Molecular Genetics
Table 1.
Molecular Genetics of Autosomal Recessive Limb-Girdle Muscular Dystrophy (LGMD)
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| % of Individuals with AR LGMD | Disease Name (Synonym) | Populations with Founder Variants | Gene | Locus 1 |
|---|
| Up to 68% of individuals with childhood onset and ~10% with adult onset 2 | Alpha-sarcoglycanopathy (LGMD2D) | None |
SGCA
| 17q21.33 |
| Beta-sarcoglycanopathy (LGMD2E) | Amish |
SGCB
| 4q12 |
| Gamma-sarcoglycanopathy (formerly SCARMD) (LGMD2C) 3 | North Africans; Gypsies 4 |
SGCG
| 13q12.12 |
| Delta-sarcoglycanopathy (LGMD2F) | Brazilian 5 |
SGCD
| 5q33.3 |
| ~10% 6 | Calpainopathy (LGMD2A) | Amish, La Reunion Island, Basque (Spain), Turkish |
CAPN3
| 15q15.1 |
| ~5% | Dysferlinopathy (LGMD2B) | Libyan Jewish |
DYSF
| 2p13.2 |
| 3% | LGMD2G | Italian (?) |
TCAP
| 17q12 |
| Unknown | LGMD2H | Manitoba Hutterites only |
TRIM32
| 9q33.1 |
| 6% 7 | LGMD2I (MDDGC5) 8 | Unknown |
FKRP
| 19q13.32 |
| Unknown | LGMD2J | Finland |
TTN
| 2q31.2 |
| Unknown | LGMD2K (MDDGC1) 8 | Turkish |
POMT1
| 9q34.13 |
| ~25% in the UK population |
LGMD2L
| Northern European 9, 10 |
ANO5
| 11p14.3 |
| Unknown | LGMD2M (MDDGC4) 8 | Unknown |
FKTN
| 9q31.2 |
| Unknown | LGMD2N (MDDGC2) 8 | Unknown |
POMT2
| 14q24.3 |
| Unknown | LGMD2O (MDDGC3) 8 | Unknown |
POMGNT1
| 1p34.1 |
| Unknown | LGMD2Q | Turkish |
PLEC
| 8q24.3 |
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SCARMD = severe childhood autosomal recessive muscular dystrophy
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- 5.
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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.
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- 10.
Sarcoglycanopathies, including α-sarcoglycanopathy (LGMD2D) caused by mutation of SGCA; β-sarcoglycanopathy (LGMD2E) caused by mutation of SGCB; γ-sarcoglycanopathy (LGMD2C) caused by mutation of SGCG; δ-sarcoglycanopathy (LGMD2F) caused by mutation of SGCD. 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 nonconsanguineous populations, the relative frequency of pathogenic variants in the four genes is alpha >> beta >> gamma >> delta in an 8:4:2:1 ratio [Duggan et al 1997a]. No common pathogenic variants have been identified in nonconsanguineous populations except the p.Arg77Cys variant, which accounts for up to one third of the mutated SGCA alleles [Hackman et al 2005]. Founder variants 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 pathogenic variants 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 genotype-phenotype correlations have been established [Cagliani et al 2003].
LGMD2G (TCAP). Homozygosity for a TCAP pathogenic variant 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 pathogenic variants.
LGMD2H (TRIM32). Pathogenic variants reported in TRIM32 include two missense variants, one codon deletion, and two frameshift variants [Frosk et al 2002, Saccone et al 2008, Cossée et al 2009]. The first-described TRIM32 pathogenic variant, p.Asp487Asn, is a founder variant 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 pathogenic variant 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 α-dystroglycan and abnormal glycosylation of this molecule is a common finding in these forms of LGMD. Pathogenic variants of these genes have been associated with muscular dystrophies of variable severity ranging from congenital muscular dystrophies with various eye and brain involvement to milder forms with later onset (limb-girdle muscular dystrophies). Relatively few individuals with an LGMD phenotype and pathogenic variants 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 pathogenic missense or nonsense variants. No common pathogenic variants have been reported except in LGMD2I.
LGMD2I (FKRP). Individuals who are homozygous or compound heterozygous for pathogenic missense variants in FKRP have an LGMD phenotype. In contrast, individuals who are homozygous or compound heterozygous for pathogenic nonsense variants (complete loss of function) have a severe congenital muscular dystrophy (MDC1C).
