebabkan oleh mutasi yang sama dalam TRIM32 [Schoser et al 2005, Borg et al 2009]. TRIM32 kode untuk ligase E3-Ub bertanggung jawab pasca-translasi peraturan tingkat protein [Frosk et al 2002]. O-linked glikosilasi enzim (dystroglycanopathies) termasuk LGMD2I (disebabkan oleh mutasi FKRP), LGMD2K (POMT1), LGMD2M (FKTN), LGMD2O (POMGNT1), LGMD2N (POMT2). Kelima gen yang berbeda mengkodekan glycosyltransferases terlibat dalam penambahan residu karbohidrat glikosilasi -dystroglycan dan abnormal dari molekul ini adalah temuan umum dalam bentuk LGMD. Mutasi gen ini telah dikaitkan dengan dystrophies otot keparahan variabel mulai dari dystrophies otot bawaan dengan mata berbagai keterlibatan otak (lihat Ikhtisar Dystrophy Muscular kongenital) ke bentuk yang lebih ringan dengan onset kemudian (ekstremitas-korset dystrophies otot). Relatif sedikit individu dengan fenotipe LGMD dan mutasi di POMT1, FKTN,, POMGNT1 atau POMT2 telah dilaporkan [Balci et al 2005, Godfrey et al 2006, Biancheri et al 2007, Godfrey et al 2007, Clement et al 2008]. Individu yang terkena dilaporkan senyawa heterozigot untuk mutasi missense atau omong kosong. Tidak ada mutasi umum telah dilaporkan kecuali di LGMD2I. LGMD2I (FKRP). Individu yang heterozigot homozigot atau senyawa untuk mutasi missense di FKRP memiliki fenotip LGMD. Sebaliknya, individu yang heterozigot homozigot atau senyawa untuk mutasi nonsense (hilangnya lengkap fungsi) memiliki distrofi otot yang parah bawaan (MDC1C) (lihat Ikhtisar Dystrophy Muscular kongenital). Sampai saat ini, dua mutasi yang umum, 826C> A dan 427C> A, telah diamati pada individu dengan LGMD2I tetapi tidak pada mereka dengan MDC1C [et al Brockington 2001]. Identifikasi individu tanpa gejala yang homozigot untuk salah satu dari mutasi umum dan individu tanpa gejala lainnya yang merupakan senyawa heterozigot untuk mutasi umum menunjukkan bahwa gen lain memodifikasi presentasi penyakit dan / atau usia onset [Boito et al 2005]. Perhatikan bahwa mutasi kedua di heterozigot majemuk dapat menjadi salah

