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PubMedDate not supplied

[Changes in the motor apparatus of the bronchial cilia. Comparative study of two types of myopathies: nemaline myopathy and the Werdnig-Hoffmann syndrome].

The Authors during an extensive applications of nasal brushing in infancy according to Rutland and Cole, remarked--first time in literature--the contemporary presence in a child of the nemaline myopathy syndrome and immotile cilia syndrome. Supposing the possibility that in other myopathy may be present the same ciliary immotile syndrome, they studied with nasal brushing three cases of Werdnig-Hoffman syndromes: but they presented normal ciliary conformation. The Authors suppose that in case in future it should be found in other cases of nemaline myopathy the contemporary presence of dinein arms lack, it should be demonstrated that this syndrome takes derivation from a genetic alteration both of the muscular apparatus and the ciliary mobility system of bronchial epithelius.

Bronchi↗
PubMed2001

Abnormalities in the expression of nebulin in chromosome-2 linked nemaline myopathy.

Nemaline myopathy is clinically and genetically heterogeneous. The most common autosomal recessive form affecting infants (NEM2) links to chromosome 2q, and is caused by mutations in the gene for nebulin. We have examined the immunocytochemical expression of nebulin in skeletal muscle in 11 cases of nemaline myopathy, from ten families, with linkage compatible to chromosome 2q.22, the locus for nebulin. Mutations in the gene for nebulin have been found in eight of these cases. Immunolabelling with polyclonal antibodies to C-terminal regions of nebulin was compared with antibodies to fibre-type-specific myofibrillar proteins, including myosin heavy chain isoforms and alpha-actinin isoforms. No cases showed a complete absence of C-terminal nebulin, and no enhancement of labelling of the rods was seen with conventional fluorescence microscopy. In control muscle an antibody to the M176-181 repeat region of nebulin showed higher expression in fibres with slow myosin, while ones to the serine-rich domain and to the SH3 domain showed uniform expression. In some cases of nemaline myopathy differences in these patterns were observed. Two siblings with a homozygous mutation in exon 185, that produces a stop codon, showed an absence of labelling only with the SH3 antibody, and other cases showed uneven labelling with this antibody or some fibres devoid of label. Fibre type correlations also showed differences from controls, as some fibres had a fast isoform of one protein but a slow isoform of another. These results indicate that analysis of nebulin expression may detect abnormalities in some cases linked to the corresponding locus and may help to direct molecular analysis. In addition, they may also be relevant to studies of fibre type plasticity and diversity in nemaline myopathy.

Actinin↗
PubMed2002

Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy.

Nemaline myopathy is a clinically and genetically heterogeneous muscle disorder. In the nebulin gene we have detected a number of autosomal recessive mutations. Both autosomal dominant and recessive mutations have been detected in the genes for alpha-actin and alpha-tropomyosin 3. A recessive mutation causing nemaline myopathy among the Old Order Amish has recently been identified in the gene for slow skeletal muscle troponin T. As linkage studies had shown that at least one further gene exists for nemaline myopathy, we investigated another tropomyosin gene expressed in skeletal muscle, the beta-tropomyosin 2 gene. Screening 66 unrelated patients, using single strand conformation polymorphism analysis and sequencing, we found four polymorphisms and two heterozygous missense mutations. Both mutations affect conserved amino acids, and in both cases, the mutant allele is expressed. We speculate that the observed mutations affect the formation of the tropomyosin dimer and its actin-binding properties.

Amino Acid Sequence↗
PubMed2003

Rod distribution and muscle fiber type modification in the progression of nemaline myopathy.

Nemaline myopathy is a structural congenital myopathy associated with the presence of rodlike structures inside the muscle fibers and type I predominance. It may be caused by mutations in at least five genes: slow alpha-tropomyosin 3 (chromosome 1q22-23), nebulin (chromosome 2q21.1-q22), actin (chromosome 1q42), tropomyosin 2 (chromosome 9p13), and troponin T1 (chromosome 19q13.4). The effect of these mutations in the expression of the protein and the mechanism of rod formation is still under investigation. We analyzed the possibility of progressive alterations with time and/or disease evolution, such as transformation of type I to type II fiber and rod pattern and distribution in muscle fibers from patients with nemaline myopathy, through a morphometric and immunohistochemical analysis of different muscle protein isoforms. A tendency of diffuse rods to be organized in the subsarcolemmal region was observed in two patients who were submitted to subsequent biopsies after 10 and 13 years. Additionally, we observed the expression of type II protein isoforms in type I fibers and a higher proportion of type II fibers in the younger patient of a pair of affected sibs, giving further support to the hypothesis of progressive conversion of type II to type I fibers in nemaline myopathy.

