Form Of Limb-girdle Muscular Dystrophy Research Articles

Clinical and Genetic Characteristics of Limb-Girdle Muscular Dystrophy in Iranian Patients

Background: Limb-girdle muscular dystrophy (LGMD) is a bothersome muscle disease associated with weakness of the shoulder and pelvic girdle. Objectives: The study aimed to determine the genetic diversity and relative frequency of various forms of LGMD in Iranian children. Methods: In this descriptive research, 60 children referred to the neurology or emergency department of the Pediatric Medical Center were studied from April 2019 to April 2020. Additional tests (muscle biopsy and genetic testing) were performed to confirm the diagnosis of LGMDs. Quantitative data such as disease level, motor, respiratory, and cardiac functions, and molecular data underwent statistical analysis. Results: A total of 41 patients with a mean age of 11.1 were studied. Twenty-two patients were diagnosed with genetic tests and 19 with muscle biopsies. Also, there were 26.8% cases of alpha sarcoglycanopathy, 24.4% beta sarcoglycanopathy, 17.1% gamma sarcoglycanopathy, 7.3% calpainopathy, 7.3% dysferlinopathy, 7.3% dystroglycanopathy, 7.3% titinopathy, and one case of laminopathy. Among genetically confirmed individuals, 27.3% had SGCB mutation, and 18.2% had SGCA mutation. A significant relationship was seen between the mutation type and creatine phosphokinase (CPK) levels (P < 0.05). Conclusions: The prevalence of alpha and beta sarcoglycanopathy phenotypes in the study population showed that the severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan expression.

CRISPR/Cas9 Genome Editing in LGMD2A/R1 Patient-Derived Induced Pluripotent Stem and Skeletal Muscle Progenitor Cells.

Large numbers of Calpain 3 (CAPN3) mutations cause recessive forms of limb-girdle muscular dystrophy (LGMD2A/LGMDR1) with selective atrophy of the proximal limb muscles. We have generated induced pluripotent stem cells (iPSC) from a patient with two mutations in exon 3 and exon 4 at the calpain 3 locus (W130C, 550delA). Two different strategies to rescue these mutations are devised: (i) on the level of LGMD2A-iPSC, we combined CRISPR/Cas9 genome targeting with a FACS and Tet transactivator-based biallelic selection strategy, which resulted in a new functional chimeric exon 3-4 without the two CAPN3 mutations. (ii) On the level of LGMD2A-iPSC-derived CD82+/Pax7+ myogenic progenitor cells, we demonstrate CRISPR/Cas9 mediated rescue of the highly prevalent exon 4 CAPN3 mutation. The first strategy specifically provides isogenic LGMD2A corrected iPSC for disease modelling, and the second strategy can be further elaborated for potential translational approaches.

Molecular therapies: present and future in neuromuscular diseases

The possibilities in the field of molecular therapies of neuromuscular diseases have rapidly developed in recent years. First compounds are already available in clinical practice and numerous other substances are in advanced phases of clinical trials. This article gives an exemplary overview of the current state of clinical research in molecular therapies of neuromuscular diseases. It also gives a view into the near future of the clinical application, including the challenges. Using Duchenne muscular dystrophy (DMD) and myotubular myopathy as examples, the principles of gene addition in monogenetic skeletal muscle diseases, which are already manifested in childhood are described. In addition to initial successes, the challenges and setbacks hindering the approval and regular clinical application of further compounds are demonstrated. Furthermore, the state of current clinical research in Becker-Kiener muscular dystrophy (BMD) and the numerous forms of limb-girdle muscular dystrophy (LGMD) are summarized. Numerous new therapeutic approaches and acorresponding outlook are also shown for facioscapulohumeral muscular dystrophy (FSHD), Pompe disease, and myotonic dystrophy. Clinical research in the field of molecular therapy of neuromuscular diseases is one of the pacesetters of modern precision medicine; however, challenges need to be seen, jointly addressed and overcome in the future.

