Recessive Limb-girdle Muscular Dystrophy Research Articles

The Limb-Girdle Muscular Dystrophies: Is Treatment on the Horizon?

There has been an ever-expanding list of the Limb-Girdle Muscular Dystrophies (LGMD). There are currently 8 subtypes of autosomal dominant (AD) and 26 subtypes of autosomal recessive (AR) LGMD. Despite continued research efforts to conquer this group of genetic neuromuscular disease, patients continue to be treated symptomatically with the aim of prevention or addressing complications. Mouse models have been helpful in clarifying disease pathogenesis as well as strategizing pathways for treatment. Discoveries in translational research as well as molecular therapeutic approaches have kept clinicians optimistic that more promising clinical trials will lead the way to finding the cure for these devastating disorders. It is well known that the challenge for these rare diseases is the ability to assemble adequate numbers of patients for a clinically meaningful trial, but current efforts in developing patient registries have been encouraging. Natural history studies will be essential in establishing and interpreting the appropriate outcome measures for clinical trials. Nevertheless, animal studies continue to be key in providing proof of concept that will be necessary in moving research along. This review will briefly discuss each type of LGMD, highlighting their distinguishing features, then focus on research efforts that have been published in the literature for the past few years, many of which are still in the preclinical trial stage.

Limb girdle muscular dystrophy 2G in a religious minority of Bulgarian Muslims homozygous for the c.75G>A, p.Trp25X mutation

Mutations in TCAP gene cause autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G), congenital muscular dystrophy and autosomal dominant dilated and hypertrophic cardiomyopathy. We studied 18 affected individuals from 12 pedigrees, belonging to a Bulgarian Muslim minority from the South-West of Bulgaria, homozygous for the c.75G>A, p.Trp25X mutation in TCAP gene. The heterozygous carrier rate of p.Trp25X among 100 newborns in this region was found to be 2%. The clinical features in the Bulgarian TCAP group include disease onset in the first to the third decade of life, proximal muscle weakness in the lower limbs, followed or accompanied by difficulties in ankle dorsiflexion and involvement of the proximal muscles of the upper limbs 5–9 years after the disease onset. Asymmetry between left and right was present in more than 20% of the affected. Respiratory and cardiac functions were not affected. On the MRI the muscles of the posterior pelvic area, thigh and anterior leg were predominantly affected, while sartorius, gracilis and biceps femoris muscles remained relatively spared.In conclusion, LGMD2G appears to be a common form among Bulgarian Muslims. Homozygosity for c.75G>A, p.Trp25X is associated with a homogeneous clinical presentation, but the clinical course and severity of the disease show inter- and intra-familial variation.

Perceptions of the transition from receiving the diagnosis recessive limb-girdle muscular dystrophy to becoming in need of human support and using a wheelchair: an interview study

Purpose: To describe perceptions of the transition from receiving the diagnosis recessive limb-girdle muscular dystrophy to becoming in need of human support to manage daily life and using a wheelchair for ambulation, from the affected young adults’ and their parents’ perspectives.Method: A qualitative and descriptive study design was used. Semi-structured interviews were held with 14 young adults diagnosed with recessive limb-girdle muscular dystrophy and 19 parents. Phenomenography was used for data analysis.Results: The diagnosis was described as being a shock and difficult to comprehend but also as a relief and a tool for information. Beginning to use a wheelchair was perceived to be mentally difficult but it also provided freedom. New ways of living involved physical, emotional, practical, and social difficulties as well as experiences of learning to adapt to the disease. The transition was overshadowed by concern about disease progression and influenced by facilitating factors, which were young adult being seen as a person; supportive family and friends; mobilized internal resources; meaningful daily activities; adapted environment; and professional support.Conclusions: The different perceptions expressed in this study highlight the importance of identifying personal perceptions and needs in order to optimize support provided by healthcare professionals.Implications for RehabilitationThe different perceptions described in this study emphasize the need for person-centered care for young adults living with recessive limb-girdle muscular dystrophy and their parents.Regular controls and professional support to cope with the disease and its consequences should be offered, not only at the time of diagnosis but also throughout disease progression.Beginning to use a wheelchair can be a psychologically distressing process, which has to be acknowledged by healthcare professionals when introducing it.Healthcare professionals should not only recognize the importance of having social relations and activities that are meaningful but also be a link to authorities in society and to interest organizations that can help to facilitate the person’s management of the disease.

