Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing.

Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but this gene is not systematically analysed because of the absence of specific signs and difficulties in protein analysis. By using high-throughput variants screening techniques, we identified variants in TRIM32 in two patients presenting nonspecific LGMD.

Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1.

Background: Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or double-walled membrane tubules in muscle fibres. Recently, STIM1, encoding a major calcium sensor of the endoplasmic reticulum, was identified as a TAM gene.

Methods: The present study aims to define the clinical, histological and ultrastructural phenotype of tubular aggregate myopathy and to assess the STIM1 mutation spectrum.

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease.

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France.

Distal myopathies.

The distal myopathies are a heterogeneous group of genetic disorders defined by a predominant distal weakness at onset or throughout the evolution of the disease and by pathological data supporting a myopathic process. The number of genes associated with distal myopathies continues to increase. Fourteen distinct distal myopathies are currently defined by their gene and causative mutations, compared to just five entities delineated on clinical grounds two decades ago.

Compound heterozygous mutations of the TNXB gene cause primary myopathy.

Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising.

ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation.

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported.

HTLV-1-associated inflammatory myopathies: low proviral load and moderate inflammation in 13 patients from West Indies and West Africa.

Background: The Human T-cell Leukemia Virus type 1 (HTLV-1) is the causative agent of several inflammatory diseases, including HTLV-1-associated inflammatory myopathies (HAIM). Little is known about the virological and immunological characteristics of this viral disease.

Objectives: To characterize the histological and virological features of HAIM patients, in order to better understand the pathogenetic mechanisms and unravel new biological markers of this disease.

Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms.

In humans, congenital myopathy-linked tropomyosin mutations lead to skeletal muscle dysfunction, but the cellular and molecular mechanisms underlying such dysfunction remain obscure. Recent studies have suggested a unifying mechanism by which tropomyosin mutations partially inhibit thin filament activation and prevent proper formation and cycling of myosin cross-bridges, inducing force deficits at the fiber and whole-muscle levels. Here, we aimed to verify this mechanism using single membrane-permeabilized fibers from patients with three tropomyosin mutations (TPM2-null, TPM3-R167H and TPM2-E181K) and measuring a broad range of parameters.

Variable phenotype of del45-55 Becker patients correlated with nNOSμ mislocalization and RYR1 hypernitrosylation.

Duchenne and Becker muscular dystrophies (DMD and BMD) are muscle-wasting diseases caused by mutations in the DMD gene-encoding dystrophin. Usually, out-of-frame deletions give rise to DMD, whereas in-frame deletions result in BMD. BMD patients exhibit a less severe disease because an abnormal but functional dystrophin is produced.

A myopathy-related actin mutation increases contractile function.

Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure.

Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy.

Nebulin is a giant protein expressed at high levels in skeletal muscle. Mutations in the nebulin gene (NEB) lead to muscle weakness and various congenital myopathies. Despite increasing clinical and scientific interest, the pathogenesis of weakness remains unknown.

Nemaline bodies as unique pathological feature in the course of treated dermatomyositis.

Dermatomyositis was diagnosed on clinical and muscle histological criteria in a 42-year-old woman. Despite treatment, the patient complained of deterioration of her muscle condition. Since her symptoms were discordant with the rest of the data, muscle biopsy was performed and disclosed rod-bearing non-atrophic fibers as the unique and predominant pathological feature.

Early onset collagen VI myopathies: Genetic and clinical correlations.

Objective: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations.

Methods: Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%).

Multiexon deletions account for 15% of congenital myasthenic syndromes with RAPSN mutations after negative DNA sequencing.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders that give rise to a defect in neuromuscular transmission. We described here three patients with a characteristic phenotype of recessive CMS and presenting mutation in the gene encoding rapsyn (RAPSN). Familial analysis showed that one allelic mutation failed to be detected by direct sequencing.

Myopathies caused by homozygous titin mutations: limb-girdle muscular dystrophy 2J and variations of phenotype.

Limb-girdle muscular dystrophy 2J caused by mutations in C-terminal titin has so far been identified in Finnish patients only. This may in part be due to limited availability of diagnostic tests for titin defects. In this report, a French family with an autosomal-dominant late-onset distal myopathy of the tibial muscular dystrophy phenotype segregating in several members of the family was described.

[Treatment of autoimmune myasthenia].

Myasthenia gravis is the most common neuromuscular junction disorder and the best understood autoimmune disease of the nervous system. The autoimmune attack leads to decreased concentrations of the AChR and results in fatigability of skeletal muscles increasing with activity and improving with rest. The treatment of myasthenia has improved dramatically over the last few decades, with an increasing number of immunotherapies used in management although not all of them have been formally tested in double-blind, prospective trials.

Contraception and screening for cervical and breast cancer in neuromuscular disease: a retrospective study of 50 patients monitored at a clinical reference centre.

Objective: To analyse contraceptive methods and the extent of screening for breast and cervical cancer in women with neuromuscular disease, compare these results with data and guidelines for the general population and determine the environmental and attitudinal barriers encountered.

Patients And Methods: A retrospective, descriptive study in a population of female neuromuscular disease patients (aged 20 to 74) monitored at a clinical reference centre.

Results: Complete datasets were available for 49 patients.

Clinical outcome in 19 French and Spanish patients with valosin-containing protein myopathy associated with Paget's disease of bone and frontotemporal dementia.

We report the clinical, histological and genetic findings in 10 families (19 patients) presenting mutations in the valosin-containing protein (VCP). The mean age at onset was 42 years. The clinical pattern was characterized by an early involvement of the proximal upper limbs with scapular winging.

[Cutaneous EBV-associated lymphoproliferative disorder in a dermatomyositis treated with immunosuppressive agents].

We report a case of Epstein Barr virus-associated large B cell lymphoproliferative disorder, with an abdominal cutaneous localization, in an adult treated for 10 years with immunosuppressive agents for a dermatomyositis. This is the third case of immunosuppressive induced lymphoproliferative disorder localized to skin in a patient with dermatomyositis. Diagnosis was unexpectedly obtained by the histologic examination of surgical samples of skin necrosis possibly induced by edetate calcium disodium subcutaneous injections in calcinosis cutis.

Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD).

Mutations in C-terminal titin cause autosomal dominant tibial muscular dystrophy (TMD) as reported previously. Samples from 25 new families and 25 sporadic new distal myopathy cases were screened for titin mutations. Three novel mutations were discovered in two families from Spain and two families from France.