LGMD-D2 TNPO3 related : a wide clinical spectrum Quality of Life and microRNAs study in two families (P6-8.011)

<h3>Objective:</h3> To investigate clinical progression, quality of life and circulating microRNAs in patients with LGMD-D2. <h3>Background:</h3> LGMD-D2 is a rare dominant form of limb-girdle muscular dystrophy (LGMD), due to a mutation of TNPO3 gene, that encodes a nuclear protein Transportin-3. Muscle MRI has become a useful tool for diagnosis and to follow the muscle disease evolution in patients with LGMD. We analyse clinical disease evolution, MRI features, MiR-206 expression level in mother and daughter (Family 1) and mother and son (Family 2) with known mutation and a second family with a different mutation. <h3>Design/Methods:</h3> We obtained clinical data, including onset and progression of the disease, from the four patients in two different Italian-Spanish and Hungarian families. The onset of symptoms was characterized by difficulty in walking or climbing stairs, collected by a standard questinnaire, monitored by GSGC score. Muscle MRI was done with 1.5 Tesla Philips apparatus. Individualized Neuromuscular Quality of Life (INQoL) test was used to investigate four patients and two caregivers by telemedicine. Considering the small sample, we used Mann-Whitney U Test for domains of INQoL. <h3>Results:</h3> In 4 years there was substantial disease progress. In family 1 one female case was wheel-chair-bound, in the second family a male child lost ambulation at 14 years. All patients suffered from Covid-19 infection with consequent fatigue and depressive symptoms. This patients have elevated MiR −206 in comparison with healthy controls. Regarding the Quality of Life, we found that there are differences between caregivers and patients in the following domains: body image (p &lt; 0.05) and INQoL Score (p = 0.05). <h3>Conclusions:</h3> The caregiver in both families had a worst evaluation of both physical pain, consequence on Body Image and Social relationship It has been observed that INQoL Score domains (Activities, Independence, Relationships, Emotions and Body image) are worse in this LGMD-D2, than in previous limb-girdle-muscular-dystrophies observations. <b>Disclosure:</b> Miss Rodríguez has nothing to disclose. Valentina Pegoraro has nothing to disclose. Dr. Angelini has nothing to disclose.

GDP-Mannose Pyrophosphorylase B (GMPPB)-Related Disorders.

GDP-mannose pyrophosphorylase B (GMPPB) is a cytoplasmic protein that catalyzes the formation of GDP-mannose. Impaired GMPPB function reduces the amount of GDP-mannose available for the O-mannosylation of α-dystroglycan (α-DG) and ultimately leads to disruptions of the link between α-DG and extracellular proteins, hence dystroglycanopathy. GMPPB-related disorders are inherited in an autosomal recessive manner and caused by mutations in either a homozygous or compound heterozygous state. The clinical spectrum of GMPPB-related disorders spans from severe congenital muscular dystrophy (CMD) with brain and eye abnormalities to mild forms of limb-girdle muscular dystrophy (LGMD) to recurrent rhabdomyolysis without overt muscle weakness. GMPPB mutations can also lead to the defect of neuromuscular transmission and congenital myasthenic syndrome due to altered glycosylation of the acetylcholine receptor subunits and other synaptic proteins. Such impairment of neuromuscular transmission is a unique feature of GMPPB-related disorders among dystroglycanopathies. LGMD is the most common phenotypic presentation, characterized by predominant proximal weakness involving lower more than upper limbs. Facial, ocular, bulbar, and respiratory muscles are largely spared. Some patients demonstrate fluctuating fatigable weakness suggesting neuromuscular junction involvement. Patients with CMD phenotype often also have structural brain defects, intellectual disability, epilepsy, and ophthalmic abnormalities. Creatine kinase levels are typically elevated, ranging from 2 to >50 times the upper limit of normal. Involvement of the neuromuscular junction is demonstrated by the decrement in the compound muscle action potential amplitude on low-frequency (2-3 Hz) repetitive nerve stimulation in proximal muscles but not in facial muscles. Muscle biopsies typically show myopathic changes with variable degrees of reduced α-DG expression. Higher mobility of β-DG on Western blotting represents a specific feature of GMPPB-related disorders, distinguishing it from other α-dystroglycanopathies. Patients with clinical and electrophysiologic features of neuromuscular transmission defect can respond to acetylcholinesterase inhibitors alone or combined with 3,4 diaminopyridine or salbutamol.

