Gamma Sarcoglycan Research Articles

Histopathological analysis of gamma sarcoglycanopathy in Moroccan patients: A case series.

In Morocco, diagnosing Gamma Sarcoglycanopathies mainly relies on histopathological analysis of muscle biopsies due to limited genetic and molecular research access. This study highlights the significance of muscle biopsies and explores potential predictive factors and possible correlation between histopathological abnormalities and clinical phenotypes. Muscle biopsies of six patients diagnosed with γ-sarcoglycanopathy were collected over two years. Pathological analysis was initially performed on slides stained with Hematoxylin-Eosin and Gomori Trichrome. Additionally, cryosections marked for dystrophin, alpha, beta, and gamma sarcoglycans were reviewed. In the second phase of the analysis, formalin-fixed sections from each biopsy were immunostained for various markers: "anti-CD68" for macrophagic cells, "anti-CD56" for satellite cells, and "anti-CD31" for vascular capillary. These stained sections were then carefully examined. The clinical presentation of the disease was uniform and consistent with Duchenne-like dystrophy. However, the histological abnormalities were heterogeneous and did not correlate with the severity of the clinical phenotype. The Loss of expression of a Sarcoglycan and earlier age of onset appear to be the most significant predictive markers of disease progression. Immuno-staining patterns for CD68, CD56, and CD31 indicated an impairment in the muscle regeneration process, probably, at an early stage of the disease. This study's findings are crucial for understanding pathogenesis and identifying new therapeutic targets. However, because of the small sample size, further confirmation through a larger cohort is necessary.

Limb-Girdle Muscular Dystrophy Type 2C: Case Report

Limb-Girdle muscular dystrophy (LGMD) is a group of inherited disorders that lead to muscle weakness and skeletal muscle wasting involving the muscles around the hips and shoulders. This can cause a gait disturbance, difficulty running or even a complete loss of the ability to walk. The appearance of the disorder, the course and the muscles affected are variable between the different subtypes of the disease. Typically, patients with type 2C Limb-Girdle dystrophy (LGMD2C) start having symptoms early in infancy and lose their ability to walk around the age of 12. Others have less symptomatology and have late expression in adulthood. This disorder can affect the heart muscle in some patients. They can also have osteoarticular and vertebral deformations. The prognosis depends on the muscles often affected by respiratory failure.LGMD2C is caused by a pathogenic mutation in the SGCG gene. We report the case of a 13-year-old child, with a notion of femoral fracture at the age of 5 years and first degree consanguinity in the parents, no similar case in the family, and who presents since 3 years difficulty walking Clinical examination: walking, positive sign of Gowers, scapula alta, enlarged calves. On the biological level: CPK 6380, LDH 482, PAL 219, ASAT 68, ALAT 103. The electromyogram shows a slowing of the motor conduction speed of the external popliteal sciatic nerve with a slight loss of amplitude. Muscle biopsy objective a discreet dystrophic formula with a total absence of expression of gamma sarcoglycans and proteins of the muscle membrane. Gamma glycanopathy is genetically confirmed by the mutation of the δ-SG gene. A cardiac ultrasound was without abnormality.

An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress

Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress.

A novel mutation in alpha sarcoglycan gene in an Iranian family with limb girdle muscular dystrophy 2D

Objective and importance: The sarcoglycanopathies (SGPs) are a subgroup of autosomal recessive limb girdle muscular dystrophies. They are caused by mutations in gamma, alpha, beta, and delta sarcoglycans (SGs) genes. Alpha-SGPs are the most frequent form of SGPs. Muscle biopsy studies in patients with SGPs have indicated that loss of one SG subunit leads to instability of whole SG complex. Autozygosity mapping is a powerful gene mapping approach for rare recessive inherited disorders in consanguineous families.Clinical presentation: In the present study, proband was a 9 year old girl from consanguineous parents. She was diagnosed at the age of 5 when she had problems climbing stairs. Her creatine kinase level was 16428 U/L. Proximal weakness and ankle contracture were also observed in the patient.Techniques: Autozygosity mapping, using short tandem repeat (STR) markers linked to the SG genes, showed co-segregation of the phenotype with STR markers linked to the SGCA (Alpha-sarcoglycan) gene. Her muscle biopsy also suggested alpha sarcoglycanopathy. Mutation analyses revealed a novel homozygous deletion of 11 base pairs in exon 4 of this gene. This deletion introduces a premature termination codon after the 4th amino acid. This will eliminate the expression of the downstream part of the extracellular domain of the protein. This domain has a critical role by associating with other molecules of dystrophin–glycoprotein complexes.Conclusion: IHC (Immunohistochemistry) studies combined with autozygosity mapping and mutation screening is an efficient diagnostic method in the SGPs.

