Nemaline Myopathy Research Articles

Congenital Nemaline Myopathy with Dense Protein Masses.

Congenital Nemaline Myopathy with Dense Protein Masses.

Troponin-T type 1 (TNNT1)-related nemaline myopathy: unique respiratory phenotype and muscle pathology findings

Biallelic pathogenic variants in the troponin T type 1 (TNNT1) gene cause a severe form of congenital nemaline myopathy. Typical features include severe motor delay, proximal contractures and weakness, pectus carinatum, chest wall rigidity and tremor. If left untreated, respiratory failure leads to early death at a median age of 18 months. Here we report on three non-Amish, unrelated patients harbouring novel TNNT1 variants. The peculiar combination of respiratory muscle weakness and chest wall stiffness caused early severe hypoventilation warranting the use of high pressures on BiPAP ventilator, with subsequent rapid escalation of pressures delivered with limited efficacy secondary to the extreme rib cage stiffness. Severe respiratory impairment occurred despite a relatively milder motor involvement in one patient. Muscle biopsies from two individuals showed predominant involvement of type 1 fibres, abundant nemaline bodies, marked fibrosis and loss of TNNT1 protein. We aim to increase the awareness of the challenges of managing respiratory support in patients with this unique respiratory phenotype.

A nemaline myopathy-linked point mutation destabilizes the second actin binding site of tropomodulin family proteins

Proper function of striated muscle sarcomeres depends on strict regulation of thin filament lengths. Leiomodin (Lmod) and tropomodulin (Tmod), homologous proteins both with an affinity for actin and tropomyosin, bind to the pointed end of thin filaments, altering actin polymerization dynamics and controlling thin filament lengths. Several mutations in the skeletal isoform of Lmod (Lmod3) have been linked to nemaline myopathy, a disease characterized by aberrant sarcomere assembly, hypotonia, and severe muscle weakness ultimately leading to death.

Rituximab as a treatment for human immunodeficiency virus-associated nemaline myopathy: What does the literature have to tell us?

We presented a letter about a case of a 37-year-old Black female with a history of human immunodeficiency virus and an undetectable viral load. She was evaluated with weakness in the scapular (grade III) and pelvic girdles (grade II), elevation of creatine phosphokinase levels and muscle biopsy compatible with nemaline myopathy. She was treated with rituximab showing improvement of the condition.

Clinical and genetic features of infancy-onset congenital myopathies from a Chinese paediatric centre

BackgroundCongenital myopathies are a group of rare neuromuscular diseases characterized by specific histopathological features. The relationship between the pathologies and the genetic causes is complex, and the prevalence of myopathy-causing genes varies among patients from different ethnic groups. The aim of the present study was to characterize congenital myopathies with infancy onset among patients registered at our institution.MethodThis retrospective study enrolled 56 patients based on the pathological and/or genetic diagnosis. Clinical, histopathological and genetic features of the patients were analysed with long-term follow-up.ResultsTwenty-six out of 43 patients who received next-generation sequencing had genetic confirmation, and RYR1 variations (12/26) were the most prevalent. Eighteen novel variations were identified in 6 disease-causing genes, including RYR1, NEB, TTN, TNNT1, DNM2 and ACTA1. Nemaline myopathy (17/55) was the most common histopathology. The onset ages ranged from birth to 1 year. Thirty-one patients were followed for 3.83 ± 3.05 years (ranging from 3 months to 11 years). No patient died before 1 year. Two patients died at 5 years and 8 years respectively. The motor abilities were stable or improved in 23 patients and deteriorated in 6 patients. Ten (10/31) patients developed respiratory involvement, and 9 patients (9/31) had mildly abnormal electrocardiograms and/or echocardiograms.ConclusionThe severity of congenital myopathies in the neonatal/infantile period may vary in patients from different ethnic groups. More concern should be given to cardiac monitoring in patients with congenital myopathies even in those with static courses.

The Clinical Spectrum of Mutations in CAP2

Background: Dilated cardiomyopathy leads to contractile dysfunction, progressive heart failure, and excessive risk of sudden cardiac death. We reported a homozygous damaging variation in CAP2 causing dilated cardiomyopathy and supraventricular tachycardia in two cousins of one family. Additional homozygous mutations in CAP2 with clinical presentations were reported. Aim: To present the different CAP2 mutations described in patients of various populations with a spectrum of clinical descriptions and possibly correlate the mutations to the clinical findings. This is important for the diagnosing and prognosis of patients with mutations in this gene. Methods: Clinical evaluation of an additional patient of the family we previously reported. Literature searches of clinical studies of patients affected by mutations in CAP2, animal models for the gene, and the role of CAP2 in the assembly of actin in the thin filaments of the sarcomere. Results: All patients had dilated cardiomyopathy necessitating heart transplants at a very young age. Two patients with one loss of function mutation presented additionally with structural heart abnormalities. Another loss of function mutation in one patient associated with nemaline myopathy, mild hypotonia, atrophic, and widened scarring. One report did not detail the patient's mutation and presented tricuspid and pulmonary atresia. Animal models of mice and sheep had additional defects not reported in human patients. The pathology is caused by the loss of the function of CAP2 in actin polymerization and in the “α-actin switch” occurring during differentiation and required for the sarcomere structure and function. Conclusions: The homozygous mutations in CAP2 cause severe Dilated cardiomyopathy. Additional phenotypes may not be seen in all individuals, and the severity of the mutation and disease do not correlate.