Specificities of the DMD Gene Mutation Spectrum in Russian Patients.

Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common form of muscular dystrophy, accounting for over 50% of all cases. In this regard, in Russia we carry out a program of selective screening for DMD/BMD, which mainly involves male patients. The main inclusion criteria are an increase in the level of creatine phosphokinase (&gt;2000 U/L) or an established clinical diagnosis. At the first stage of screening, patients are scanned for extended deletions and duplications in the DMD gene using multiplex ligase-dependent probe amplification (MLPA SALSA P034 and P035 DMD probemix, MRC-Holland). The second stage is the search for small mutations using a custom NGS panel, which includes 31 genes responsible for various forms of limb-girdle muscular dystrophy. In a screening of 1025 families with a referral Duchenne/Becker diagnosis, pathogenic and likely pathogenic variants in the DMD gene were found in 788 families (in 76.9% of cases). In the current study, we analyzed the mutation spectrum of the DMD gene in Russian patients and noted certain differences between the examined cohort and the multi-ethnic cohort. The analysis of the DMD gene mutation spectrum is essential for patients with DMD/BMD because the exact mutation type determines the application of a specific therapeutic method.

Molecular and genetic features of calpainopathy

Calpainopathy is the most common form of limb-girdle muscular dystrophy, prevalence in the population is approximately 1 in 15,00042,700 individuals. In the Russian Federation, there is an insufficient number of studies, which researched prevalence of calpainopathy among patients with limb-girdle muscular dystrophy, but according to available data, approximately in 43% of cases the disease is associated with mutations of the CAPN3 gene. Molecular genetic analysis is the main method for diagnosing these patients. Studies indicate many pathogenic mutations that cause calpainopathy with corresponding phenotypes, however, it is quite difficult to establish clear correlations between genotype and phenotype due to the high variability of symptoms and severity, even among patients with the same CAPN3 gene mutations. Currently, there is no effective etiotropic treatment for limb-girdle muscular dystrophy, but new technologies are developing to improve patients condition and quality of life. This research collects data from various studies on the prevalence of calpainopathy in different countries and the main molecular genetic features of the CAPN3 gene and calpain-3 protein, which will further allow the development of possible treatment options for patients with limbgirdle muscular dystrophy.

Validation of the North Star Assessment for Limb-Girdle Type Muscular Dystrophies.

ObjectiveThe North Star Assessment for limb-girdle type muscular dystrophies (NSAD), a clinician-reported outcome measure (ClinRO) of motor performance, was initially developed and validated for use in dysferlinopathy, an autosomal recessive form of limb-girdle muscular dystrophy (LGMD R2/2B). Recent developments in treatments for limb-girdle muscular dystrophies (LGMD) have highlighted the urgent need for disease-specific ClinROs. The purpose of this study was to understand the ability of the NSAD to quantify motor function across the broad spectrum of LGMD phenotypes.MethodsAssessments of 130 individuals with LGMD evaluated by the physical therapy teams at Nationwide Children’s Hospital and the John Walton Muscular Dystrophy Research Centre were included in the analysis. NSAD, 100-m timed test (100MTT), and Performance of Upper Limb 2.0 assessment data were collected. Psychometric analysis with Rasch measurement methods was used to examine the NSAD for suitability and robustness by determining the extent to which the observed data “fit” with predictions of those ratings from the Rasch model. The NSAD score was correlated with the 100MTT and Performance of Upper Limb 2.0 assessment scores for external construct validity.ResultsThe NSAD demonstrated a good spread of items covering a continuum of abilities across both individuals who had LGMD and were ambulatory and individuals who had LGMD and were weaker and nonambulatory. Items fit well with the construct measured, validating a summed total score. The NSAD had excellent interrater reliability [intraclass correlation coefficient (ICC) = 0.986, 95% CI = 0.981–0.991] and was highly correlated with the 100MTT walk/run velocity (Spearman rho correlation coefficient of rs(134) = .92).ConclusionAlthough LGMD subtypes may differ in age of onset, rate of progression, and patterns of muscle weakness, the overall impact of progressive muscle weakness on motor function is similar. The NSAD is a reliable and valid ClinRO of motor performance for individuals with LGMD and is suitable for use in clinical practice and research settings.ImpactRecent developments in potential pharmacological treatments for LGMD have highlighted the urgent need for disease-specific outcome measures. Validated and meaningful outcome measures are necessary to capture disease presentation, to inform expected rates of progression, and as endpoints for measuring the response to interventions in clinical trials. The NSAD, a scale of motor performance for both individuals who have LGMD and are ambulatory and those who are nonambulatory, is suitable for use in clinical and research settings.

