NEM6, KBTBD13-Related Congenital Myopathy: Myopathological Analysis in 18 Dutch Patients Reveals Ring Rods Fibers, Cores, Nuclear Clumps, and Granulo-Filamentous Protein Material

2021 ◽  
Vol 80 (4) ◽  
pp. 366-376
Author(s):  
Karlijn Bouman ◽  
Benno Küsters ◽  
Josine M De Winter ◽  
Cynthia Gillet ◽  
Esmee S B Van Kleef ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Light Microscopy ◽  
Clinical Phenotype ◽  
Fiber Type ◽  
Muscle Relaxation ◽  
Nemaline Myopathy ◽  
Congenital Myopathy ◽  
Thin Filaments ◽  
Core Myopathy

AbstractNemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.

Clinical course correlates poorly with muscle pathology in nemaline myopathy

Neurology ◽  
2003 ◽  
Vol 60 (4) ◽  
pp. 665-673 ◽  
Author(s):  
M. M. Ryan ◽  
B. Ilkovski ◽  
C. D. Strickland ◽  
C. Schnell ◽  
D. Sanoudou ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
North American ◽  
Fiber Type ◽  
Size Variation ◽  
Nemaline Myopathy ◽  
Clinical Severity ◽  
Pathologic Findings ◽  
Fiber Size ◽  
Nemaline Bodies

Objective: To report pathologic findings in 124 Australian and North American cases of primary nemaline myopathy.Methods: Results of 164 muscle biopsies from 124 Australian and North American patients with primary nemaline myopathy were reviewed, including biopsies from 19 patients with nemaline myopathy due to α-actin (ACTA1) mutations and three with mutations in α-tropomyosinSLOW (TPM3). For each biopsy rod number per fiber, percentage of fibers with rods, fiber-type distribution of rods, and presence or absence of intranuclear rods were documented.Results: Rods were present in all skeletal muscles and diagnosis was possible at all ages. Most biopsies contained nemaline bodies in more than 50% of fibers, although rods were seen only on electron microscopy in 10 patients. Rod numbers and localization correlated poorly with clinical severity. Frequent findings included internal nuclei and increased fiber size variation, type 1 fiber predominance and atrophy, and altered expression of fiber type specific proteins. Marked sarcomeric disruption, increased glycogen deposition, and intranuclear rods were associated with more severe clinical phenotypes. Serial biopsies showed progressive fiber size variation and increasing numbers of rods with time. Pathologic findings varied widely in families with multiple affected members.Conclusions: Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption were common in nemaline myopathy associated with mutations in skeletal α-actin. Nemaline myopathy due to mutations in α-tropomyosinSLOW was characterized by preferential rod formation in, and atrophy of, type 1 fibers. Light microscopic features of nemaline myopathy correlate poorly with disease course. Electron microscopy may correlate better with disease severity and genotype.

scholarly journals A Systematic Review and Meta-Analysis of the Prevalence of Congenital Myopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Kun Huang ◽  
Fang-Fang Bi ◽  
Huan Yang
Keyword(s):  
Systematic Review ◽  
Fiber Type ◽  
Pediatric Population ◽  
Meta Analysis ◽  
Nemaline Myopathy ◽  
Congenital Myopathy ◽  
Orphan Diseases ◽  
Congenital Myopathies ◽  
Prevalence Estimates ◽  
Core Myopathy

Background: Congenital myopathy constitutes a heterogeneous group of orphan diseases that are mainly classified on the basis of muscle biopsy findings. This study aims to estimate the prevalence of congenital myopathy through a systematic review and meta-analysis of the literature.Methods: The PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched for original research articles published in English prior to July 30, 2021. The quality of the included studies was assessed by a checklist adapted from STrengthening the Reporting of OBservational studies in Epidemiology (STROBE). To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using the random effects model. Heterogeneity was assessed using the Cochrane Q statistic as well as the I2 statistic.Results: A total of 11 studies were included in the systematic review and meta-analysis. Of the 11 studies included, 10 (90.9%) were considered medium-quality, one (9.1%) was considered low-quality, and no study was assessed as having a high overall quality. The pooled prevalence of congenital myopathy in the all-age population was 1.50 (95% CI, 0.93–2.06) per 100,000, while the prevalence in the child population was 2.73 (95% CI, 1.34–4.12) per 100,000. In the pediatric population, the prevalence among males was 2.92 (95% CI, −1.70 to 7.55) per 100,000, while the prevalence among females was 2.47 (95% CI, −1.67 to 6.61) per 100,000. The prevalence estimates of the all-age population per 100,000 were 0.20 (95% CI 0.10–0.35) for nemaline myopathy, 0.37 (95% CI 0.21–0.53) for core myopathy, 0.08 (95% CI −0.01 to 0.18) for centronuclear myopathy, 0.23 (95% CI 0.04–0.42) for congenital fiber-type disproportion myopathy, and 0.34 (95% CI, 0.24–0.44) for unspecified congenital myopathies. In addition, the prevalence estimates of the pediatric population per 100,000 were 0.22 (95% CI 0.03–0.40) for nemaline myopathy, 0.46 (95% CI 0.03–0.90) for core myopathy, 0.44 (95% CI 0.03–0.84) for centronuclear myopathy, 0.25 (95% CI −0.05 to 0.54) for congenital fiber-type disproportion myopathy, and 2.63 (95% CI 1.64–3.62) for unspecified congenital myopathies.Conclusions: Accurate estimates of the prevalence of congenital myopathy are fundamental to supporting public health decision-making. The high heterogeneity and the lack of high-quality studies highlight the need to conduct higher-quality studies on orphan diseases.

