Becker muscular dystrophy severity is linked to the structure of dystrophin.

In-frame exon deletions of the Duchenne muscular dystrophy (DMD) gene produce internally truncated proteins that typically lead to Becker muscular dystrophy (BMD), a milder allelic disorder of DMD. We hypothesized that differences in the structure of mutant dystrophin may be responsible for the clinical heterogeneity observed in Becker patients and we studied four prevalent in-frame exon deletions, i.e.

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.

Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations.

Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2.

A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.

Objective: Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases. Our objective was the evaluation of the specificity and sensitivity of the signs encountered with POLG mutations.

Design: Forty-four patients out of 154 with sequenced POLG gene had mutations affecting either one (POLG(+/-) group) or two POLG alleles (POLG(+/+) group).

Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene.

Background: Autosomal dominant (AD) central core disease (CCD) is a congenital myopathy characterised by the presence of cores in the muscle fibres which correspond to broad areas of myofibrils disorganisation, Z-line streaming and lack of mitochondria. Heterozygous mutations in the RYR1 gene were observed in the large majority of AD-CCD families; however, this gene was excluded in some of AD-CCD families.

Objective: To enlarge the genetic spectrum of AD-CCD demonstrating mutations in an additional gene.

Diagnostic and clinical classification of autoimmune myasthenia gravis.

Myasthenia gravis is characterized by muscle weakness and abnormal fatigability. It is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction. In most cases, the autoantibodies are against the acetylcholine receptor (AChR).

Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial.

Objective: To assess whether bezafibrate increases fatty acid oxidation (FAO) and lowers heart rate (HR) during exercise in patients with carnitine palmitoyltransferase (CPT) II and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies.

Methods: This was a 3-month, randomized, double-blind, crossover study of bezafibrate in patients with CPT II (n = 5) and VLCAD (n = 5) deficiencies. Primary outcome measures were changes in FAO, measured with stable-isotope methodology and indirect calorimetry, and changes in HR during exercise.

Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations.

Objective: To report that homoplasmic deleterious mutations in the mitochondrial DNA MT-ATP6/8 genes may be responsible for acute episodes of limb weakness mimicking periodic paralysis due to channelopathies and dramatically responding to acetazolamide.

Methods: Mitochondrial DNA sequencing and restriction PCR, oxidative phosphorylation functional assays, reactive oxygen species metabolism, and patch-clamp technique in cultured skin fibroblasts.

Results: Occurrence of a typical MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome in a single member of a large pedigree with episodic weakness associated with a later-onset distal motor neuropathy led to the disclosure of 2 deleterious mitochondrial DNA mutations.

[Myasthenia, from the internist's point of view].

Myasthenia gravis is an autoimmune disease due to specific antibodies inducing a neuromuscular transmission defect causing muscle fatigability. If onset of the disease may be at any age, myasthenia gravis concerns mostly young adults, in majority females. The disease characteristic features are the following: ocular symptoms (ptosis or diplopia) as main initial manifestation, extension to other muscles in 80 % of the cases, variability of the deficit, effort induced worsening, successive periods of exacerbation during the disease course, severity depending on respiratory and swallowing impairment (if rapid worsening, a myasthenic crisis is to be suspected), association with thymoma in 20 % of patients and with other various autoimmune diseases, most commonly hyperthyroidism and Hashimoto's disease.

Combined cap disease and nemaline myopathy in the same patient caused by an autosomal dominant mutation in the TPM3 gene.

The slow α-tropomyosin gene (TPM3) has been associated with three distinct histological entities: nemaline myopathy (NM, NEM1), congenital fibre-type disproportion (CFTD), and cap disease (CD). Here we describe a patient presenting an early-onset congenital myopathy associated with a combination of well separated cap structures and nemaline bodies in his muscle biopsy. Exome sequencing analysis allowed us to identify a de novo missense mutation in the TPM3 gene.

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.

POLG mutations associated with remitting/relapsing neurological events.

Recent experimental data underline the relationship between mitochondria and immune function. Clinical reports of patients presenting with mitochondrial dysfunction associated with dysimmune responses in the central nervous system reinforce this new concept. We describe the first case of a woman presenting with symptoms related to a novel compound heterozygous mutation of the mitochondrial polymerase γ (POLG) gene, associated with neurological events suggestive of a demyelinating process.

Neutral lipid storage disease with myopathy: a whole-body nuclear MRI and metabolic study.

Neutral lipid storage disease with myopathy (NLSDM) is caused by a mutation in the gene encoding adipose triglyceride lipase (ATGL), and is characterized by the presence of numerous triglyceride-containing cytoplasmic droplets in type I muscle fibers. Major clinical manifestations concern the heart and skeletal muscle, and some patients also present diabetes mellitus. We report the clinical, metabolic, and whole-body nuclear magnetic resonance imaging findings of three patients with NLSDM.

