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Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype–phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype–phenotype correlations, we found clustering to overcome the limits of the "single-dimension" paradigm traditionally used to describe genotype–phenotype relationships. [ABSTRACT FROM AUTHOR]

Background: International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders.Results: Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients.Conclusion: EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level. [ABSTRACT FROM AUTHOR]

Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next-generation sequencing has increasingly been used for their diagnosis. We reviewed clinical and genetic forms of congenital myopathy and defined possible strategies to improve cost-effectiveness in histological and imaging diagnosis. [ABSTRACT FROM AUTHOR]

Background: A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases.Results: During the clinical follow-up (range: 2-44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias.Conclusion: The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases. [ABSTRACT FROM AUTHOR]

Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype-phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations. We recruited patients with CNMs from all the Italian tertiary neuromuscular centers following clinical and histological criteria. All selected patients were screened for the four 'canonical' genes related to CNMs: MTM1, DNM2, RYR1 and BIN1. Pathogenetic mutations were found in 38 of the 54 screened patients (70 %), mostly in patients with congenital onset (25 of 30 patients, 83 %): 15 in MTM1, 6 in DNM2, 3 in RYR1 and one in TTN. Among the 13 patients with a childhood-adolescence onset, mutations were found in 6 patients (46 %), all in DNM2. In the group of the 11 patients with adult onset, mutations were identified in 7 patients (63 %), again in DNM2, confirming that variants in this gene are relatively more common in late-onset phenotypes. The present study provides the relative molecular frequency of centronuclear myopathy and of its genetically defined forms in Italy and also proposes a diagnostic algorithm to be used in clinical practice to address genetic investigations. [ABSTRACT FROM AUTHOR]

Abstract: We report an 11-year-old boy with exercise-related myopathy, and a novel mutation m.5669G>A in the mitochondrial tRNA Asparagine gene (mt-tRNAAsn, MTTN). Muscle biopsy studies showed COX-negative, SDH-positive fibers at histochemistry and biochemical defects of oxidative metabolism. The m.5669G>A mutation was present only in patient’s muscle resulting in the first muscle-specific MTTN mutation. Mt-tRNAAsn steady-state levels and in silico predictions supported the pathogenicity of this mutation. A mitochondrial myopathy should be considered in the differential diagnosis of exercise intolerance in children. [Copyright &y& Elsevier]

Hereditary inclusion body myopathy (IBM2) was mainly reported in Middle Eastern Jewish patients. Distal myopathy with rimmed vacuoles has been described as a worldwide distributed distal myopathy. Both diseases are caused by mutations of the UDP- N-acetylglucosamine 2-epimerase/ N-acetylmannosamine kinase ( GNE) gene. Herein we report two patients: an Egyptian Muslim patient with the “common” Middle Eastern mutation (M712T), rarely described in non-Jewish patients; and an Italian patient carrying a novel GNE mutation (L179F) in the epimerase domain. Our patients share common clinical and histopathological features, with some interesting aspects. The first patient presented a clinical deterioration during her first pregnancy confirming that an increased requirement of sialic acid during pregnancy may trigger a clinical worsening. The second patient showed a slowly progressive deterioration, different from other patients carrying mutations in the epimerase domain, who had a severe and rapid progression. [ABSTRACT FROM AUTHOR]

Abstract: We describe the clinical features, muscle pathology features, and molecular studies of seven patients with Chanarin–Dorfman syndrome (CDS) or neutral lipid storage disease and ichthyosis (NLSDI), a multisystem triglyceride storage disease with massive accumulation of lipid droplets in muscle fibers. All patients presented with congenital ichthyosiform erythroderma, cytoplasmic lipid droplets in blood cells, mild to severe hepatomegaly, and increased serum CK levels and liver enzymes. Three patients showed muscle symptoms and three had steathorrea. Molecular analysis identified five mutations, three of which are novel. These findings expand the clinical and mutational spectrum and underline the genetic heterogeneity of this disease. [Copyright &y& Elsevier]

