Cap Myopathy Research Articles

The role of ultrasound in fetal congenital myopathy detection: a novel case of fetal‐onset cap myopathy

What's already known about this topic? Rare heterogeneous group of neuromuscular disorders. Associated with severe, often fatal phenotypes – Prenatal parental counselling and ‘high risk screening’ important Prenatal diagnosis primarily reliant upon ultrasound detectionWhat does this study add? Introduces a novel, lethal fetal form of cap myopathy. Evaluates range of ultrasound features and how detection can be facilitated Reconfirms fetal‐onset CM represents important, complex diagnostic challenge.

Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies

The β-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and β-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of β-tropomyosin-related myopathies through the identification of a novel β-tropomyosin mutation in two clinical contexts not previously associated with β-tropomyosin. The first clinical phenotype is core-rod myopathy, with a β-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of β-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric β-tropomyosin, a change predicted to alter protein-protein binding between β-tropomyosin and other molecules and to disturb head-to-tail polymerization of β-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del β-tropomyosin in the developing zebrafish. p.K7del β-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail β-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel β-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with β-tropomyosin and pathogenic data from the first animal model of β-tropomyosin-related myopathies.

Somatic mosaicism in TPM2-related myopathy with nemaline rods and cap structures

The TPM2 gene encodes for beta-tropomyosin. Dominant mutations in TPM2 are associated with different congenital myopathies, including nemaline and cap myopathy [8]. In one family, a TPM2 mutation (p.Glu41Lys) has been reported to cause a myopathy with nemaline rods in the mother and cap structures in the daughter [7]. We describe a family with two siblings affected by congenital myopathy showing both rods and cap-like structures caused by a TPM2 mutation. Their clinically asymptomatic father was a somatic mosaic for the mutation. The proband, a 15-year-old girl, presented with slowly progressing muscle weakness in the first decade. At age 13, she developed rapidly progressing scoliosis and respiratory failure, leading to hypercapnic coma, with subsequent tracheostomy. On examination, she had moderate diffuse weakness more pronounced in ankle extensors, long narrow face, scoliosis and rigid spine. CK level and cardiological examinations were normal. Her 14-year-old brother displayed a similar, although milder, phenotype. He had elongated face, high arched palate, rigid spine and mild scoliosis. Ankle extensors, neck flexors, supra and infraspinatus muscles were weak. Forced vital capacity was 60 % of predicted value. Their parents were reported to be healthy. Muscle MRI features are shown in Fig. 1. Given the clinical and radiological phenotype and the possibly recessive pattern of inheritance, SEPN1 mutations were ruled out. Muscle biopsy disclosed in both patients the presence of nemaline rods, cap structures (Fig. 1d–i) and type 1 fiber predominance. These findings prompted us to examine the TPM2 gene, and a heterozygous deletion, c.412_414delGAG (p.E138del) in exon 4, was found (Fig. 1k). When their parents were examined, the 47-year-old father, who did not complain of any neuromuscular symptom and routinely practiced mountaineering, did not show any obvious weakness or contractures but had mild scoliosis and high arched palate. EMG displayed some polyphasic, short amplitude motor unit potentials. Muscle MRI showed features consistent with those of the siblings (Fig. 1c). Muscle biopsy showed mild myopathic features, with cap structures in rare fibers (Fig. 1j) and no nemaline rods. The electropherogram of the TPM2 gene revealed a relatively low level of the mutation in blood DNA suggesting a somatic mosaicism. SNaPshot analysis [1] confirmed the presence of mosaicism (Fig. 1k). The p.E138del pathogenic deletion found in the family has been previously reported only in pure cap disease [3, 5]. Our findings further substantiate the concept that nemaline rods and cap structures belong to the same spectrum of pathological alterations [4] and, although both nemaline myopathy and cap disease are genetically heterogeneous entities, the coexistence of both features should suggest investigating TPM2 first [7]. In the family, the proband’s father had the mildest phenotype so far reported in association with TPM2 G. Tasca G. Silvestri Don Carlo Gnocchi Onlus Foundation, Milan, Italy