satu dari sejumlah missense, omong kosong, penghapusan, dan mutasi penyisipan. Individu homozigot untuk 826C> Sebuah mutasi umum memiliki fenotip ringan daripada mereka yang heterozigot senyawa [Brockington et al, 2001, Mercuri et al 2003, Poppe et al 2003]. LGMD2L (ANO5). Anoctamin, dikodekan oleh ANO5, adalah kalsium klorida-aktif diduga channel mungkin terlibat dalam mekanisme membran perbaikan di dystrophies otot. Sampai saat ini, mutasi yang umum, satu pasangan basa duplikasi c.191dupA (p.Asn64LysfsX15), telah dilaporkan baik dalam keadaan homozigot dan heterozigot, itu dianggap mutasi pendiri di Eropa utara. ANO5 mutasi diidentifikasi sampai saat ini meliputi situs sambatan, missense, dan pergeseran kerangka perubahan [Bolduc et al 2010, Hicks et al 2011, Penttil et al 2012]. Lihat ANO5-Terkait Penyakit otot. LGMD2J (TTN). Dalam gangguan ini, semua individu yang terkena ditandai sampai saat ini memiliki penghapusan 11-bp homozigot / penyisipan di ekson terakhir (disebut Mex6) dari TTN. Penghapusan mengubah empat asam amino dan dekat dengan situs calpain-3 mengikat. Mutasi ini biasa terjadi pada populasi Finlandia. Dalam keadaan heterozigot mutasi ini menyebabkan miopati distal UDD [Hackman et al 2002]. LGMD2K (POMT1). LGMD2K adalah bentuk LGMD2 dengan cacat intelektual ringan diidentifikasi dalam lima individu dari keluarga kerabat [Balci et al 2005] dan dalam tiga pasien tambahan [Godfrey et al 2007]. Mutasi diidentifikasi meliputi tiga missense, satu omong kosong, dan satu frame-shift mutasi POMT1, gen yang berhubungan dengan Walker-Warburg sindrom (lihat Ikhtisar Dystrophy Muscular kongenital). Mutasi p.Ala200Pro adalah mutasi pendiri leluhur pada populasi Turki [Balci et al 2005]. LGMD2Q (PLEC). LGMD2Q adalah distrofi anak-onset awal berotot dengan kursus progresif dan tidak ada keterlibatan kulit. Mutasi PLEC diidentifikasi dalam tiga keluarga adalah 9-bp homozigot penghapusan (c.1_9del) di ekson 1f gen termasuk kodon inisiasi. C.1_9del adalah mutasi pendiri leluhur dalam populasi Turki dari wilayah Laut Hitam [Gundesli et al 2010]. Plectin 1f adalah salah satu perancah khusus untuk protein costameric penting untuk pembentukan struktur yang tepat myofiber [Gundesli et al 2010]. Lain PLEC terkait fenotipe termasuk epidermolisis bulosa simpleks dengan akhir-onset distrofi otot progresif [Pulkkinen et al 1996] dan myasthenic sindrom dengan akhir-onset miopati [Banwell et al 1999]. Temuan Klinis Tabel 2. Autosomal resesif LGMD: Clinical Temuan Penyakit Nama (Sinonim) / Gene Simbol lain Presentasi Temuan Usia Gejala Kelemahan Kontraktur otot betis / Scoliosis Onset (Rata-rata) kursi Bound Sarcoglycanopathies: LGMD2C / SGCG LGMD2D / SGCA LGMD2E / SGCB LGMD2F / SGCD defisiensi Lengkap: run kesulitan, berjalan Hipertrofi proksimal Akhir 3-15 thn (8,5 thn) ~ 15 yrs Partial Kekurangan: kram, intoleransi latihan Remaja - dewasa muda