G.P.224: A regional panorama of sarcoglycanopathies

In this study, it was aimed to describe the clinical, histopathological and genetic features of 35 patients with sarcoglycanopathies confirmed by muscle biopsies and genetic analysis. We retrospectively reviewed 35 patients who underwent muscle biopsy examination between 2007 and 2013 at pathology laboratory of Izmir Neuromuscular Diseases' Centre. All patients clinically diagnosed as muscular dystrophy and biopsies were collected from 5 different centers of neurological disorders. All DNAs were extracted from muscle tissues or blood of patients and genetic tests (mutation analyses and deletion-duplication analyses for all 4 sarcoglycan genes) were performed at Ankara Duzen Laboratory. The mean age of patients was 7.61years (0–21years). Only one case (2.85%) was older than 14years. The mean CPK level was 10,545U/L (between 700 and 35,000). There were 6 siblings in these series. Expression defects of alpha, beta or gamma sarcoglycans were determined in (male: 23/34.2% and female: 12/66.8%) all patients with muscle biopsy. Gamma sarcoglycanopathies were the most (n=25) and alpha sarcoglycanopathies were the second common (n=7) muscular dystrophy in this series. Although focal delta sarcoglycan staining defects were determined in some patients by muscle biopsy, any genetic defects were found in them. The present study demonstrated that, both muscle biopsy and DNA analysis remain important methods for diagnosis of muscular dystrophies. Because differential diagnosis of sarcoglycanopathies and distrophinopathies, is impossible to achieve on clinical grounds alone; therefore immunohistochemical straining on muscle biopsy and molecular genetic analysis are mandatory for correct diagnosis.

G.P.225: Concomitant alpha and gamma sarcoglycan deficiencies in a Turkish boy with a novel deletion in the alpha sarcoglycan gene

Limb-girdle muscular dystrophy type 2D (LGMD-2D) is caused by autosomal recessive defects in the alpha-sarcoglycan gene located on chromosome 17q21. In this study, we present a child with alpha-sarcoglycanopathy and describe a novel deletion in the alpha-sarcoglycan gene. A 5-year-old boy had a very high serum creatinine phosphokinase level, which was determined incidentally, and a negative molecular test for the dystrophin gene. Muscle biopsy showed dystrophic features. Immunohistochemistry showed that, there was diminished expression of alpha and gamma sarcoglycans. DNA analysis revealed a novel 7bp homozygous deletion in exon 3 of the alpha-sarcoglycan gene. His parents were consanguineous heterozygous carriers of the same deletion. We believe this is the first confirmed case of primary alpha-sarcoglycanopathy with a novel deletion in Turkey. In addition, this study demonstrated that, both muscle biopsy and DNA analysis remain important methods for the differential diagnosis of muscular dystrophies because dystrophinopathies and sarcoglycanopathies are so similar.

G.P.226: Sarcolemmal deficiency of sarcoglycan complex in an eighteen months old Turkish boy with a huge deletion in the beta sarcoglycan gene

Limb-girdle muscular dystrophy type 2E (LGMD-2E) is caused by autosomal recessive defects in the beta-sarcoglycan gene located on chromosome 4q12. In this study, the clinical findings, histopathological features and molecular genetic data in a boy with beta-sarcoglycanopathy are presented. An eighteen-month-old boy had a very high serum creatinine phosphokinase level, which was determined incidentally. He had consanguineous parents. The result of molecular analyses for dystrophin gene was found normal. He underwent a muscle biopsy which showed dystrophic features. Immunohistochemistry showed that, there was a total loss of sarcolemmal sarcoglycan complex (alpha, beta, delta and gamma sarcoglycans) while sarcolemmal dystrophin expression was normal. DNA analysis revealed a huge deletion in the beta-sarcoglycan gene. The deletion was homozygous and occurred from exon 1 to 6. This study demonstrated that the total absence or abnormal expressions of all 4 sarcoglycans are more likely to indicate a primary defect in the beta sarcoglycan gene.