D.P.8 Expanding the clinical and genetic phenotype of TPM2-related myopathies

The beta-tropomyosin gene (TPM2) encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin–myosin interactions, and TPM2 mutations have been associated with nemaline myopathy, cap myopathy and distal arthrogryposis. In this study, we expand the allelic spectrum of TPM2-related myopathies through the identification of a novel TPM2 mutation in a family with core-rod myopathy and in a family with trismus-pseudocamptodactyly. In addition, we describe the first animal models of TPM2 related myopathies, and use these models to compare and contrast pathogenic mechanisms related to distinct TPM2 mutations. The first new phenotype is core-rod myopathy, with the TPM2 mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy. The second phenotype is trismus-pseudocamptodactyly syndrome (previously associated exclusively with MYH8 mutations), with mutation identified by candidate gene analysis based on the observation of nemaline rods on muscle biopsy. In both cases, the mutation identified is a novel three base pair in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the 7th amino acid position. Conceptual modeling of this mutation predicts that it disrupts the N-terminal homodimeric alpha helix of TPM2, a change that likely alters protein–protein binding between TPM2 and other molecules. We are now utilizing the zebrafish model system to generate a transgenic model of both this TPM2 mutation as well as a recurrent TPM2 mutation (E139del) associated with cap myopathy. These models are used to determine the underlying pathomechanisms associated with different TPM2 mutations via direct comparisons as well as through comparison with existing nemaline myopathy and core myopathy zebrafish models. In all, we describe a novel TPM2 mutation, two clinical-histopathologic phenotypes not previously associated with TPM2, and the first animal models of TPM2 related myopathies.

C.P.16 Mutations in the β-tropomyosin (TPM2) and γ-tropomyosin (TPM3) genes causing a spectrum of neuromuscular disorders

Published case reports of mutations in the tropomyosin genes describe a variety of neuromuscular disorders. The tropomyosins (Tms) exist as coiled-coil homo- or heterodimers forming head-to-tail polymers, running along the length of the actin molecule. They are encoded by four different genes; αTm (TPM1), βTm (TPM2), γTm (TPM3), and δTm (TPM4), generating more than 40 different tropomyosin isoforms. The tropomyosin genes TPM1, TPM2 and TPM3 are expressed in skeletal muscle encoding isoforms αTmfast, βTm, and δTmslow respectively. We extend the mutational and clinical spectrum of disorders caused by mutations of the β-tropomyosin (TPM2) and γ-tropomyosin (TPM3) genes and provide an overview of new and published cases. The clinical and histological findings of patients with cap myopathy, nemaline myopathy, CFTD, DA1A, DA2B and Escobar syndrome are correlated to the patients’ genotypes. We have also characterized the phosphorylation pattern of β-tropomyosin, both wt and β-tropomyosins containing patient mutations, and identified four novel phosphorylation sites.

Abnormal actin binding of aberrant β-tropomyosins is a molecular cause of muscle weakness in TPM2-related nemaline and cap myopathy

NM (nemaline myopathy) is a rare genetic muscle disorder defined on the basis of muscle weakness and the presence of structural abnormalities in the muscle fibres, i.e. nemaline bodies. The related disorder cap myopathy is defined by cap-like structures located peripherally in the muscle fibres. Both disorders may be caused by mutations in the TPM2 gene encoding β-Tm (tropomyosin). Tm controls muscle contraction by inhibiting actin-myosin interaction in a calcium-sensitive manner. In the present study, we have investigated the pathogenetic mechanisms underlying five disease-causing mutations in Tm. We show that four of the mutations cause changes in affinity for actin, which may cause muscle weakness in these patients, whereas two show defective Ca2+ activation of contractility. We have also mapped the amino acids altered by the mutation to regions important for actin binding and note that two of the mutations cause altered protein conformation, which could account for impaired actin affinity.

Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3

We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of α-tropomyosin slow in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis.

Cap myopathy caused by a mutation of the skeletal alpha-actin gene ACTA1

Cap myopathy is a congenital myopathy with cap-like structures under the sarcolemma. Mutations in TPM2 and TPM3 genes have been reported in cap myopathy so far. We report a newborn boy with persistent profound weakness who required gastro-jejunal tube feeding, tracheostomy and life-long ventilation until he died at 5 years of age. Muscle biopsy at 5 weeks of age was uninformative. Repeat biopsy at 4.5 years revealed subsarcolemmally located caps that were immunopositive for alpha-actinin, actin and to some extent, desmin. EM confirmed loosely arranged thin filaments and paucity of thick filaments. Molecular analysis of ACTA1 gene identified a novel de novo Met47Val mutation. In addition to a new ACTA1 gene mutation, our case emphasizes the genetic heterogeneity of cap myopathy and its association with ACTA1 gene as well as the importance of repeat muscle biopsy in patients with undiagnosed muscle weakness.