Adolescent↗
PubMed2005

An alphaTropomyosin mutation alters dimer preference in nemaline myopathy.

Nemaline myopathy is a human neuromuscular disorder associated with muscle weakness, Z-line accumulations (rods), and myofibrillar disorganization. Disease-causing mutations have been identified in genes encoding muscle thin filament proteins: actin, nebulin, slow troponin T, betaTropomyosin, and alphaTropomyosin(slow). Skeletal muscle expresses three tropomyosin (Tm) isoforms from separate genes: alphaTm(fast)(alphaTm, TPM1), betaTm (TPM2), and alphaTm(slow) (gammaTm, TPM3). In this article, we show that the level of betaTm, but not alphaTm(fast) protein, is reduced in human patients with mutations in alphaTm(slow) and in a transgenic mouse model of alphaTm(slow)(Met9Arg) nemaline myopathy. A postnatal time course of Tm expression in muscles of the mice indicated that the onset of alphaTm(slow)(Met9Arg) expression coincides with the decline of betaTm. Reduction of betaTm levels is independent of the degree of pathology (rods) within a muscle and is detected before the onset of muscle weakness. Thus, reduction in the level of betaTm represents an early clinical diagnostic marker for alphaTm(slow)-based mutations. Examinations of tropomyosin dimer formation using either recombinant proteins or sarcomeric extracts show that the mutation reduces the formation of the preferred alpha/beta heterodimer. We suggest this perturbation of tropomyosin isoform levels and dimer preference alters sarcomeric thin filament dynamics and contributes to muscle weakness in nemaline myopathy.

Animals↗
PubMed2004

Alpha-actin gene mutations and polymorphisms in Italian patients with nemaline myopathy.

Nemaline myopathy is a rare neuromuscular disorder, showing striking clinical and genetic heterogeneity. Patients can show a spectrum of disease ranging from severe congenital to an adult-onset mild form. Disease-causing mutations have been reported in five genes encoding sarcomeric thin filament proteins, and inheritance can be either autosomal recessive or dominant. No phenotype-genotype correlation is apparent at the moment. alpha-actin gene mutations are responsible for about 20% of cases. We have collected 18 patients from 17 families. Our patients exhibit an overall marked clinical variability, but 10 out of 18 show typical features of nemaline myopathy (slowly progressive congenital form). We have identified disease-causing mutations in the alpha-actin gene in 5 out of 17 families, through direct sequencing of its whole coding sequence. One patient carried two mutations, thus we describe a total of 6 mutations, all arising de novo. We also describe some intronic polymorphisms which constitute two common alpha-actin gene haplotypes; we show that haplotype characterisation may have a strong impact in mutation detection due to preferential amplification of a chromosome in subjects carrying both haplotypes. Screening of the alpha-actin gene coding sequence may account for the identification of disease-causing mutations in 20-30% of nemaline myopathy patients. Since the chance to identify mutations is independent of the clinical picture, we suggest that it is appropriate to check for mutations in all patients. Demonstration of a de novo origin of the mutation is of great relevance for families seeking genetic counselling.

Actins↗
PubMed1992

Anaesthesia for cardiac surgery in children with nemaline myopathy.

Nemaline myopathy is a rare congenital myopathy associated with skeletal deformities and respiratory complications. Three children with nemaline myopathy who underwent cardiac surgery are described where the heart rate decreased during induction of anaesthesia and body temperature increased during or after the surgery. The anaesthetic implications in the management of patients with nemaline myopathy are discussed.

Anesthesia, General↗
PubMed1982

Fatal neonatal nemaline myopathy.

Nemaline myopathy was first reported in 1963 and has been considered to be a congenital, non-progressive myopathy with weakness since birth. However, severe forms leading to death in infancy have been rarely reported. Recently we necropsied a female infant with fatal neonatal nemaline myopathy who required mechanical ventilatory support immediately following delivery. She had suffered from recurrent pneumonia and died at five months of age. Light and electron microscopic studies on both muscle biopsy and autopsy specimens were diagnostic of nemaline myopathy. Characteristic rod-like structures were demonstrated within skeletal muscles, and accumulations of thin filaments were seen in numerous muscle fibers. The origin of these structures in the Z-disks and other morphologic features were the same as those of the rods occurring in congenital cases of rod myopathy. No involvement was observed in the cardiac muscle or in the smooth muscle of the gastrointestinal tract. It is likely that involvement of the skeletal muscles of the pharyngeal areas, intercostal spaces, and diaphragm might have contributed to the difficulty in swallowing and respiratory distress.