Characterizing oxiodoreductase Pyrox-D1

PYROX-D1 (pyridine oxidoreductase domain 1) is a human enzyme involved with intracellular oxidation management. Natural mutations in this protein have been identified and implicated with causing a newly defined form of limb-girdle muscular dystrophy. Pedigree analysis reveals an autosomal recessive inheritance pattern (requiring a mutated allele from both parents). The disease manifests with bulk muscle wasting, atypical connective tissue elasticity, progressive proximal and distal weakness, nasal speech, elevated creatine kinase, flat feet, and ambulation issues usually beginning between 20-30 years of age.

Improvement in childhood limb-girdle muscular dystrophy with Ayurvedic management: A case report

The Limb-Girdle Muscular Dystrophies (LGMDs) include a heterogeneous group of disorders characterized by the progressive wasting and weakness of the proximal limb-girdle muscles. Sarcoglycanopathies are forms of LGMD that result from defect in the sarcoglycan complex. Ayurveda explains the condition in the line of Srotorodha (~obstructive pathology occurring in channels), especially at the Mamsa dhatu (~muscle tissue) level. This is the case report of an eight year old male child of autosomal recessive LGMD with no relevant family history. The patient was presented with gradual onset of proximal muscle weakness in all four limbs for two years along with pseudohypertrophy of bilateral calf muscles. He had elevated Creatine Phosphokinase (CPK) level and the genetic test findings revealed a homozygous missense variation in exon 2 of the SGCA gene. He visited the outpatient department of the tertiary Government Ayurveda Hospital and Ayurveda medications were administered along with dietary advices for two months followed by in-patient management for one month. There was a significant improvement in the clinical findings assessed by the Vignos scale of lower extremity and Barthel index along with reduction in the level of CPK value after three months of Ayurvedic management. Significant improvement in this short period of management substantiates the benefit of Ayurvedic medicines in the management of LGMD.

Clinical and mutational spectrum of sarcoglycanopathies in a large cohort of Indian patients

Sarcoglycanopathies are autosomal recessive forms of Limb-girdle muscular dystrophies(LGMD) caused by mutations in SGCA, SGCB, SGCG, and SGCD. The genetic architecture of sarcoglycanopathies in Indian patients is inadequate. In the present study, we aimed to investigate the clinical manifestations and the genetic basis of patients who are suspicious of being affected by sarcoglycanopathies.

Аutosomal recessive limb-girdle muscular dystrophy type 2A: two cases in Ukraine with different age of onset

