Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure.

DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.

A cryptic intronic LAMA2 insertion in a boy with mild congenital muscular dystrophy type 1A.

Recessive mutations in the LAMA2 gene lead to congenital muscular dystrophy type 1A and limb girdle muscular dystrophy R23 with complete or partial laminin α2 chain deficiency. Complete laminin α2 chain deficiency presents with early onset of severe hypotonia and generalized weakness, whereas partial deficiency shows a milder and more variable course with limb girdle weakness. Here, we report a child with mildly delayed motor development, elevated serum creatine kinase levels (>1000 U/l) and brain white matter hypointensity, indicative of laminin α2 chain deficiency.

MEGF10 related myopathies: A new case with adult onset disease with prominent respiratory failure and review of reported phenotypes.

Recessive mutations in MEGF10 (multiple epidermal growth factor 10) have been reported in a severe early onset disorder named Early Myopathy, Areflexia, Respiratory Distress and Dysphagia, and a milder form with cores in the muscle biopsy; and a possible genotype-phenotype correlation determining the clinical presentation has been suggested. We undertook exome sequencing in a 66 year old male with a 20 year history of progressive proximal and distal weakness of upper and lower limbs, facial weakness and dysphagia, who developed respiratory failure requiring ventilation while still ambulant in his 50s. Muscle biopsy demonstrated myopathic changes with aggregation of myofibrillar proteins.

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.

Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement.

Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion.

Congenital myopathies define a heterogeneous group of neuromuscular diseases with neonatal or childhood hypotonia and muscle weakness. The genetic cause is still unknown in many patients, precluding genetic counselling and better understanding of the physiopathology. To identify novel genetic causes of congenital myopathies, exome sequencing was performed in three consanguineous families.

Factors associated with low fitness in adolescents--a mixed methods study.

Background: Fitness and physical activity are important for cardiovascular and mental health but activity and fitness levels are declining especially in adolescents and among girls. This study examines clustering of factors associated with low fitness in adolescents in order to best target public health interventions for young people.

Methods: 1147 children were assessed for fitness, had blood samples, anthropometric measures and all data were linked with routine electronic data to examine educational achievement, deprivation and health service usage.

Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene.

Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four LIM domains and a single zinc-finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery-Dreifuss muscular dystrophy, or an early onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene.

Progressive dysphagia in limb-girdle muscular dystrophy type 2B.

Dysphagia has not been reported in genetically confirmed limb-girdle muscular dystrophy type 2B (LGMD2B). A 40-year-old woman reported exercise-induced calf pain at age 34, followed by progressive lower and upper limb weakness. At age 38, progressive dysphagia for solids, and subsequently liquids, ensued.

The relationship between addiction and reward bundling: an experiment comparing smokers and non-smokers.

Aims: Previous studies indicate that addicts show reduced preference for more delayed versus more immediate rewards compared to non-addicts. This may reflect a lower propensity to view such decisions in terms of the larger sequences to which they typically belong (e.g.

Dysferlin associates with the developing T-tubule system in rodent and human skeletal muscle.

Mutations in the dysferlin gene cause limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, and distal anterior compartment myopathy. Dysferlin mainly localizes to the sarcolemma in mature skeletal muscle where it is implicated in membrane fusion and repair. In different forms of muscular dystrophy, a predominantly cytoplasmic localization of dysferlin can be observed in regenerating myofibers, but the subcellular compartment responsible for this labeling pattern is not yet known.

Immunohistochemical analysis of calpain 3: advantages and limitations in diagnosing LGMD2A.

Immunoblot is currently the preferred laboratory test to assist the diagnosis of limb-girdle muscular dystrophy (LGMD) 2A (calpainopathy). To assess whether immunohistochemistry may offer a reliable alternative screening we used two antibodies, Calp3-2C4 (exon 1) and Calp3-12A2 (exon 8), to label blots and sections of skeletal muscle from controls and patients with LGMD2A and other muscle diseases. In LGMD2A muscle biopsies a high degree of concordance was found with Calp3-2C4: labelling on sections was absent in patients with no bands on immunoblot and detected in those where CAPN3 bands were seen.

New aspects on patients affected by dysferlin deficient muscular dystrophy.

Mutations in the dysferlin gene lead to limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. A cohort of 36 patients affected by dysferlinopathy is described, in the first UK study of clinical, genetic, pathological and biochemical data. The diagnosis was established by reduction of dysferlin in the muscle biopsy and subsequent mutational analysis of the dysferlin gene.

Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy.

Skeletal muscle requires an efficient and active membrane repair system to overcome the rigours of frequent contraction. Dysferlin is a component of that system and absence of dysferlin causes muscular dystrophy (dysferlinopathy) characterized by adult onset muscle weakness, high serum creatine kinase levels and a prominent inflammatory infiltrate. We have observed that dysferlinopathy patient biopsies show an excess of immature fibres and therefore investigated the role of dysferlin in muscle regeneration.

Sarcoglycanopathies: can muscle immunoanalysis predict the genotype?

Muscle immunoanalysis of the sarcoglycan complex is an important part of the diagnostic evaluation of muscle biopsies in patients with autosomal recessive limb-girdle muscular dystrophy. Reduced or absent sarcolemmal expression of one or all of the four sarcoglycans (alpha-, beta-, gamma-, delta-sarcoglycan) can be found in patients with limb-girdle muscular dystrophy 2C-F (LGMD2C-F) and also in patients with Duchenne and Becker muscular dystrophy (DMD/BMD). It has previously been suggested that different patterns of sarcoglycan expression could predict the primary genetic defect, and that genetic analysis could be directed by these patterns.

Caveolinopathy--new mutations and additional symptoms.

Mutations in the caveolin-3 gene (CAV3) can lead to a broad spectrum of clinical phenotypes. Phenotypes that have so far been associated with primary caveolin-3 deficiency include limb girdle muscular dystrophy, rippling muscle disease, distal myopathy and hyperCKaemia. This is the first report describing the clinical, pathological and genetic features of patients with caveolinopathy from the UK.

Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A.

Diagnosis of limb girdle muscular dystrophy type 2A can be complex due to phenotypic variability, lack of precision of protein analysis in muscle biopsies, and absence of mutational hot spots in the CAPN3 gene. The aim of this study was to review clinical and biopsy data from a group of patients with known CAPN3 genetic status to validate and refine our current diagnostic strategy, which combines clinical information and protein analysis to direct gene testing. We analysed 85 patients in whom CAPN3 gene sequencing had been performed.

Mouse model for hereditary hemorrhagic telangiectasia has a generalized vascular abnormality.

Background: Mutations in endoglin or activin like kinase-1, both involved in the endothelial transforming growth factor-beta signaling pathway, cause the autosomal dominant bleeding disorder hereditary hemorrhagic telangiectasia. We and others have reported mouse models for this disease that share the characteristic phenotype of dilated vessels and sporadic hemorrhage. The reasons for the variable phenotype in hereditary hemorrhagic telangiectasia are not understood.