Histopathological and genetic features of patients with limb girdle muscular dystrophy type 2c

In this study, it was aimed to describe the clinical, histopathological and genetic features of 20 patients with gamma sarcoglycanopathy confirmed by muscle biopsies and genetic analysis. We retrospectively reviewed 20 patients from whom muscle biopsy specimens were obtained between 2007 and 2012. All patients were clinically diagnosed as muscular dystrophy and biopsy materials were collected from five different centers of neurological disorders. All DNAs were extracted from muscle tissues or blood samples of patients and genetic tests (mutation analyses for gamma sarcoglycan gene and deletion-duplication analyses for all 4 sarcoglycan genes) were performed. The mean age of the patients was 7.6 years (2 -21 years). Only one case (5%) was older than 14 years. The mean CPK level was 10311 U/L (1311 - 35000 U∕L). There were 4 siblings in these series. Expression defects of gamma sarcoglycan staining were determined in (15 males, and 5 females) all patients with muscle biopsy specimens. But only in 9 of them, disease-causing defects could be determined with genetic analyses. The present study has demonstrated that both examination of muscle biopsy specimens and DNA analysis remain important methods in the differential diagnosis of muscular dystrophies. Because dystrophinopathies and sarcoglycanopathies have similar clinical manifestation.

M.I.2 The matrix as a modifier for muscular dystrophy

Duchenne muscular dystrophy and the limb girdle muscular dystrophies, like other Mendelian disorders, are modified by genetic and environmental factors. We set out to identify modifiers of muscular dystrophy using a mouse model of LGMD 2C. Mice deleted for gamma sarcoglycan (Sgcg), a dystrophin associated protein, were used for mapping genetic modifiers because humans with LGMD 2C often display a variable phenotype despite having the same identical mutation. We used an intercross between Sgcg mice in the DBA2J background, which confers a severe phenotype, and Sgcg mice in the 129T2/SvEmsJ, which confers a mild background. A genomewide scan identified a locus on murine chromosome 7 that modified two different aspects of muscular dystrophy pathology. The chromosome 7 locus regulated fibrosis and also Evans blue dye uptake into skeletal muscle, a marker of sarcolemmal leakage. An insertion/deletion polymorphism was identified in the Ltbp4 gene, and this polymorphism correlated with severity of muscular dystrophy. In collaboration with the United Dystrophinopathy project, we queried whether human LTBP4 genotype correlated with outcome in DMD patients. We identified that LTBP4 acted as a modifier of DMD. LTBP4 is the latent TGFbeta binding protein and a member of the fibrillin superfamily. The members of this family reside within the extracellular matrix where they participate in binding and sequestering TGFbeta proteins. Release of TGFbeta proteins from the matrix permits ligand binding to cell surface TGFbeta receptors and activation of intracellular TGFbeta signaling. Together, these data, from mouse models and human patients, support that hyper-TGFbeta signaling is pathogenic in DMD and LGMDs, and suggest that reduction of TGFbeta signaling may be therapeutic.

A Rare Cause of High Transaminasemia: Autosomal Muscle Dystrophy with Gamma Sarcoglycan

A Rare Cause of High Transaminasemia: Autosomal Muscle Dystrophy with Gamma Sarcoglycan

Merosin-positive congenital muscular dystrophy: a large inbred family.

Large families with congenital muscular dystrophy are rare. We report a clinical, histopathological, immunocytochemical, electrophysiological, radiological and genetic study of 10 cases affected by "pure" CMD belonging to two generations of a large inbred Palestinian family. The disease showed autosomal recessive inheritance. All patients had generalised muscular weakness and hypotonia at birth without arthrogryposis. They had a relatively benign clinical course with stabilisation of the clinical picture at different ages and at variable degrees of severity. The pattern of muscle weakness and wasting was more marked in the proximal upper limb-girdle and trunk muscles. Lower limb muscles were more mildly involved. Serum CK was normal or moderately increased. All patients had normal intelligence, normal computed tomography (CT) scans of the brain and normal somatosensory evoked potentials (SEP). Electromyography (EMG) and muscle biopsy showed morphological changes compatible with muscular dystrophy. Immunocytochemistry for dystrophin, laminin alpha 2 of merosin, and for alpha, beta, gamma sarcoglycans was normal. Linkage analysis excluded all the known loci for CMD, including laminin alpha 2 on chromosome 6q2, the Fukuyama congenital muscular dystrophy locus on 9q3, the integrin alpha 7 locus on chromosome 12q13 and the recently identified locus on 1p35-36. The family we present is clinically and genetically distinct from the already mapped forms of congenital muscular dystrophy. Genetic studies are in progress to localise the gene responsible for this condition.

Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 in the muscular dystrophies.

Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 are responsible for a subset of the muscular dystrophies. In this study we aim to characterise the nature and frequency of abnormalities...