Abnormalities, Multiple↗
PubMed2001

Nebulin expression in patients with nemaline myopathy.

Nemaline myopathy is a structural congenital myopathy which may show both autosomal dominant and autosomal recessive inheritance patterns. Mutations in three different genes have been identified as the cause of nemaline myopathy: the gene for slow alpha-tropomyosin 3 (TPM3) at 1q22-23, the nebulin gene (NEB) at 2q21.1-q22, and the actin gene (ACTA1) at 1q42. The typical autosomal recessive form appears to be the most common one and is caused by mutations in the nebulin gene. We have studied the pattern of nebulin labeling, in patients with the typical congenital form (ten patients), the severe congenital form (two patients) or the mild, childhood-onset form (one patient), using antibodies against three different domains of nebulin. A qualitative and quantitative nebulin analysis in muscle tissue showed the presence of nebulin in myofibers from all patients. Some differences relating to the rod structure were observed. The majority of the largest subsarcolemmal rods were not labeled with the N2 nebulin antibody (I-band epitope) and showed an indistinct pattern with the two antibodies directed to the Z-band portion of nebulin (epitopes M176-181 and serine-rich domain). Diffuse rods were not revealed using the three antibodies. A discordant pattern of nebulin N2 epitope labeling was found in two affected sisters with a mutation in the nebulin gene, suggesting that modifications in nebulin distribution inside the rods might occur with the progression of the disease. Western blot analysis showed no direct correlation with immunofluorescence data. In nine patients, the band had a molecular weight comparable to the normal control, while in one patient, it was detected with a higher molecular weight. Our results suggest that presence/absence of specific nebulin Z-band epitopes in rod structures is variable and could depend on the degree of rod organization.

Adolescent↗
PubMed1995

A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy.

Nemaline myopathies are diseases characterized by the presence in muscle fibres of pathognomonic rod bodies. These are composed largely of alpha-actinin and actin. We have identified a missense mutation in the alpha-tropomyosin gene, TPM3, which segregates completely with the disease in a family whose autosomal dominant nemaline myopathy we had previously localized to chromosome 1p13-q25. The mutation substitutes an arginine residue for a highly conserved methionine in a putative actin-binding site near the N terminus of the alpha-tropomyosin. The mutation may strengthen tropomyosin - actin binding, leading to rod body formation, by adding a further basic residue to the postulated actin-binding motif.

Amino Acid Sequence↗
PubMed2006

Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy.

Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder of skeletal muscle caused by mutations in at least five different genes encoding thin filament proteins of the striated muscle sarcomere. We have previously described 18 different mutations in the last 42 exons of the nebulin gene (NEB) in 18 families with NM. Here we report 45 novel NEB mutations detected by denaturing high-performance liquid chromatography (dHPLC) and sequence analysis of all 183 NEB exons in NM patients from 44 families. Altogether we have identified, including the deletion of exon 55 identified in the Ashkenazi Jewish population, 64 different mutations in NEB segregating with autosomal recessive NM in 55 families. The majority (55%) of the mutations in NEB are frameshift or nonsense mutations predicted to cause premature truncation of nebulin. Point mutations (25%) or deletions (3%) affecting conserved splice signals are predicted in the majority of cases to cause in-frame exon skipping, possibly leading to impaired nebulin-tropomyosin interaction along the thin filament. Patients in 18 families had one of nine missense mutations (14%) affecting conserved amino acids at or in the vicinity of actin or tropomyosin binding sites. In addition, we found the exon 55 deletion in four families. The majority of the patients (in 49/55 families) were shown to be compound heterozygous for two different mutations. The mutations were found in both constitutively and alternatively expressed exons throughout the NEB gene, and there were no obvious mutational hotspots. Patients with more severe clinical pictures tended to have mutations predicted to be more disruptive than patients with milder forms.

Chromatography, High Pressure Liquid↗
PubMed2001

A mutation in alpha-tropomyosin(slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy.