The paper reports on two cases of young women from Ukraine with autosomal recessive limb-girdle muscular dystrophy type 2A with different age of symptoms onset and an absence of any family history presented with gradual onset of proximal muscle weakness in four limbs and thinning of shoulders, arms and thighs. Both patients had elevated creatine phosphokinase level and c.550delA mutations in CAPN3 gene. Sequence analysis and deletion/duplication testing of the 159 genes from skeletal muscles disease testing panel of 5-year-old girl identified deletion of exon 8 (heterozygous) and c.550delA (p.Thr184Argfs*36) mutation (heterozygous), were in CAPN3 gene. Magnetic Resonance Imaging of soft tissue of the proximal lower extremities was performed which showed signs of symmetrical atrophic changes in the major adductor muscle, the long and short adductor muscles, the semitendinosus muscle of the thigh, as a manifestations of autosomal recessive limb-girdle muscular dystrophy type 2A. Homozygous, pathogenic variant of the defect in the CAPN3 gene c.550del (p.Thr184Argfs * 36) was identified in a 25-year-old woman. Type 2A is the most common form of limb-girdle muscular dystrophy, accounting for about 30% of cases. The autosomal recessive limb-girdle muscular dystrophy type 2A is on caused by mutations in the CAPN3 gene, and it is characterized by selective atrophy and weakness of proximal limb and girdle muscles. The age of onset of muscle weakness is extremely variable; the most common being between 8 and 15 years, although it can range between 2 and 50 years. The diagnosis can be suspected by findings on a muscle biopsy or when a doctor experienced in muscular dystrophy examines you. A serum creatine kinase blood test may also show raised levels which indicate a problem in the muscles. The diagnosis has to be confirmed by means of identifying a mutation in the CAPN3 gene which is done on a deoxyribonucleic acid sample from a blood test. To date there are no specific treatments for limb-girdle muscular dystrophy, however careful management of the symptoms of the condition can improve a person’s quality of life. Joint contractures (tightening) can occur in limb-girdle muscular dystrophy and therefore regular physiotherapy is recommended.

Sarcoglycan A mutation in miniature dachshund dogs causes limb-girdle muscular dystrophy 2D

BackgroundA cohort of related miniature dachshund dogs with exercise intolerance, stiff gait, dysphagia, myoglobinuria, and markedly elevated serum creatine kinase activities were identified.MethodsMuscle biopsy histopathology, immunofluorescence microscopy, and western blotting were combined to identify the specific pathologic phenotype of the myopathy, and whole genome SNP array genotype data and whole genome sequencing were combined to determine its genetic basis.ResultsMuscle biopsies were dystrophic. Sarcoglycanopathy, a form of limb-girdle muscular dystrophy, was suspected based on immunostaining and western blotting, where α, β, and γ-sarcoglycan were all absent or reduced. Genetic mapping and whole genome sequencing identified a premature stop codon mutation in the sarcoglycan A subunit gene (SGCA). Affected dachshunds were confirmed on several continents.ConclusionsThis first SGCA mutation found in dogs adds to the literature of genetic bases of canine muscular dystrophies and their usefulness as comparative models of human disease.

Diseases related to Notch glycosylation

The Notch receptors are a family of transmembrane proteins that mediate direct cell-cell interactions and control numerous cell-fate specifications in humans. The extracellular domains of mammalian Notch proteins contain 29-36 tandem epidermal growth factor-like (EGF) repeats, most of which have O-linked glycan modifications: O-glucose added by POGLUT1, O-fucose added by POFUT1 and elongated by Fringe enzymes, and O-GlcNAc added by EOGT. The extracellular domain is also N-glycosylated. Mutations in the glycosyltransferases modifying Notch have been identified in several diseases, including Dowling-Degos Disease (haploinsufficiency of POFUT1 or POGLUT1), a form of limb-girdle muscular dystrophy (autosomal recessive mutations in POGLUT1), Spondylocostal Dysostosis 3 (autosomal recessive mutations in LFNG), Adams-Oliver syndrome (autosomal recessive mutations in EOGT), and some cancers (amplification, gain or loss-of-function of POFUT1, Fringe enzymes, POGLUT1, MGAT3). Here we review the characteristics of these diseases and potential molecular mechanisms.