To date, two common pathogenic variants, 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 pathogenic variants and other asymptomatic individuals who are compound heterozygous for the common pathogenic variants suggests that other genes modify the disease presentation and/or age of onset [Boito et al 2005]. Note that the second pathogenic variant in compound heterozygotes may be any one of a number of missense, nonsense, deletion, and insertion variants. Individuals homozygous for the 826C>A common pathogenic variant 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 pathogenic variant, one base-pair duplication c.191dupA (p.Asn64LysfsTer15), has been reported both in the homozygous and heterozygous state; it is considered a founder variant in northern Europe. ANO5 pathogenic variants identified to date include splice site, missense, and frameshift changes [Bolduc et al 2010, Hicks et al 2011, Penttilä et al 2012]. See ANO5-Related 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 pathogenic variant is common in the Finnish population. In the heterozygous state this variant 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]. Pathogenic variants identified include three missense, one nonsense, and one frameshift variant in POMT1, the gene associated with Walker-Warburg syndrome. The p.Ala200Pro pathogenic variant is an ancestral founder variant 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 pathogenic variant 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 variant 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 late-onset myopathy [Banwell et al 1999].
Clinical Findings
Table 2.
Autosomal Recessive LGMD: Clinical Findings
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| Disease Name (Synonym) / Gene | Presentation | Other Findings | Age |
|---|
| Symptoms | Weakness | Calf Muscle | Contractures/ Scoliosis | Onset (Average) | Wheelchair Bound |
|---|
Sarcoglycanopathies:
LGMD2C / SGCG
LGMD2D / SGCA
LGMD2E / SGCB
LGMD2F / SGCD | Complete deficiency: difficulty run, walk | Proximal | Hypertrophy | Late | 3-15 yrs (8.5 yrs) | ~15 yrs |
| Partial deficiency: cramps, exercise intolerance | | | | Adolescent - young adulthood | |
Calpainopathy
(LGMD2A) / CAPN3 | Difficulty run, walk, toe walk; stiff back (rare) | Proximal (normal hip extensors & adductors), scapular winging | Atrophy | Early | 2-40 yrs (8-15 yrs) | 11-28 yrs after onset |
Dysferlinopathy
(LGMD2B) / DYSF | Inability to tiptoe; difficulty run, walk | Distal and/or pelvic-femoral (no scapular winging) | Transient hypertrophy (rare) | | 17-23 yrs | |
| LGMD2G /TCAP | Difficulty run, walk; foot drop | Proximal and distal lower limb; proximal upper limb | | | 9-15 yrs | ~18 yrs after onset |
| LGMD2H / TRIM3 | Facial weakness; waddling gait, difficulty w/stairs | Proximal lower limb; neck | Muscle wasting | Not reported | 1-9 yrs | Late in life |
| LGMD2I / FKRP | Difficulty run, walk | Proximal; upper > lower limb | Hypertrophy | Rare, late | 1.5-27 yrs (11.5 yrs) | 23-26 yrs after onset |
| LGMD2J / TTN | | Proximal | | | 5-25 yrs | Average 20 yrs after onset |
| LGMD2K / POMT1 | Fatigability, difficulty climbing stairs & running; cognitive delay w/limited language development | Mild weakness; proximal > distal | Hypertrophy of calves & thighs | Ankle contractures present in 2 of 5 individuals; elbow, spine, & neck contractures in 1 patient | 1-3 yrs | ~17 yrs (based on 1 individual; 4 remaining individuals, ages 7-17, still ambulatory) |
| LGMD2L / ANO5 | Adult onset (>20 yrs) of proximal lower & upper limbs weakness &/or difficulties standing on toes | Proximal pelvic-femoral or distal in the lower limbs | Quadriceps, hamstring and biceps brachi atrophy | Contractures (wrist, finger, TA) | Late teens-50s | Not reported |
| LGMD2M / FKTN | Early-onset muscle weakness, difficulties climbing stairs, severe weakness after intercurrent illness -steroid responsive | Proximal; lower > upper limb | Hypertrophy of calves, thighs, & triceps | Not reported | 4 mo - 4 yrs | Not reported |
| LGMD2N / POMT2 | Slowness in running & getting up | None | Hypertrophy of calves | Scapular winging & mild lordosis; intellectual disability | 18 mo; asymptomatic at 5 yrs | 20 yrs (1 patient) |
| LGMD2O / POMGNT1 | Difficulties raising from sitting & climbing stairs; severe myopia | Proximal > distal | Hypertrophy of calves & quadriceps; wasting of hamstrings & deltoids | Ankle contractures | 12 yrs | 19 yrs (1 patient) |
| LGMD2Q / PLEC | Delayed motor milestone, difficulties climbing stairs, keeping up w/peers | Proximal | Muscle atrophy in 1 patient | Multiple contractures in 1 patient | 2-3 yrs | 24 yrs (1 patient) |
Sarcoglycanopathies, including α-sarcoglycanopathy, (LGMD2D); β-sarcoglycanopathy, (LGMD2E); γ-sarcoglycanopathy, (LGMD2C); δ-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 & Lochmüller 2011]. Overall, about 30% of individuals have evidence of cardiomyopathy on ECG and echocardiogram. Significant discordance between sibs has been observed, including two sibs with SGCA pathogenic variants: 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 pathogenic variants in 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 pathogenic variant 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 [Dinçer 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-Möbius) 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 pathogenic variant 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, Müller 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].