Calpain 3 and CaMKIIβ signaling are required to induce HSP70 necessary for adaptive muscle growth after atrophy

Mutations in CAPN3 cause autosomal recessive limb girdle muscular dystrophy 2A. Calpain 3 (CAPN3) is a calcium dependent protease residing in the myofibrillar, cytosolic and triad fractions of skeletal muscle. At the triad, it colocalizes with calcium calmodulin kinase IIβ (CaMKIIβ). CAPN3 knock out mice (C3KO) show reduced triad integrity and blunted CaMKIIβ signaling, which correlates with impaired transcriptional activation of myofibrillar and oxidative metabolism genes in response to running exercise. These data suggest a role for CAPN3 and CaMKIIβ in gene regulation that takes place during adaptation to endurance exercise. To assess whether CAPN3- CaMKIIβ signaling influences skeletal muscle remodeling in other contexts, we subjected C3KO and wild type mice to hindlimb unloading and reloading and assessed CaMKIIβ signaling and gene expression by RNA-sequencing. After induced atrophy followed by 4 days of reloading, both CaMKIIβ activation and expression of inflammatory and cellular stress genes were increased. C3KO muscles failed to activate CaMKIIβ signaling, did not activate the same pattern of gene expression and demonstrated impaired growth at 4 days of reloading. Moreover, C3KO muscles failed to activate inducible HSP70, which was previously shown to be indispensible for the inflammatory response needed to promote muscle recovery. Likewise, C3KO showed diminished immune cell infiltration and decreased expression of pro-myogenic genes. These data support a role for CaMKIIβ signaling in induction of HSP70 and promotion of the inflammatory response during muscle growth and remodeling that occurs after atrophy, suggesting that CaMKIIβ regulates remodeling in multiple contexts: endurance exercise and growth after atrophy.

Sarcoglycanopathies: Clinical, Molecular and Genetic Characteristics, Epidemiology, Diagnostics and Treatment Options

Sarcoglycanopathies are a group of autosomal recessive limb-girdle muscular dystrophies (LGMD) caused by mutations in sarcoglycan genes: SGCA (LGMD 2D, MIM 600119), SGCB (LGMD 2E, MIM 604286), SGCG (LGMD 2C, MIM 353700), and SGCD (LGMD 2F, MIM 601287). These genes encode four transmembrane sarcoglycan subunits participating in formation of the large sarcolemmal dystrophin- glycoprotein complex. Clinical symptoms of sarcoglycanopathies resemble the ones in Duchenne/Becker muscular dystrophy and several autosomal recessive LGMD, which causes difficulties in the differential diagnostics between these diseases. This review covers the main aspects of sarcoglycanopathies, such as etiology, spectrum of mutations, clinical features and diagnostics. In addition, we review the fundamental pathogenesis mechanisms leading to sarcoglycanopathies, which can also help to understand the potential options for treatment for patients with muscular dystrophies.

Coincidence of hereditary motor and sensory neuropathy type 1A and limb lumbo-muscular dystrophy type 2A

A rare case of two neuromuscular disorders in a 29-year-old female is presented: autosomal dominant hereditary motor and sensory neuropathy type 1A (HMSN1A) due to PMP22 duplication and autosomal recessive limb girdle muscular dystrophy type 2A (LGMD2A) produced by CAPN3 common mutation c.550delA and novel c.575C>G (p.Thr192Ser).Walking difficulties appeared in 27 years, the patient had signs of both disorders, more of LGMD, but was not disabled. HMSN1A was inherited from her father whose disease was not recognized earlier.