Dilated cardiomyopathy in patients with mutations in anoctamin 5.

Background: Homozygous mutations in ANO5, a gene encoding anoctamin 5, a putative calcium-activated chloride channel, have recently been reported in patients with adult-onset myopathies or isolated high-CK levels. Cardiomyopathy has not previously been reported in these populations despite a proven expression of anoctamin 5 in the cardiac muscle.

Methods: Patients presenting for the management of high-CK levels or overt myopathy with proven ANO5 mutations were prospectively investigated between June 2010 and March 2012 in Pitié Salpêtrière Hospital, according to a standardised protocol.

Blocked muscle fat oxidation during exercise in neutral lipid storage disease.

Objective: To determine whether impaired exercise capacity in neutral lipid storage disease with myopathy is solely caused by muscle weakness or whether a defect in energy metabolism (blocked fat oxidation) may also play a role.

Design: We studied a 37-year-old woman with neutral lipid storage disease with myopathy, who cycled while lipid oxidation was assessed using U-(13)C palmitate tracer dilution technique. The effect of a glucose infusion during exercise was also studied.

Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.

Objective: In this study we aim to demonstrate the occurrence of adult forms of TK2 mutations causing progressive mitochondrial myopathy with significant muscle mitochondrial DNA (mtDNA) depletion.

Methods: Patients' investigations included serum creatine kinase, blood lactate, electromyographic, echocardiographic, and functional respiratory analyses as well as TK2 gene sequencing and TK2 activity measurement. Mitochondrial activities and mtDNA were analyzed in the patients' muscle biopsy.

Miyoshi-like distal myopathy with mutations in anoctamin 5 gene.

Miyoshi myopathy is the most common form of recessive distal myopathy. Recessive mutations in the ANO5 gene have been recently identified in Northern Europe as a cause of non dysferlin-linked distal myopathy and limb girdle muscular dystrophy. We report here the first French cases of anoctamin 5 myopathy in 2 brothers presenting with a Miyoshi-like pattern.

Disorders of muscle lipid metabolism: diagnostic and therapeutic challenges.

Disorders of muscle lipid metabolism may involve intramyocellular triglyceride degradation, carnitine uptake, long-chain fatty acids mitochondrial transport, or fatty acid β-oxidation. Three main diseases leading to permanent muscle weakness are associated with severe increased muscle lipid content (lipid storage myopathies): primary carnitine deficiency, neutral lipid storage disease and multiple acyl-CoA dehydrogenase deficiency. A moderate lipidosis may be observed in fatty acid oxidation disorders revealed by rhabdomyolysis episodes such as carnitine palmitoyl transferase II, very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein deficiencies, and in recently described phosphatidic acid phosphatase deficiency.

Rigid spine syndrome revealing late-onset Pompe disease.

The authors describe a 50-year-old man who was evaluated for a rigid spine syndrome with onset at age 15, and subsequent walking difficulties. Cardiac and pulmonary functions were normal. Deltoid biopsy revealed the presence of small vacuoles and increased glycogen with Periodic Acid Schiff staining in a limited number of fibers.

[Multiple acyl-CoA dehydrogenase deficiency (MADD): a curable cause of genetic muscular lipidosis].

Introduction: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare genetic disease involving fatty acid oxidation. It is due to the deficiency of one of the two electron transporters: electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxydoreductase (ETF-QO). Symptoms begin more often in childhood or in young adulthood with a multisystemic disease with encephalopathy or muscular weakness.

[Diagnosis of a myopathic disease in adult].

Strategy for the diagnosis of a muscle weakness includes two steps: to rely the weakness to a muscular origin and to find the aetiology. A muscular deficit is purely motor, without sensory signs, involving mainly axial and proximal muscles. The essential informations for aetiological characterization are: 1st) a family history, indicating a genetic origin, 2nd the chronological profile, 3rd) the clinical pattern (deficit topography, modification of muscle volume, fatigability, contractures, myotonia, oculobulbar, respiratory or cardiac involvement), 4th) investigations (CK level, EMG, muscle imaging muscle, biopsy, genetic testing).

[Antibodies in myasthenia gravis].

In autoimmune myasthenia gravis, 75 to 80% of patients have antiacetylcholine receptor antibodies (anti-AChR abs) quantified by immunoprecipitation. Anti-AChR abs are polyclonal, directed against all AChR subunits, with a major fraction against the main immunogenic region, (alpha-subunit, aminoacids 67-76); they cause AChR loss by three mechanisms: blocking of acetylcholine binding; accelerated degradation or AChR due to bridging of two adjacent AChR molecules (antigenic modulation); lysis of postsynaptic membrane induced by complement. Neither anti-AChR ab level nor antigenic repertoire are correlated with disease severity.