Calpainopathy (LGMD2A) / CAPN3 run Kesulitan, berjalan, berjalan kaki, punggung kaku (jarang) proksimal (ekstensor pinggul normal dan adductors), Atrophy winging scapular Awal 2-40 thn (8-15 thn) 11-28 yrs setelah onset Dysferlinopathy (LGMD2B) / Ketidakmampuan DYSF berjinjit, berjalan kesulitan, berjalan distal dan / atau panggul-femoral (no winging scapular) hipertrofi Transient (jarang) 17-23 thn LGMD2G / TCAP Kesulitan run, berjalan, kaki penurunan ekstremitas bawah proksimal dan distal, proksimal ekstremitas atas 9-15 thn ~ 18 thn setelah onset LGMD2H / TRIM3 kelemahan wajah, kiprah Waddling, kesulitan dengan tangga proksimal ekstremitas bawah, otot leher membuang-buang Tidak dilaporkan 1-9 thn Akhir dalam hidup LGMD2I / FKRP run Kesulitan, berjalan proksimal, atas> tungkai bawah Hipertrofi Langka, akhir 1,5-27 tahun (11,5 thn) 23-26 yrs setelah onset LGMD2J / TTN proksimal 5-25 thn Rata-rata 20 thn setelah onset LGMD2K / POMT1 debar, kesulitan memanjat tangga dan berjalan, keterlambatan kognitif dengan perkembangan bahasa kelemahan yang terbatas Mild; proksimal> Hipertrofi distal dari betis dan paha kontraktur Ankle hadir dalam 2 dari 5 orang, kontraktur siku, tulang belakang, dan leher pada 1 pasien 1-3 thn ~ 17 thn (berdasarkan 1 individu, 4 orang tersisa, usia 7-17, masih rawat jalan) LGMD2L / ANO5 Adult onset (> 20 thn) kelemahan tungkai proksimal bawah dan atas dan / atau kesulitan berdiri di jari kaki proksimal panggul-femoralis distal atau di paha depan tungkai bawah, hamstring dan brachi bisep Kontraktur atrofi (pergelangan tangan, jari, TA) Biaya remaja-50s Tidak dilaporkan LGMD2M / FKTN Awal-awal kelemahan otot, kesulitan naik tangga, kelemahan parah setelah kambuhan penyakit-steroid responsif proksimal, lebih rendah> ekstremitas Hipertrofi atas betis, paha, dan trisep Tidak dilaporkan 4 mo - 4 thn Tidak dilaporkan LGMD2N / POMT2 kelambatan dalam menjalankan dan bangun Hipertrofi Tidak ada lordosis betis winging dan ringan Scapular, intelektual cacat 18 mo, asimtomatik pada 5 thn 20 thn (1 pasien) LGMD2O / POMGNT1 Kesulitan meningkatkan dari duduk dan memanjat tangga, miopia parah proksimal> Hipertrofi distal dari betis dan paha depan, paha belakang dan membuang-buang dari kontraktur deltoids Ankle 12 thn 19 thn (1 pasien) LGMD2Q / PLEC Tertunda bermotor tonggak, kesulitan naik tangga, menjaga dengan rekan-rekan atrofi otot proksimal pada 1 kontraktur Beberapa pasien dalam 1 pasien 2-3 thn 24 thn (1 pasien) Sarcoglycanopathies, termasuk -sarcoglycanopathy, (LGMD2D), sarcoglycanopathy, (LGMD2E); -sarcoglycanopathy, (LGMD2C); sarcoglycanopathy (LGMD2F). Temuan berkisar dari onset anak usia dini dengan perkembangan yang parah (mirip dengan Duchenne distrofi otot) onset kemudian dengan perkembangan ringan (mirip dengan distrofi otot Becker) (lihat Tabel 2). Hipertrofi Calf umum. Keterlibatan jantung adalah variabel, tapi biasanya kurang parah daripada di dystrophinopathies. Cardiomyopathy adalah umum dalam beta-, delta-, dan