Reporting a rare form of myopathy, myopathy with extrapyramidal signs, in an Iranian family using next generation sequencing: a case report

BackgroundMyopathy with extrapyramidal signs (MPXPS) is an autosomal recessive mitochondrial disorder which is caused by mutation in mitochondrial calcium uptake 1 (MICU1) gene located on chromosome 10q22.1. Next Generation Sequencing (NGS) technology is the most effective method for identification of pathogenic variants with the ability to overcome some limitations which Sanger sequencing may encountered. There are few reports on this rare disease around the world and here in this study we first revealed genetic identification of two affected individuals in an Iranian family with a novel mutation.Case presentationThe proband was a 5-year-old girl from consanguenous parents. She was first clinically suspicious of affected with limb-girdle muscular dystrophy (LGMD). Muscle biopsy studies and autozygosity mapping, using four short tandem repeat (STR) markers linked to 6 genes of the most prevalent forms of LGMD, ruled out calpainopathy, dysferlinopathy, and sarcoglycanopathis. DNA sample of the proband was sent for NGS. Whole exome sequencing (WES) revealed a novel mutation c.1295delA in exon 13 of MICU1 gene. This homozygous deletion creates a frameshift and a premature stop codon downstream of canonical EF4 calcium binding motif of MICU1. According to the American College of Medical Genetics and Genomics (ACMG) guidline for sequence interpretation, this variant was a pathogenic one. Sanger sequencing in all family members confirmed the results of the WES.ConclusionsThis study was the first report of MPXPS in Iranian population which also revealed a novel mutation in the MICU1 gene.

Long-Term Treatment of Tamoxifen and Raloxifene Alleviates Dystrophic Phenotype and Enhances Muscle Functions of FKRP Dystroglycanopathy

The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available. Selective estrogen receptor modulators, tamoxifen and raloxifene, have been widely used for human conditions for their anti-inflammatory, antifibrosis, prevention of bone loss, and muscle building effects (essential features for muscular dystrophy therapies). We evaluated therapeutic values of tamoxifen and raloxifene in FKRPP448L mutant mouse with severe dystrophic phenotype. The mice were treated with the drugs for 1 year through daily gavage. We demonstrate that tamoxifen and raloxifene significantly ameliorated the disease progression. The improvement includes increase in grip force production, extended running time and distance in treadmill test, and enhancement in cardiac and respiratory functions. Significant reduction in muscle pathology includes diminished fibrosis and fiber degeneration. Tamoxifen and raloxifene also significantly mitigated bone loss. Tamoxifen, but not raloxifene, caused severe adverse effects on male reproductive organs. The results demonstrate that tamoxifen and raloxifene hold significant potential for treating FKRP-related muscular dystrophy and probably other muscular dystrophies. Sex-related differential effects of the drugs call for a careful consideration for the drug and dosage selection in male and female patient populations.

THREE CASE SERIES INVOLVING PROGRESIVE MOTOR DEFICIT

The muscular dystrophies are a group of inherited, non-inflammatory disorders, consisting of progressive muscle wasting, without peripheral or central nerve involvement. We present a series of three cases involving progressive motor deficit and their different evolutions. The first case is about a 57 year old female patient, without a significant family medical history, presenting for progressive motor deficit involving the shoulder and pelvic muscles, started at the age of 20 year old, when she was diagnosed with a sporadic form of limb-girdle muscular dystrophy. The second case is about a 27 year old male, diagnosed with muscular dystrophy at the age of 15. The third case is about a 43 year old male admitted for frequent falls and weakness of the limbs, mainly distal, started 10 years ago. He was diagnosed with myotonic dystrophy. Although there is still no treatment for muscular dystrophies, the pathology is under investigation in clinical trials.

EP 45. Polymyositis? limb-girdle muscular dystrophy!