Nemaline myopathy is a hereditary disease of skeletal muscle defined by a distinct pathology of electron-dense accumulations within the sarcomeric units called rods, muscle weakness and, in most cases, a slow oxidative (type 1) fiber predominance. We generated a transgenic mouse model to study this disorder by expressing an autosomal dominant mutant of alpha-tropomyosin(slow) previously identified in a human cohort. Rods were found in all muscles, but to varying extents which did not correlate with the amount of mutant protein present. In addition, a pathological feature not commonly associated with this disorder, cytoplasmic bodies, was found in the mouse and subsequently identified in human samples. Muscle weakness is a major feature of this disease and was examined with respect to fiber composition, degree of rod-containing fibers, fiber mechanics and fiber diameter. Hypertrophy of fast, glycolytic (type 2B) fibers was apparent at 2 months of age. Muscle weakness was apparent in mice at 5-6 months of age, mimicking the late onset observed in humans with this mutation. The late onset did not correlate with observed changes in fiber type and rod pathology. Rather, the onset of muscle weakness correlates with an age-related decrease in fiber diameter and suggests that early onset is prevented by hypertrophy of fast, glycolytic fibers. We suggest that the clinical phenotype is precipitated by a failure of the hypertrophy to persist and therefore compensate for muscle weakness.

Amino Acid Substitution↗
PubMed2006

Skeletal muscle repair in a mouse model of nemaline myopathy.

Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is a variably severe neuromuscular disorder for which no effective treatment is available. Although a number of genes have been identified in which mutations can cause NM, the pathogenetic mechanisms leading to the phenotypes are poorly understood. To address this question, we examined gene expression patterns in an NM mouse model carrying the human Met9Arg mutation of alpha-tropomyosin slow (Tpm3). We assessed five different skeletal muscles from affected mice, which are representative of muscles with differing fiber-type compositions, different physiological specializations and variable degrees of pathology. Although these same muscles in non-affected mice showed marked variation in patterns of gene expression, with diaphragm being the most dissimilar, the presence of the mutant protein in nemaline muscles resulted in a more similar pattern of gene expression among the muscles. This result suggests a common process or mechanism operating in nemaline muscles independent of the variable degrees of pathology. Transcriptional and protein expression data indicate the presence of a repair process and possibly delayed maturation in nemaline muscles. Markers indicative of satellite cell number, activated satellite cells and immature fibers including M-Cadherin, MyoD, desmin, Pax7 and Myf6 were elevated by western-blot analysis or immunohistochemistry. Evidence suggesting elevated focal repair was observed in nemaline muscle in electron micrographs. This analysis reveals that NM is characterized by a novel repair feature operating in multiple different muscles.

Animals↗
PubMed1978

Nemaline myopathy.

Nemaline myopathy occurred sporadically in a 59-year-old woman. She had slowly progressive weakness. A muscle biopsy specimen showed nemaline rods, increased variation in fiber size, apparent loss of Type IIb fiber differentiation, and a "moth-eaten" pattern of the intermyofibrillar network. At least 44 cases of this disorder have been reported. Clinically, they showed several different modes of onset, patterns of muscle group involvement, and rates of progression. There was a suggestion of familial involvement in at least half. In addition to the presence of nemaline rods, pathological abnormalities of muscle biopsy specimens were quite variable. Results of recent biochemical studies have shown abnormal myosin in a patient with rod myopathy. A hypothesis is proposed that relates the diverse clinical and histological features of this disease to a hereditary molecular abnormality of myosin synthesis.

Female↗
PubMed1999

Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.

Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle alpha-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA.

Actins↗
PubMed1999

Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy.

The nemaline myopathies are muscle disorders of variable severity and age of onset, with characteristic nemaline bodies in the sarcoplasm. Genes for dominant (NEM1) and recessive (NEM2A) nemaline myopathy have been localised to chromosomes one and two, respectively. A missense mutation in the alpha-tropomyosin gene (TPM3) has been associated with NEM1 in one family. Probands from 76 other nemaline myopathy families have now been screened for TPM3 mutations. One proband, who was not noted to have any weakness neonatally, but who died at 21 months of age, was shown to be homozygous for a single strand conformation polymorphism (SSCP) in skeletal-muscle-specific exon 1 of TPM3. Sequencing revealed homozygosity for a nonsense mutation at codon 31 (CAG to TAG). The patient should have no functioning alpha-tropomyosin slow protein. The nemaline bodies in this patient were exclusively in type one fibres, consistent with the expression of TPM3 only in type one fibres.

Fatal Outcome↗