gamma-sarcoglycanopathy, tapi jarang di alpha-sarcoglycanopathy [et Melacini, al 1999 Fanin et al 2003, Kirschner & Lochmuller 2011]. Secara keseluruhan, sekitar 30% dari individu memiliki bukti kardiomiopati pada EKG dan ekokardiogram. Kejanggalan yang signifikan antara saudara kandung telah diamati, termasuk dua saudara kandung dengan mutasi SGCA: satu memiliki onset pada usia 20 tahun dan yang lain adalah tanpa gejala pada usia 35 tahun [Angelini et al 1998]. Sebagian besar individu dengan berat, anak-onset distrofi otot ekstremitaskorset memiliki mutasi SGCA, SGCB, SGCC, atau SGCD [Duggan et al 1997a]. Dengan demikian, seorang individu dengan presentasi klinis dan perkembangan yang mirip dengan Duchenne distrofi otot tetapi dengan immunostaining distrofin normal pada otot cenderung memiliki sarcoglycanopathy utama. Sebaliknya, hanya sekitar 10% dari individu dengan ekstremitas-korset distrofi otot dengan penyakit ringan (onset pada masa remaja atau dewasa) memiliki sarcoglycanopathy a. Beberapa individu heterozigot untuk mutasi di SGCA memiliki gejala klinis yang ringan termasuk winging scapular dan hipertrofi betis [Fischer et al 2003]. Genotipe / fenotipe korelasi dalam seri besar telah diterbitkan dalam beberapa populasi [Dincer et al 1997, Duggan dkk 1997a, 1997b Duggan et al, Vainzof et al 1999, Merlini et al 2000]. Calpainopathy (LGMD2A, yang disebabkan oleh mutasi CAPN3). Intra-dan interfamilial variabilitas berkisar klinis dari berat menjadi ringan. Tiga fenotipe calpainopathy telah diidentifikasi berdasarkan pada distribusi kelemahan otot dan usia saat onset: Pelvifemoral LGMD (Leyden-Mbius) fenotipe, fenotip calpainopathy paling sering diamati, di mana kelemahan otot yang pertama jelas dalam korset panggul dan kemudian di sabuk bahu dengan onset sebelum usia 12 tahun atau setelah usia 30 tahun; Scapulohumeral LGMD (Erb) fenotipe, biasanya fenotip ringan dengan onset awal jarang terjadi, di mana kelemahan otot yang pertama jelas dalam korset bahu dan kemudian di korset panggul, dan HyperCKemia, biasanya diamati pada anak-anak atau orang muda, di mana individu gejala hanya memiliki tinggi konsentrasi serum CK. Temuan klinis termasuk kecenderungan untuk berjalan berjinjit, kesulitan dalam menjalankan, winging scapular, kiprah waddling, dan hyperlordosis sedikit. Awal Achilles tendon shortening dan scoliosis dapat hadir. Dysferlinopathy (LGMD2B, yang disebabkan oleh mutasi DYSF). Spektrum penyakit otot ditandai terutama oleh dua fenotipe: Limb-girdle sindrom distrofi otot (LGMD2B) dengan kelemahan awal dan atrofi otot korset panggul dan bahu pada masa remaja atau dewasa muda, dengan perkembangan lambat. Otot-otot pernafasan dan jantung tidak terlibat. Miyoshi miopati dengan kelemahan otot dan atrofi pada dewasa muda, sebagian besar ditandai di bagian distal dari kaki, terutama otot-otot gastrocnemius dan soleus. Selama periode tahun, kelemahan dan atrofi menyebar ke paha dan otot glutealis. Lengan bawah dapat menjadi ringan atrofi dengan penurunan kekuatan pegangan, tetapi otot-otot kecil tangan terhindar. Dua fenotipe lainnya terlihat:

