Muscular Dystrophy, Limb-Girdle, Autosomal Recessive 3

A number sign (#) is used with this entry because of evidence that autosomal recessive limb-girdle muscular dystrophy-3 (LGMDR3) is caused by homozygous or compound heterozygous mutation in the alpha-sarcoglycan gene (SGCA; 600119) on chromosome 17q21.

Description

Autosomal recessive limb-girdle muscular dystrophy-3 affects mainly the proximal muscles and results in difficulty walking. Most individuals have onset in childhood; the disorder is progressive. Other features may include scapular winging, calf pseudohypertrophy, and contractures. Cardiomyopathy has rarely been reported (summary by Babameto-Laku et al., 2011).

For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

Nomenclature

At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2D was renamed LGMDR3.

Clinical Features

Romero et al. (1994) reported a French family with a progressive form of muscular dystrophy that was clinically milder than severe autosomal recessive muscular dystrophy (SCARMD; 253700). Four sibs had mild to overt symptoms, including proximal muscle weakness beginning at about age 10 years, calf hypertrophy, and elevated serum creatine kinase. Muscle biopsies showed variable degrees of necrosis and regeneration with little fibrosis. In all 4 cases, the 50-kD dystrophin-associated glycoprotein adhalin was completely absent in muscle sections, whereas dystrophin and other members of the dystrophin-associated protein complex were normal, except for the 35-kD dystrophin-associated glycoprotein gamma-sarcoglycan (SGCG; 608896), which was slightly reduced. Linkage analysis excluded the SCARMD locus on chromosome 13q, indicating a genetically distinct disorder. Romero et al. (1994) stated that there are 2 kinds of myopathies with adhalin deficiency: one with a primary defect of adhalin and one in which absence of adhalin is secondary to a separate gene defect on chromosome 13.

Fadic et al. (1996) demonstrated adhalin deficiency in a 13-year-old boy who had previously been given a diagnosis of Becker muscular dystrophy (300376) and was referred for dilated cardiomyopathy and congestive heart failure. He had been asymptomatic until 9 years of age when proximal muscle weakness developed. Examination at that time showed flexion contracture at the ankles, hypertrophy of the calf muscle, and Gowers sign. The serum creatine kinase level was very high. There was no family history of consanguinity or neuromuscular disease. Both his sister and his mother had normal serum creatine kinase levels. His congestive heart failure was refractory to diuretic therapy and to inotropic therapy. He required a left ventricular assist device for circulatory support for 6 weeks and then underwent successful heart transplantation. Cardiac abnormalities had been described in patients with adhalin deficiency or muscular dystrophy but expression of dystrophin-associated proteins, including adhalin, in cardiac muscle had not been determined. Fadic et al. (1996) found normal immunostaining in both skeletal and cardiac muscle with antibodies directed against the 3 portions of the dystrophin molecule. On the other hand, immunostaining of adhalin was drastically reduced in skeletal muscle and undetectable by immunofluorescence in cardiac muscle. The disorder was thought to be recessive in this patient. McNally et al. (1996) commented that mutations in several genes can cause adhalin deficiency and that the patient reported by Fadic et al. (1996) did not necessarily have a mutation in the SGCA gene. McNally et al. (1996) noted that mutation in any of 3 proteins in the 'sarcoglycan complex,' alpha-, beta-, or gamma-sarcoglycan, can cause muscular dystrophy as well as a decrease in immunostaining for all 3 sarcoglycan components.

Angelini et al. (1998) described 2 sibs with a homozygous mutation in the alpha-sarcoglycan gene (600119.0005) who presented strikingly different clinical phenotypes. The brother was asymptomatic and the sister had mild limb-girdle muscular dystrophy that was steroid responsive. Immunohistochemistry for alpha-sarcoglycan showed reduced intensity in the sister and findings similar to normal in the brother. Unknown epigenetic or environmental factors appeared to be important in determining protein and clinical phenotype expression. The sister, 40 years old at the time of report, had presented at the age of 10 to 12 years with mild thoracic scoliosis. At the age of 20 years she presented with waddling gait. Proximal weakness in the lower limbs was noted at 28 years, together with difficulty getting up from the floor or rising from a low chair. Weakness in the upper limbs was noted at the age of 30 years, with difficulty lifting objects over her head. The 35-year-old brother had increased creatine kinase levels but a negative neuromuscular examination, except for mild scoliosis.

Passos-Bueno et al. (1999) studied 140 patients from 40 Brazilian families with one of 7 autosomal recessive limb-girdle muscular dystrophies (LGMD2A-LGMD2G). Among the sarcoglycanopathies, serum creatine kinase levels were highest in the LGMD2D patients.