TNNT1 myopathy with novel compound heterozygous mutations

Nemaline myopathies are clinically and genetically heterogeneous disorders caused by several different genes. One of them is TNNT1, which was initially described in Amish families and has not been reported in Asian populations. Although most TNNT1 myopathies are caused by loss-of-function mutations, several recent studies have shown that missense mutations can also be pathogenic. A 16-year-old Korean boy with progressive muscle weakness visited the Seoul National University Hospital. He showed generalized myopathy, which was predominant in the paraspinal and neck muscles. Moreover, nemaline rods were observed in a muscle biopsy. Whole-exome sequencing of DNA samples of the patient and his younger brother, who had a similar phenotype, revealed novel compound heterozygous mutations in TNNT1 (c.724G>C (p.Ala242Pro) and c.611+1G>A). Sanger sequencing of cDNA extracted from muscle samples of the patient confirmed partial or total skipping of exon 11 in the splicing variant. The impact of the missense variant on muscle integrity and locomotor activity was verified using a zebrafish loss-of-function model. Here, we reported novel familial cases of TNNT1 myopathy with intermediate clinical presentations caused by compound heterozygous mutations and demonstrated their functional defects using an animal model.

What Is in the Myopathy Literature?

This edition concentrates on inflammatory myopathies with reports of reclassification of polymyositis, cancer associations, evaluation of subclinical cardiac involvement, myositis-specific and -associated antibodies, and immune checkpoint inhibitor myositis. A number of reports address sporadic late-onset nemaline myopathy and point out its diagnostic difficulty and the importance of identifying an associated monoclonal gammopathy that is likely of clinical significance and may warrant aggressive immunotherapy. Finally, treatment of nondystrophic channelopathies is addressed.

Formation of Cytoplasmic Actin-Cofilin Rods is Triggered by Metabolic Stress and Changes in Cellular pH

Actin dynamics plays a crucial role in regulating essential cell functions and thereby is largely responsible to a considerable extent for cellular energy consumption. Certain pathological conditions in humans, like neurological disorders such as Alzheimer’s disease or amyotrophic lateral sclerosis (ALS) as well as variants of nemaline myopathy are associated with cytoskeletal abnormalities, so-called actin-cofilin rods. Actin-cofilin rods are aggregates consisting mainly of actin and cofilin, which are formed as a result of cellular stress and thereby help to ensure the survival of cells under unfavorable conditions. We have used Dictyostelium discoideum, an established model system for cytoskeletal research to study formation and principles of cytoplasmic actin rod assembly in response to energy depletion. Experimentally, depletion of ATP was provoked by addition of either sodium azide, dinitrophenol, or 2-deoxy-glucose, and the formation of rod assembly was recorded by live-cell imaging. Furthermore, we show that hyperosmotic shock induces actin-cofilin rods, and that a drop in the intracellular pH accompanies this condition. Our data reveal that acidification of the cytoplasm can induce the formation of actin-cofilin rods to varying degrees and suggest that a local reduction in cellular pH may be a cause for the formation of cytoplasmic rods. We hypothesize that local phase separation mechanistically triggers the assembly of actin-cofilin rods and thereby influences the material properties of actin structures.

Nemaline Myopathy Initially Diagnosed as Right Heart Failure with Type 2 Respiratory Failure.

Nemaline myopathy (NM) is a rare muscle disease with various clinical types. In some cases, NM can lead to type 2 respiratory failure and right heart failure. We herein report a patient with congenital NM with nebulin gene mutation who presented with acute right heart failure and type 2 respiratory failure due to respiratory muscle paralysis after upper respiratory tract infection, needing a permanent ventilator for assistance. However, the limb and trunk muscle strengths were within normal limits. This case showed that NM should be considered as a cause of right heart failure and type 2 respiratory failure.