We report a novel T14687C mutation in the mitochondrial transfer ribonucleic acid glutamic acid gene in a 16-year-old boy with myopathy and lactic acidosis, retinopathy, and progressive respiratory failure leading to death. A muscle biopsy showed cytochrome c oxidase-negative ragged-red fibers, and biochemical analysis of the respiratory chain enzymes in muscle homogenate revealed complex I and complex IV deficiencies. The mutation, which affects the trinucleotide (TVC) loop, was nearly homoplasmic in the muscle DNA of the proband, but it was absent in his blood and in the blood from the asymptomatic mother, suggesting that it may have been a spontaneous somatic mutation in muscle. (J Child Neurol 2003;18:300-303). [ABSTRACT FROM AUTHOR]

In muscle ATP is primarily known for its function as an energy source and as a mediator of the "excitation-transcription" process, which guarantees muscle plasticity in response to environmental stimuli. When quickly released in massive concentrations in the extracellular space as in presence of muscle membrane damage, ATP acts as a damage-associated molecular pattern molecule (DAMP). In experimental murine models of muscular dystrophies characterized by membrane instability, blockade of eATP/P2X7 receptor (R) purinergic signaling delayed the progression of the dystrophic phenotype dampening the local inflammatory response and inducing Foxp3+ T Regulatory lymphocytes. These discoveries highlighted the relevance of ATP as a harbinger of immune-tissue damage in muscular genetic diseases. Given the interactions between the immune system and muscle regeneration, the comprehension of ATP/purinerigic pathway articulated organization in muscle cells has become of extreme interest. This review explores ATP release, metabolism, feedback control and cross-talk with members of muscle inflammasome in the context of muscular dystrophies. [ABSTRACT FROM AUTHOR]

Abstract: Phosphoglycerate mutase (PGAM) deficiency causes a rare metabolic myopathy characterized by exercise-related myalgia and myoglobinuria. This disorder was described in 13 patients and five different mutations in the PGAM-M gene were identified. We report on a new patient with an unusual clinical presentation. As a youth, he participated in different sports without complaining of muscular symptoms, but at 44years of age, after a brief, intense effort, he experienced lightheadedness without fainting. Serum CK was elevated and the ischemic exercise test showed a pathological lactate response. Muscle biopsy showed only mild abnormalities, but biochemical study revealed a defect of PGAM and genetic analysis showed two different mutations in the PGAM-M gene. Our case expands the clinical spectrum of PGAM deficiency and suggests that the frequency of this metabolic myopathy may be underestimated. [Copyright &y& Elsevier]

We report two new mutations in the myophosphorylase gene (PYGM) in two unrelated Italian patients with myophosphorylase deficiency (McArdle''s disease). In one, we identified a missense C-to-T mutation at codon 269 in exon 7, changing CGA (arginine) to TGA (stop codon) (R269X). The second patient carried a G-to-C mutation, changing GCT (alanine) to CCT (proline) at codon 686 (A686P) in exon 17. Both were compound heterozygous, with the common mutation at codon 49 (R49X) on the other allele.Our data further expand the genetic heterogeneity in patients with McArdle''s disease, suggesting that the possibility of novel mutations has to be taken into account when performing genetic analysis in distinct ethnic groups. [Copyright &y& Elsevier]

Mutations in the MTM1 gene cause X-linked myotubular myopathy (XLMTM), characterized by neonatal hypotonia and respiratory failure, and are responsible for a premature mortality in affected males. Female carriers are usually asymptomatic but they may present with muscular weakness because of a hypothesized skewed pattern of X-chromosome inactivation. By combining next generation sequencing (NGS) and CGH array approaches, we have investigated the role of MTM1 variants in a large cohort of undiagnosed patients with a wide spectrum of myopathies. Seven novel XLMTM patients have been identified, including two girls with an unremarkable family history for myotubular myopathy. Moreover, we have detected and finely mapped a large deletion causing a myotubular myopathy with abnormal genital development. Our data confirm that the severe neonatal onset of the disease in male infants is sufficient to address the direct molecular testing toward the MTM1 gene and, above all, suggest that the number of undiagnosed symptomatic female carriers is probably underestimated. [ABSTRACT FROM AUTHOR]