Autosomal Recessive Limb Girdle Muscular Dystrophy In A Complex Consanguineous Family: The First Cases Series In Indonesia

ABSTRACTBackground: Limb girdle muscular dystrophy (LGMD) is a neuromuscular abnormality with clinical heterogeneity and various severity, where over 30 subtypes have been identified. Meanwhile, molecular diagnosis of LGMD is not commonly carried out in Indonesia. We present a large pedigree of familial LGMD, with over 14 years of follow-up.Case Presentation: A 12-year old female patient came with muscle weakness. She had toe walking since age of 6, followed by calf hypertrophy for over three years. Family history revealed complex consanguinity. Her younger sister and her parents’ cousin had similar condition, with the latter was already bedridden.Physical examination results were waddling gait, lordotic spine, and absent deep tendon reflexes. Muscle biopsy showed sign of dystrophic process. Immunoperoxidase staining of some proteins resulted normal. Single nucleotide polymorphism (SNP) array in two siblings revealed homozygosity on chromosome 15 containing CAPN3 gene of LGMD2A subtype.Recently, the patient is wheelchair bound and undergoes rehabilitation. Her sister is still able to walk with abnormal gait, while her parents’ cousin had passed away in age 55. From the multiple consanguinity, it could be concluded as autosomal recessive type LGMD.Conclusion: A large family with LGMD from Indonesia was presented with more than 14 years of care. Clinical diagnosis was made based on physical and additional examination, however molecular analysis for establishing definitive diagnosis is still limited. Further studies such as targeted or whole exome sequencing is warranted to elucidate the cause of disease. Long-term evaluation and supportive care, in addition to proper counseling may increase quality of life.

Left ventricular deformation abnormalities in a patient with calpainopathy-a case from the three-dimensional speckle-tracking echocardiographic MAGYAR-Path Study.

Calpainopathy or limb-girdle muscular dystrophy type 2A (LGMD2A) is the most common type of autosomal recessive limb-girdle muscular dystrophies. The disease is caused by mutations in the CAPN3 gene encoding calpain, a protein involved in muscle membrane remodeling and repair. This paper gives an overview of the genetic background, clinical course, and diagnosis of the disease, and presents the first case of calpainopathy in which cardiac deformation mechanics was investigated. Three-dimensional speckle-tracking echocardiography (3DSTE) demonstrated reduced left ventricular (LV) strains and increased LV apical rotation and twist, suggestive of asymptomatic subclinical LV dysfunction. Cardiac involvement has not been previously reported in calpainopathy.

P.151 - Limb girdle muscular dystrophy 2G in a religious minority of Bulgarian muslims homozygous for the c.75G>A, p.Trp25* TCAP mutation

Mutations in TCAP gene cause autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G), congenital muscular dystrophy and dilated and hypertrophic cardiomyopathy. To describe the phenotypic spectrum of LGMD 2G in a genetically homogeneous group of patients, belonging to a religious minority of Bulgarian muslims. Sixteen affected individuals (11 male and 5 female) from 10 pedigrees underwent neurological examination, including manual muscle testing, electromyography (EMG), cardiac evaluation, ventillatory assessment, evaluation of serum creatine kinase levels (CK) and molecular-genetic testing. The pattern of muscle involvement in the lower limbs was assessed in 2 patients by 3T MRI. Fifteen of the affected were homozygous for the c.75G>A, p.Trp25*mutation, whereas one was compound heterozygous, carrying Glu132Val in exon 2 as second mutation. The mean age at onset was 17.94 ± 3.97 years, ranging between 10 and 25 years. The initial manifestations in 12 patients included proximal muscle weakness in the lower limbs, followed by difficulties in ankle dorsiflexion. In 4 of the affected the proximal and distal weakness in the legs occurred simultaneously. The proximal muscles of the upper limbs became involved 5–9 years after the disease onset. Scapular winging and lumbar hyperlordosis developed late in the course of the disease. Respiratory and cardiac functions were spared. On the MRI the muscles in all three compartments of the thigh and anterior leg ones were predominantly affected, while m. sartorius, gracilis remained relatively spared. Homozygosity for c.75G>A, p.Trp25*mutation is associated with a homogeneous clinical presentation in terms of pattern of muscle involvement. The clinical course and severity of the disease however show inter- and intra-familial variation despite the mutation homogeneity.