Limb-girdle muscular dystrophies (LGMD) are a group of progredient myopathic disorders, whose primary symptom is a progressive weakness of the proximal muscles. Most forms result from a gene dysfunction and are inherited in an autosomal recessive pattern. The phenotype an the age of onset vary between the different forms. A muscular biopsy can reveal signs of an inflammatory reaction in varying degree, though this is not necessary and occurs mostly in some subtypes. We report about a 32-year old female with severely elevated serum creatin kinase (80,000 U/l), which had been found in a routine blood sample 7 years ago. She first presented at an internal medicine department. At that time, only a mild proximal muscle weakness was present at best and physical performance was not impaired at all. Electromyography already showed myopathic changes with abnormal spontaneous activity. Muscle biopsy revealed an inflammatory reaction with distinctive signs of necrosis. Further tests gave no evidence for a paraneoplastic or rheumatologic condition. Suspecting a polymyositis, an immunosuppressive treatment was initiated, first with glucocorticosteroids, later with Methotrexate, Azathioprine, cyclosporine, intravenous immune globuline, Mycophenolat mofetil and Rituximab. Nevertheless, there was no improvement neither of serum creatin kinase nor of the muscle weakness. Instead, the weakness gradually evolved into a tetraparesis. When she finally presented to our department, she could walk no more than a few steps and was not able to get up from a chair. The progressive course of the disease under sufficient immunosuppressive therapy let us think of a chronic degenerative process, such as a muscular dystrophy. Upon further inquiry, the from Sicily originating patient told us about a consanguinity of her parents. The late manifestation (no relevant symptoms until the age of 25, the highly elevated serum creatin kinase and the inflammation in the muscle biopsy were compatible to a dysferlinopathy, a subtype of limb-girdle muscular dystrophy. Genetic testing revealed a yet unknown homozygotic mutation in the dysferlin gene causing the disease. Unfortunately, no other treatment could be proposed to the patient besides physical and occupational therapy. In summary, even though elevated serum creatin kinase and inflammatory changes in the muscle biopsy often point to polymyositis, this is not always the case. In some types of autosomal recessive forms of LGMD (besides LGMD2B notably 2L, 2M and 2N) distinctive inflammatory changes can be detected histopathologically. Especially disease progression despite sufficient immunosuppressive therapy should lead to reevaluation of the diagnosis

Analysis of phenotype, enzyme activity and genotype of Chinese patients with POMT1 mutation.

Protein O-mannosyltransferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan glycosylation. POMT1 mutations cause a wide spectrum of clinical conditions from Walker-Warburg syndrome (WWS), which involves muscle, eye and brain abnormalities, to mild forms of limb-girdle muscular dystrophy with mental retardation. We aimed to elucidate the impact of different POMT1 mutations on the clinical phenotype. We report five Chinese patients with POMT1 mutations: one had a typical clinical manifestation of WWS, and the other four were diagnosed with congenital muscular dystrophy with mental retardation of varying severity. We analyzed the influence of the POMT1 mutations on POMT activity by assaying the patients' muscles and cultured skin fibroblasts. We demonstrated different levels of decreased POMT activity that correlated highly with decreased α-dystroglycan glycosylation. Our results suggest that POMT activity is inversely proportional to clinical severity, and demonstrate that skin fibroblasts can be used for differential diagnosis of patients with α-dystroglycanopathies. We have provided clinical, histological, enzymatic and genetic evidence of POMT1 involvement in five unrelated Chinese patients.

Miyoshi myopathy: diagnosis of a familial case of dysferlinopathy

Miyoshi myopathy (MM) is a rare distal form of limb-girdle muscular dystrophies characterized by weakness primarily affecting the calves in adolescence or young adulthood, with slow progression, the ascending pattern of involvement of muscle groups in an atrophic process, and with obvious clinical polymorphism at onset (3 allelic variants are described). In MM, hypercreatine phosphatemia is noted to be 20– 50 times the normal blood concentrations. MM is referred to the dysferlinopathies with different mutations in the DYSF gene. In that manuscript we describe a 20-year familial case of 2 brothers with MM, including changes in their clinical manifestations, biochemical, CT and EMG parameters. The diagnosis was verified by whole exome sequencing of the DYSF gene to identify a homozygous missense mutations (c. 5302C&gt;T) leading to replacement in the polypeptide chain of DYSF p.Arg1768Trp. The differential diagnosis of MM with clinically similar hereditary neuromuscular diseases is discussed.