Abstract: We report a 14-year-old-boy with markedly elevated serum creatine kinase (CK) levels, in whom massive triglyceride storage was found in peripheral blood leukocytes and in muscle biopsy. Sequencing PNPLA2, the gene encoding the adipose triglyceride lipase (ATGL) and responsible for the neutral lipid storage disease with myopathy (NLSDM), we identified two heterozygous mutations, including a previously reported nonsense and a novel missense mutation in the patatin domain of the gene. Lipid storage myopathy can be clinically silent in childhood and presenting only with hyperCKemia. [Copyright &y& Elsevier]

Abstract: A subgroup of neutral lipid storage disease has been recently associated with myopathy (NLSDM) and attributed to mutations in the gene (PNPLA2) encoding an adipose triglyceride lipase involved in the degradation of intracellular triglycerides. Five NLSDM patients have been described thus far and we reported three additional patients. A 44-year old Iranian woman and two Italian brothers, aged 40 and 35, presented with exercise intolerance and proximal limb weakness, elevated CK levels, and Jordan’s anomaly. Muscle biopsies showed marked neutral lipid accumulation in all patients. The 10 exons and the intron–exon junctions of the PNPLA2 gene were sequenced. Two novel homozygous mutations in exon 5 of PNPLA2 gene were found (c.695delT and c.542delAC). Both mutations resulted in frameshifts leading to premature stop codons (p.L255X and p.I212X, respectively). These mutations predict a truncated PNPLA2 protein lacking the C-terminal hydrophobic domain. These findings indicate that NLSDM is rare, but genetically heterogeneous. [Copyright &y& Elsevier]

Abstract: To better elucidate the pathogenesis of lymphocyte recruitment of memory CD4+ T cells in inflammatory myopathies, we studied the expression of CCR5 and CCR7 on CD4 memory T cells in muscle tissue from 11 patients with juvenile dermatomyositis, six adult patients with polymyositis, two patients with Duchenne muscular dystrophy, and two patients with spinal muscular atrophy. A prevalent infiltration of CCR5+ effector CD4 T memory cells is observed in inflammatory myopathies. Moreover, we found a strong expression of CCR7 in perifascicular atrophic and in degenerating/regenerating muscle fibers in juvenile dermatomyositis (JDM) but not in fibers from adult polymyositis and Duchenne muscular dystrophy. The selective expression of CCR7 in JDM may open new perspectives in the understanding of the pathogenesis of inflammatory myopathies, offering a new tool for the differential diagnosis of these disorders. [Copyright &y& Elsevier]

Background: The mitochondrial myopathies typically affect many organ systems and are associated with mutations in mitochondrial DNA (mtDNA) that are maternally inherited. However, there is also a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. We studied the biochemical and molecular characteristics of this sporadic myopathy. Methods: We sequenced the mtDNA cytochrome b gene in blood and muscle specimens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency. We compared the clinical and molecular features of these patients with those previously described in four other patients with mutations in the cytochrome b gene. Results: We found a total of three different nonsense mutations (G15084A, G15168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (nucleotides 15498 to 15521) in the cytochrome b gene in the five patients. Each of these mutations impairs the enzymatic function of the cytochrome b protein. In these patients and those previously described, the clinical manifestations included progressive exercise intolerance, proximal limb weakness, and in some cases, attacks of myoglobinuria. There was no maternal inheritance and there were no mutations in tissues other than muscle. The absence of these findings suggests that the disorder is due to somatic mutations in myogenic stem cells after germ-layer differentiation. All the point mutations involved the substitution of adenine for guanine, but all were in different locations. Conclusions: The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA. This myopathy is one cause of the common and often elusive syndrome of exercise intolerance. (N Engl J Med 1999;341:1037-44.) [ABSTRACT FROM AUTHOR]