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.36 Food consumption, nutrition, and functioning of patients with nemaline myopathy and related disorders in Finland

The molecular mechanisms of nemaline myopathy and related disorders (NMs) have been widely studied, whereas little scientific attention has been paid to the general health of the patients. We set out to study nutrition and food consumption and their correlation with self-experienced functioning and health in adult NM patients. We used food diaries and a food frequency questionnaire (D2D-FFQ) to study food consumption, internationally validated PROMIS®-questionnaires to study functioning, and laboratory analyses of nutritional parameters.

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.40 Neuromuscular junction defects in ACTA1-related nemaline myopathy

Nemaline myopathies (NMs) are a clinically heterogenous group of non-dystrophic congenital muscle diseases caused by mutations in at least 13 genes. NMs are characterised by muscle weakness, hypotonia and respiratory insufficiency, with presence of cytoskeletal protein aggregates (rods) in skeletal muscle fibers. In the present study we investigated whether neuromuscular junctions (NMJ) are affected in ACTA1-related nemaline myopathy, which accounts for about 50% of severe cases of NMs. For this purpose, we analysed the morphology and function of NMJs in the Acta1(H40Y) knock-in mouse model of the disease.

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.35 Cross-Sectional phenotypic and genotypic analysis of a large cohort of patients with nemaline myopathies

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.35 Cross-Sectional phenotypic and genotypic analysis of a large cohort of patients with nemaline myopathies

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.38 Generation of induced pluripotent stem cell lines from a 4-month-old severe nemaline myopathy patient with a dominant ACTA1 c.553C>A (p.R183S) variant

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.38 Generation of induced pluripotent stem cell lines from a 4-month-old severe nemaline myopathy patient with a dominant ACTA1 c.553C>A (p.R183S) variant

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.32 Respiratory management in nemaline myopathy due to mutations in the troponin-T type 1 (TNNT1) gene

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.32 Respiratory management in nemaline myopathy due to mutations in the troponin-T type 1 (TNNT1) gene

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.42 A ddPCR method for the detection of copy number variations in the nebulin triplicate region

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.42 A ddPCR method for the detection of copy number variations in the nebulin triplicate region

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.39 Adult-onset nemaline myopathy due to a novel homozygous variant in the TNNT1 gene

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.39 Adult-onset nemaline myopathy due to a novel homozygous variant in the TNNT1 gene

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.33 Severe forms of ACTA1-related nemaline myopathy: Reassessment of the morphological, clinical and molecular aspects

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.33 Severe forms of ACTA1-related nemaline myopathy: Reassessment of the morphological, clinical and molecular aspects

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.43 Utilization of RNA sequencing to diagnose and to provide mechanistic insight in NEB-related myopathy

The congenital myopathies are a genetically heterogenous group of skeletal muscle disorders characterized by early onset muscle weakness and variable myopathic findings on muscle biopsy, of which a third of patients remain genetically uncharacterized. Biallelic variants in NEB, encoding nebulin, are a known cause for nemaline myopathy; however, given NEB’s 183 exon expanse, and complexity of resulting isoforms, the functional impact of variants can be difficult to interpret. RNA sequencing is an emerging tool for understanding how such variants impact transcription and cause disease. Recently it has been shown that NEB contains alternatively spliced exons 143 and 144 (E144) and a role for specific isoforms in myogenesis and fiber typing has been postulated, with E144 showing predominant inclusion in the adult isoform of nebulin. We present two brothers (11 and 15 years) with congenital myopathy with myopathic muscle biopsy findings without nemaline rods, normal CK, myopathic findings on EMG, and normal cardiac and pulmonary function. Quartet exome sequencing identified compound heterozygous variants in NEB (NM_001271208.2), a maternally inherited p.Cys693Ter and a paternally inherited c.21522+3A>G splice variant with unknown impact as it is adjacent to alternatively spliced E144. To evaluate this variant, we did RNA sequencing on muscle tissue. Patient's transcriptome showed skipping of E144, in contrast to controls who express a transcript ratio of approximately 1:4 (143:144), suggesting that the disease may partially be driven by a lack of NEB E144 inclusion, affecting the predominant adult isoform. Given this evidence, we compared patterns of muscle involvement from MRI to the literature to assess if the pattern of involvement in our patient correlated to relative expression of E144 in adult muscle. This case highlights the usefulness of RNA sequencing in evaluating variants and for providing insight into the potential role of isoforms in disease pathogenesis.

CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES: EP.34 3′UTR variant in KLHL40 causes nemaline myopathy

Nemaline myopathy 8 (NEM8) is typically a severe autosomal recessive disorder associated with variants in the kelch-like family member 40 gene (KLHL40). To date, patients with NEM8 have only been identified with coding pathogenic variants and almost all have presented with severe disease. Common features include fetal akinesia/hypokinesia, fractures, contractures, dysphagia, respiratory failure, and neonatal death (average age at death ∼5 months). Here, we describe a 26-year-old man with milder NEM8.