Experiences of being parents of young adults living with recessive limb-girdle muscular dystrophy from a salutogenic perspective

Recessive limb-girdle muscular dystrophies (LGMD2) involve progressive muscle weakness. Parental support is important for young adults living with LGMD2, but no study has been identified focusing on the parents' experiences. The salutogenic perspective concentrates on how daily life is comprehended, managed and found meaningful, i.e. the person's sense of coherence. The aim of this study was to describe, from a salutogenic perspective, experiences of being parents of young adults living with LGMD2. Nineteen participants were included. Data were collected by semi-structured interviews and the self-administrated 13-item sense of coherence questionnaire. Interview data were analysed with content analysis and related to self-rated sense of coherence. The result shows experiences of being influenced, not only by thoughts and emotions connected to the disease but also by caregiving duties and the young adults' well-being. Simultaneously, difficulty in fully grasping the disease was expressed and uncertainty about progression created worries about future management. Trying their best to support their young adults to experience well-being and to live fulfilled lives, the importance of having a social network, support from concerned professionals and eventually access to personal assistance was emphasized. The need to have meaningful pursuits of one's own was also described. The median sense of coherence score was 68 (range 53–86). Those who scored high (≥68) described satisfaction with social network, external support provided, work and leisure activities to a greater extent than those who scored low (<68). The result shows that the young adults' disease has a major impact on the parents' lives. Assessment of how the parents comprehend, manage and find meaning in everyday life may highlight support needed to promote their health.

Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy.

The multi-C2 domain protein dysferlin localizes to the plasma membrane and the T-tubule system in skeletal muscle; however, its physiological mode of action is unknown. Mutations in the DYSF gene lead to autosomal recessive limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Here, we show that dysferlin has membrane tubulating capacity and that it shapes the T-tubule system. Dysferlin tubulates liposomes, generates a T-tubule-like membrane system in non-muscle cells, and links the recruitment of phosphatidylinositol 4,5-bisphosphate to the biogenesis of the T-tubule system. Pathogenic mutant forms interfere with all of these functions, indicating that muscular wasting and dystrophy are caused by the dysferlin mutants' inability to form a functional T-tubule membrane system.

A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.

Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb‐girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O‐glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces O‐glucosyltransferase activity on Notch and impairs muscle development. Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle‐specific α‐dystroglycan hypoglycosylation not present in patients' fibroblasts. Primary myoblasts from patients showed slow proliferation, facilitated differentiation, and a decreased pool of quiescent PAX7+ cells. A robust rescue of the myogenesis was demonstrated by increasing Notch signaling. None of these alterations were found in muscles from secondary dystroglycanopathy patients. These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch‐dependent loss of satellite cells.

Limb girdle muscular dystrophies: classification, clinical spectrum and emerging therapies.

The aim of the study was to describe the clinical spectrum of limb girdle muscular dystrophies (LGMDs), the pitfalls of the current classification system for LGMDs, and emerging therapies for these conditions. Close to half of all LGMD subtypes have been discovered within the last 6 years of the 21-year-period in which the current classification system for LGMD has existed. The number of letters for annotation of new recessive LGMD conditions is exhausted, and multiple already classified LGMDs do not strictly fulfill diagnostic criteria for LGMD or are registered in other classification systems for muscle disease. On the contrary, diseases that fulfill classical criteria for LGMD have found no place in the LGMD classification system. These shortcomings call for revision/creation of a new classification system for LGMD. The rapidly expanding gene sequencing capabilities have helped to speed up new LGMD discoveries, and unveiled pheno-/genotype relations. Parallel to this progress in identifying new LGMD subtypes, emerging therapies for LGMDs are under way, but no disease-specific treatment is yet available for nonexperimental use. The field of LGMD is rapidly developing from a diagnostic and therapeutic viewpoint, but a uniform and universally agreed classification system for LGMDs is needed.

Health perceptions of young adults living with recessive limb-girdle muscular dystrophy.