 Distal miopati kompartemen anterior (DMAT), yang menyajikan pada dekade ketiga dengan kelemahan otot tibialis anterior. Penyakit ini cepat progresif mengakibatkan kelemahan proksimal yang parah pada tungkai bawah pertama, diikuti oleh tungkai atas [Illa et al 2001]. Dysferlinopathy dengan tulang belakang kaku, yang menyajikan dengan kelemahan ekstremitas bawah dan atrofi selain kontraktur dari leher, dada, pinggul, dan lutut [Nagashima et al 2004] LGMD2G (disebabkan oleh mutasi TCAP). Variabilitas yang signifikan telah terlihat di antara 14 orang yang dilaporkan dari empat keluarga. Beberapa orang menunjukkan atrofi distal sementara yang lain menunjukkan hipertrofi betis. Semua memiliki kelemahan proksimal signifikan. Keterlibatan jantung terjadi pada sekitar setengah. Betina tampaknya terlalu terpengaruh dibandingkan lakilaki [Zatz et al 2003]. LGMD2H (TRIM32). Keparahan berkisar dari tanpa gejala kelemahan proksimal yang parah. Kelemahan wajah dan "senyum datar" yang umum [Weiler et al 1998, Saccone et al 2008]. Individu yang terkena dapat tetap rawat jalan baik menjadi dewasa dengan beberapa laporan dari ambulasi (dengan susah payah) ke dalam dekade keenam [Weiler et al 1998, Saccone et al 2008]. Hilangnya ireversibel motilitas setelah imobilisasi lama telah dilaporkan [Saccone et al 2008]. Miopati Sarcotubular (STM), yang disebabkan oleh mutasi yang sama dalam TRIM32, merupakan ujung parah fenotip LGMD2H [Schoser et al 2005, Borg et al 2009]. LGMD2I (FKRP). Berkisar dari fenotipe parah (mirip dengan Duchenne distrofi otot) untuk ringan tanpa keterlibatan otot rangka klinis jelas [Brockington et al, 2001, de Paula et al 2003, Mercuri et al 2003, Poppe et al 2003, Poppe et al 2004, Boito et al 2005, Muller et al 2005]. Cardiomyopathy tanpa keterlibatan otot rangka telah dilaporkan. Ketika awal adalah pada tahun-tahun pertama kehidupan, kemampuan untuk berjalan hilang sekitar awal dekade kedua. Akhir lebih ringan dari spektrum lebih mirip distrofi otot Becker, dengan onset kemudian (usia 6-23 tahun) dan ambulasi terus ke dekade ketiga meskipun dengan meningkatnya kesulitan. Keterlibatan jantung terjadi pada 10% -55% dari individu yang terkena. Cardiomyopathy muncul untuk menyajikan awal heterozigot dibandingkan homozigot. Poppe et al [2004] mengidentifikasi keterlibatan pernapasan (yaitu, kapasitas vital paksa lebih rendah dari 75%) di sekitar 50% dari individu yang terkena. Gangguan memori [Bourteel et al 2009] dan gangguan ringan pada fungsi eksekutif dan visuo-spasial perencanaan tanpa penurunan substansial dalam global dan logika IQ telah dilaporkan [Bourteel et al 2009, Palmieri et al 2011]. Otak MRI studi menunjukkan sejumlah kecil pasien dengan focal sinyal kortikal yang abnormal konsisten dengan displasia, atrofi subkortikal, dan atrofi korteks frontal dengan sinyal materi periventricular nonspesifik putih [Bourteel et al 2009, Palmieri et al 2011]. LGMD2J (TTN). Gangguan ini adalah bentuk parah (state homozigot) dari distrofi otot tibialis ringan (TMD). Individu dengan LGMD2J memiliki kelemahan proksimal yang parah progresif dengan onset mulai dari dekade pertama ke awal 30-an. Di sekitar setengah dari semua kasus yang dilaporkan, kelemahan pada akhirnya melibatkan otot-otot distal dan individu diperlukan penggunaan kursi

roda, dalam kasus lain ambulasi dipertahankan. Kontraktur sendi belum dikaitkan dengan LGMD2J [et al UDD 1991]. LGMD2K (POMT1). Individu yang terkena menunjukkan kelemahan proksimal ringan dengan keterlambatan perkembangan yang signifikan. Individu mempertahankan kemampuan untuk berjalan selama setidaknya 15 tahun setelah onset penyakit. Microcephaly tanpa kelainan otak struktural, dan cacat intelektual dengan IQ rendah dilaporkan pada semua pasien [Balci et al 2005, Godfrey et al 2007, Lommel et al 2010]. Semua individu memiliki tingkat CK 1040 kali batas normal [Balci et al 2005, Godfrey et al 2007, Lommel et al 2010]. LGMD2L (ANO5). Individu yang terkena hadir dengan dua fenotipe yang berbeda: onset proksimal korset panggul Akhir kelemahan otot dengan (seringkali asimetris) atrofi femoris paha depan dan bisep brachii Kemudian-onset ringan hipertrofi betis asimetris atau kelemahan betis awal tanpa atrofi dikaitkan dengan kesulitan berjalan berjinjit Sebagai penyakit berlangsung fenotip tumpang tindih dan bergabung menjadi entitas klinis homogen [Hicks et al 2011], ditandai dengan pinggul parah dan kelemahan paha dengan keterlibatan distal. Pengecilan otot quadriceps mempengaruhi, paha belakang, dan gastrocnemius medial. Knee hiperekstensi adalah temuan umum. Dalam tahap-tahap selanjutnya dari kelemahan penyakit ringan dan membuang dari tungkai atas diamati. Keterlibatan jantung dan pernapasan tidak diamati. Lihat ANO5-Terkait Penyakit otot. LGMD2M (FKTN).

Molekuler Genetika Tabel 3.

1.

Temuan Klinis Tabel 4.

Kematian yg mendadak

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Tabel 5.

Pengujian

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Klinis

Klinis

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