Babameto-Laku et al. (2011) reported 2 Albanian sibs, born of consanguineous parents, with LGMD2D. The 7-year-old sister showed difficulty climbing stairs and getting up at age 3 years. This proximal muscle weakness progressed, with frequent falls, waddling gait, toe-walking, and difficulty raising the arms above the head. She also had calf pseudohypertrophy, Achilles tendon contractures, mild scapular winging, and hyperlordosis. Her younger brother started to manifest similar clinical symptoms of proximal muscle weakness between 2 and 3 years of age. Both patients had increased serum creatine kinase, and muscular biopsy showed dystrophic changes with decreased staining for alpha- and gamma-sarcoglycan (SGCG; 608896). The phenotype in both patients was clinically severe enough to suggest Duchenne muscular dystrophy.

Mapping

Passos-Bueno et al. (1993) found 4 Brazilian families with Duchenne-like muscular dystrophy who were not linked to 13q, indicating genetic heterogeneity for the disorder.

In a large French family with autosomal recessive limb-girdle muscular dystrophy in which Romero et al. (1994) excluded linkage to markers on 13q, Roberds et al. (1994) found perfect cosegregation between the disease and 1 allelic variant of a polymorphic microsatellite located within intron 6 of the adhalin gene on chromosome 17q.

Passos Bueno et al. (1995) performed linkage analysis with chromosome 17q markers in 3 autosomal recessive limb-girdle muscular dystrophy families and in 4 Duchenne-like muscular dystrophy families, all with adhalin deficiency and unlinked to any of the 3 chromosome sites where forms of autosomal recessive limb-girdle muscular dystrophy had been mapped: 15q (LGMDR1; 253600); 2p (LGMDR2; 253601), and 13q (LGMDR5; 253700). Linkage to 17q was observed only among 3 families with a mild phenotype. Passos Bueno et al. (1995) referred to the 17q-linked muscular dystrophy as LGMD2D.

Molecular Genetics

In a French family with mild autosomal recessive limb-girdle muscular dystrophy reported by Romero et al. (1994), Roberds et al. (1994) identified missense mutations in the adhalin gene (see, e.g., 600119.0001-600119.0002). The family was nonconsanguineous and the affected members were compound heterozygotes, with one mutation coming from each parent.

Piccolo et al. (1995) described several additional mutations (null and missense) in the adhalin gene (see, e.g., 600119.0003) in 10 affected families from Europe and North Africa. Disease severity varied in age of onset and rate of progression, and patients with null mutations were the most severely affected.

In 3 affected Brazilian families with a mild phenotype showing linkage to 17q, Passos Bueno et al. (1995) identified the same missense mutation in the adhalin gene (600119.0003).

Trabelsi et al. (2008) identified biallelic mutations in sarcoglycan genes in 46 (67%) of 69 patients with a clinical diagnosis of autosomal recessive LGMD. Twenty-six (56.5%) patients had SGCA mutations, 8 (17.3%) had SGCB (600900) mutations, and 12 (26%) had SGCG mutations. A total of 23 different mutations, including 10 novel mutations, were identified in SGCA, with a relatively high frequency of mutations in exon 3 (13 of 26, 50%) and exon 5 (6 of 26, 23%).

In 2 Albanian sibs, born of consanguineous parents, with LGMD2D, Babameto-Laku et al. (2011) identified a homozygous mutation in the SGCA gene (R192X; 600119.0007). Each unaffected parent was heterozygous for the mutation.

Genotype/Phenotype Correlations

Duggan et al. (1997) undertook to determine the frequency of sarcoglycan gene mutations and the relationship between the clinical features and genotype in 556 patients with myopathy but normal dystrophin genes. Antibody against alpha-sarcoglycan was used to stain muscle-biopsy specimens from these patients. Those whose biopsy specimens showed deficiency of alpha-sarcoglycan on immunostaining were studied for mutations of the alpha-, beta-, and gamma-sarcoglycan genes with reverse transcription of muscle RNA, analysis involving single-strand conformation polymorphisms, and sequencing. Levels of alpha-sarcoglycan were found to be decreased on immunostaining of muscle biopsy specimens from 54 of the 556 patients (10%); in 25 of these patients no alpha-sarcoglycan was detected. Screening for sarcoglycan gene mutations in 50 of the 54 patients revealed mutations in 29 patients (58%): 17 had mutations in the SGCA gene, 8 in the SGCB gene, and 4 in the SGCG gene. The prevalence of sarcoglycan gene mutations was highest among patients with severe (Duchenne-like) muscular dystrophy that began in childhood (18 of 83 patients, or 22%); the prevalence among patients with proximal (limb-girdle) muscular dystrophy with a later onset was 6% (11 of 180 patients).