The aim of this study was to describe health perceptions related to sense of coherence among young adults living with recessive limb-girdle muscular dystrophy. Limb-girdle muscular dystrophy refers to a group of progressive muscular disorders that may manifest in physical disability. The focus in health care is to optimize health, which requires knowledge about the content of health as described by the individual. A descriptive study design with qualitative and quantitative data were used. Interviews were conducted between June 2012-November 2013 with 14 participants aged 20-30years. The participants also answered the 13-item sense of coherence questionnaire. Qualitative data were analysed with content analysis and related to self-rated sense of coherence. Health was viewed as intertwined physical and mental well-being. As the disease progressed, well-being was perceived to be influenced not only by physical impairment and mental strain caused by the disease but also by external factors, such as accessibility to support and attitudes in society. Factors perceived to promote health were having a balanced lifestyle, social relations and meaningful daily activities. Self-rated sense of coherence varied. The median score was 56 (range 37-77). Those who scored ≥56 described to a greater extent satisfaction regarding support received, daily pursuits and social life compared with those who scored <56. Care should be person-centred. Caregivers, with their knowledge, should strive to assess how the person comprehends, manages and finds meaning in daily life. Through dialogue, not only physical, psychological and social needs but also health-promoting solutions can be highlighted.

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.

A rare form of limb girdle muscular dystrophy (type 2E) seen in an Iranian family detected by autozygosity mapping

Sarcoglycanopathies (SGPs) constitute a subgroup of autosomal recessive limb girdle muscular dystrophies (LGMDs) which are caused by mutations in sarcoglycan (SGs) genes. SG proteins form a core complex consisting of α, β, γ and δ sarcoglycans which are encoded by SGCA, SGCB, SGCG and SGCD genes, respectively. Genetic defect, in any of these SG proteins, results in instability of the whole complex. This effect can be helpful in interpreting muscle biopsy results. Autozygosity mapping is a gene mapping approach which can be applied in large consanguineous families for tracking the defective gene in most autosomal recessive disorders. In the present study, we used autozygosity mapping, to find the gene responsible for muscular dystrophy. Proband was a 10-year-old boy referred to our center for ruling out DMD (Duchenne muscular dystrophy). According to the pedigree and clinical reports, we assessed him for SGPs. Haplotyping, using the four short tandem repeat (STR) markers for each of the SG genes, showed that the phenotype may segregate with SGCB gene; and observing two crossing overs which occurred within the gene suggested that the mutation might be in the first two exons of SGCB gene. Mutation analysis showed a 26 bp duplication (10 bp before the initiation codon till 13 bp after the ATG start codon). This will cause a frameshift in protein synthesis.

POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.

The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1(S201F) in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1(S191F)) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases.

Limb-girdle muscular dystrophy type 2A in Brazilian children.

Calpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A) caused by mutations in CAPN3 gene. To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. All patients were female (three to 12 years). The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder.

Identification of a Novel Mutation in the Titin Gene in a Chinese Family with Limb-Girdle Muscular Dystrophy 2J.

Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of genetic myopathies characterized by progressive proximal pelvic and/or shoulder girdle muscle weakness, with the onset ages ranging from early childhood to late adulthood. The identification of these dystrophies through genetic testing will not only inform long-term prognosis but will also assist in directing care more efficiently, including more frequent cardiorespiratory monitoring and prophylactic treatments. The aim of this study was to identify the responsible gene in a five-generation Chinese Han pedigree with autosomal recessive LGMD. Exome sequencing was conducted and a novel mutation c.107788T>C (p.W35930R) in the titin gene (TTN) was identified. The mutation co-segregated with the disorder in the family and was absent in normal controls. Our discovery broadens the mutation spectrum of the TTN gene associated with LGMD2J.

P88 – 2855: Deficient alpha-dystroglycan presenting with rhabdomyolysis

Objective To describe a case of deficient alpha-dystroglycan revealed by acute rhabdomyolysis. Rhabdomyolysis frequently occurs in metabolic myopathies induced by exercise or triggered by intercurrent disease. Furthermore, rhabdomyolysis has been described in muscular dystrophies, particularly Duchenne and Becker dystrophies. It has only rarely been reported in limb girdle muscular dystrophies (LGMD), even though it may be the first and unique presenting feature of some type of LGMD. Case description and results A 12 year old boy complained about fatigue after summer holidays with more intensive exercise than usually. As laboratory investigations showed mild elevation of serum AST (264 IU/l, N Conclusion Limb girdle muscular dystrophy type 2I (LGMD2I) is one of the most common autosomal recessive limb girdle muscular dystrophies presenting in childhood. It may present with acute rhabdomyolysis as the first sign. It should be included in the diagnostic work-up of rhabdomyolysis and persistent high CK levels should prompt muscle biopsy and/or molecular diagnosis.