G.P.7.09 Functional studies of aberrant beta-tropomyosin causing nemaline myopathy and cap myopathy

G.P.7.09 Functional studies of aberrant beta-tropomyosin causing nemaline myopathy and cap myopathy

G.P.12.10 Repeat muscle biopsy in the diagnosis of cap myopathy with ACTA1 gene mutation

G.P.12.10 Repeat muscle biopsy in the diagnosis of cap myopathy with ACTA1 gene mutation

Cap disease due to mutation of the beta-tropomyosin gene (TPM2)

Cap disease or cap myopathy is a form of congenital myopathy in which peripheral, well-demarcated ‘caps’ of disorganised thin filaments are seen in muscle fibres. Mutation of the TPM2 gene, that encodes beta-tropomyosin, is the first reported genetic cause. In this paper, we describe a further case of cap disease due to a mutation in TPM2, confirming the importance of this genetic association. This is the first report of cardiac dysfunction due to a mutation in TPM2. Our patient has an identical TPM2 mutation to the first genetically diagnosed cap disease patient, a de novo heterozygous three base pair deletion that removes glutamic acid 139 from the centre of beta-tropomyosin (p.E139del). 2D-gel electrophoresis studies show that the shortened mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness.

G.P.13.02 Functional study of mutated beta-tropomyosin causing nemaline myopathy, cap myopathy and distal arthrogryposis

G.P.13.02 Functional study of mutated beta-tropomyosin causing nemaline myopathy, cap myopathy and distal arthrogryposis

C.P.1.12 One causative gene, TPM2, and two congenital myopathies. A functional study

Tropomyosins together with the troponin complex regulate the binding of actin to myosin during muscle contraction. Mutations in the beta-tropomyosin (TPM2) gene have been reported in patients with distal arthrogryposis (R91G and R133W), nemaline myopathy (Q147P and E117K) and cap myopathy (Lehtokari et al., in press). There is an overlap between the three entities both clinically and histologically. The latter two entities are both classified as congenital myopathies and they share several clinical and histological features.

Cap disease caused by heterozygous deletion of the β-tropomyosin gene TPM2

“Cap myopathy” or “cap disease” is a congenital myopathy characterised by cap-like structures at the periphery of muscle fibres, consisting of disarranged thin filaments with enlarged Z discs. Here we report a deletion in the β-tropomyosin ( TPM2) gene causing cap disease in a 36-year-old male patient with congenital muscle weakness, myopathic facies and respiratory insufficiency. The mutation identified in this patient is an in-frame deletion (c.415_417delGAG) of one codon in exon 4 of TPM2 removing a single glutamate residue (p.Glu139del) from the β-tropomyosin protein. This is expected to disrupt the seven-amino acid repeat essential for making a coiled coil, and thus to impair tropomyosin–actin interaction. Missense mutations in TPM2 have previously been found to cause rare cases of nemaline myopathy and distal arthrogryposis. This mutation is one not previously described and the first genetic cause identified for cap disease.

Miopatía en gorra: a propósito de un caso

To report a new case of a little-known congenital myopathy. Cap myopathy is a rare congenital disease caused by an alteration in the structure of the fibre, with disorganised myofibrils at the edges. Since it was first described, only a few cases have been reported in the literature. We describe the case of a 16-year-old patient with a history of neonatal hypotonia and psychomotor retardation. At the age of 4 years, the patient presented myopathic facies with atrophied pectoral muscles, winged scapula and lumbar hyperlordosis. A myopathic pattern was observed in the electromyogram. A muscle biopsy showed a very marked predominance of type I fibres, atrophy in part of the population of this type and 20% of them had cap-shaped subsarcolemmal accumulations, which were intensely positive with DPNH and SDH; in the ultrastructural study they correspond to disorganised peripheral myofibrils with preservation of the Z band and the absence of A bands. These alterations are similar to those described in what is known as cap disease or cap myopathy. Today, the patient has mild proximal tetraparesis and moderate restrictive respiratory failure.

‘Cap myopathy’: Case report of a family

We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of ‘cap myopathy’. This case report suggests that ‘cap myopathy’ and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as ‘ Z-line disorders’ possibly caused by defective myofibrillogenesis.