Gene Therapy

In a double-blind randomized control trial of 3 nonambulatory patients with genetically confirmed LGMD2D, Mendell et al. (2009) found that replacement of the SGCA gene using an adeno-associated virus type 1 (AAV1) vector resulted in 4- to 5-fold increased SGCA expression and restoration of the full sarcoglycan complex in a small foot muscle of the treated side compared to the untreated side in each patient. Examination after 3 months in 1 patient showed increased muscle fiber size in the transduced muscle. There were no adverse side effects. The study used the muscle-specific creatine kinase promoter to improve the safety profile of gene transfer targeting muscle.

Mendell et al. (2010) reported 3 additional patients treated with SGCA gene replacement therapy similar to their previous report (Mendell et al., 2009). At 6 months after gene therapy, 2 of the 3 patients showed sustained increased SGCA expression reaching wildtype levels, but only 1 had clear evidence of increased muscle fiber diameter. The third patient showed no increased SGCA gene expression after 6 months and also had early humoral and T-cell responses to the AAV1 capsid, suggestive of an amnestic inflammatory response. Combined with the earlier study, the findings provided an overall favorable response to SGCA gene therapy in patients with LGMD2D.

Population Genetics

Hayashi et al. (1995) performed an immunocytochemical survey of muscle biopsies from 243 Japanese muscular dystrophy patients over 2.5 years. They identified 5 unrelated Japanese patients (3 females and 2 males with no family history) as having adhalin deficiency. There was extremely faint but positive staining of the sarcolemma similar to that described in the 13q-linked congenital muscular dystrophy prevalent in North Africa. From these data they predicted the gene frequency for this deficiency in Japan to be between 0.1 and 0.2%, with a prevalence of the deficiency in the Japanese population to be about 1 x 10(-6). In their series, Hayashi et al. (1995) found this deficiency to account for only 4% of patients with DMD/BMD.

Ljunggren et al. (1995) screened the entire adhalin coding sequence in muscle biopsy specimens from 30 muscular dystrophy patients, finding a compound heterozygosity only in a single African American girl with childhood onset muscular dystrophy. The authors concluded that primary adhalin deficiency in patients with muscular dystrophy but normal dystrophin is relatively infrequent in North America.

Animal Model

Sampaolesi et al. (2003) reported success in treating Sgca-null mice, a model for LGMD2D, with wildtype mesoangioblasts, a class of vessel-associated stem cells that differentiate into mesodermal cell types. After intraarterial delivery, the mesoangioblasts diffused from the arterial tree into skeletal muscle, where they were incorporated into muscle fibers and restored expression of the adhalin protein. Treated mice exhibited correction of the dystrophic phenotype, both morphologically and functionally. Sampaolesi et al. (2003) also showed that mesoangioblasts isolated from juvenile Sgca-null mice and transduced with a lentiviral vector expressing SGCA reconstituted skeletal muscle similar to that seen in wildtype mice.

Imamura et al. (2005) established several transgenic mouse lines that overexpressed Sgce (604149) in skeletal muscle. Overexpression in normal mice resulted in substitution of Sgce for Sgca in the sarcoglycan complex of skeletal muscle without any obvious abnormalities. Mice overexpressing Sgce were crossed with Sgca-deficient mice, and Sgca-deficient mice overexpressing Sgce exhibited no skeletal muscle cell membrane damage or abnormal contraction. Imamura et al. (2005) suggested that overexpression of SGCE may represent a therapeutic strategy for treatment of LGMD2D.

Gargioli et al. (2008) found that intramuscular injection of 12-month-old Sgca-null mice with tendon fibroblasts containing an angiogenic factor (PGF; 601121) and a metalloproteinase (MMP9; 120361) resulted in generation of a vascular network and decreased collagen deposition. Intramuscular injection ameliorated subsequent intraarterial cell delivery of Sgca-expressing mesoangioblasts. Mice treated with both Pgf and Mmp9 showed restoration of regenerating muscle fibers reaching 60 to 70% of the numbers observed in wildtype mice.

By adeno-associated virus type 1 (AAV1)-mediated delivery of human SGCA to skeletal muscle fibers of Sgca-null mice, Rodino-Klapac et al. (2008) observed sustained SGCA expression for up to 12 weeks without evidence of cytotoxicity and restored expression of the dystrophin-glycoprotein complex. Quantified analysis by fiber counts yielded 60 to 70% successful myofiber transduction for 2 muscle creatine kinase (CKM; 123310) promoters and 34% fiber transduction with a desmin (DES; 125660) promoter.