scholarly journals The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies

2018 ◽  
Vol 19 (12) ◽  
pp. 3975 ◽  
Author(s):  
Yurii Borovikov ◽  
Olga Karpicheva ◽  
Armen Simonyan ◽  
Stanislava Avrova ◽  
Elena Rogozovets ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Fiber Type ◽  
Point Mutations ◽  
Nemaline Myopathy ◽  
Muscle Dysfunction ◽  
Thin Filaments ◽  
Mutant Proteins ◽  
Strong Binding ◽  
Genes Encoding

Point mutations in genes encoding isoforms of skeletal muscle tropomyosin may cause nemaline myopathy, cap myopathy (Cap), congenital fiber-type disproportion (CFTD), and distal arthrogryposis. The molecular mechanisms of muscle dysfunction in these diseases remain unclear. We studied the effect of the E173A, R90P, E150A, and A155T myopathy-causing substitutions in γ-tropomyosin (Tpm3.12) on the position of tropomyosin in thin filaments, and the conformational state of actin monomers and myosin heads at different stages of the ATPase cycle using polarized fluorescence microscopy. The E173A, R90P, and E150A mutations produced abnormally large displacement of tropomyosin to the inner domains of actin and an increase in the number of myosin heads in strong-binding state at low and high Ca2+, which is characteristic of CFTD. On the contrary, the A155T mutation caused a decrease in the amount of such heads at high Ca2+ which is typical for mutations associated with Cap. An increase in the number of the myosin heads in strong-binding state at low Ca2+ was observed for all mutations associated with high Ca2+-sensitivity. Comparison between the typical conformational changes in mutant proteins associated with different myopathies observed with α-, β-, and γ-tropomyosins demonstrated the possibility of using such changes as tests for identifying the diseases.

scholarly journals Congenital myopathy associated with the triadin knockout syndrome

Neurology ◽  
2017 ◽  
Vol 88 (12) ◽  
pp. 1153-1156 ◽  
Author(s):  
Andrew G. Engel ◽  
Keeley R. Redhage ◽  
David J. Tester ◽  
Michael J. Ackerman ◽  
Duygu Selcen
Keyword(s):  
Electron Microscopy ◽  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Light And Electron Microscopy ◽  
Deltoid Muscle ◽  
Congenital Myopathy ◽  
Compound Heterozygous

Objective:Triadin is a component of the calcium release complex of cardiac and skeletal muscle. Our objective was to analyze the skeletal muscle phenotype of the triadin knockout syndrome.Methods:We performed clinical evaluation, analyzed morphologic features by light and electron microscopy, and immunolocalized triadin in skeletal muscle.Results:A 6-year-old boy with lifelong muscle weakness had a triadin knockout syndrome caused by compound heterozygous null mutations in triadin. Light microscopy of a deltoid muscle specimen shows multiple small abnormal spaces in all muscle fibers. Triadin immunoreactivity is absent from type 1 fibers and barely detectable in type 2 fibers. Electron microscopy reveals focally distributed dilation and degeneration of the lateral cisterns of the sarcoplasmic reticulum and loss of the triadin anchors from the preserved lateral cisterns.Conclusions:Absence of triadin in humans can result in a congenital myopathy associated with profound pathologic alterations in components of the sarcoplasmic reticulum. Why only some triadin-deficient patients develop a skeletal muscle phenotype remains an unsolved question.

scholarly journals l-Carnitine ameliorates congenital myopathy in a tropomyosin 3 de novo mutation transgenic zebrafish

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Po-Jui Hsu ◽  
Horng-Dar Wang ◽  
Yung-Che Tseng ◽  
Shao-Wei Pan ◽  
Bonifasius Putera Sampurna ◽  
...  
Keyword(s):  
Expression Profiling ◽  
De Novo ◽  
Fiber Type ◽  
Transgenic Fish ◽  
Nemaline Myopathy ◽  
Histochemical Staining ◽  
Congenital Myopathy ◽  
De Novo Mutation ◽  
Muscle Endurance ◽  
Transgenic Zebrafish

Abstract Background Congenital myopathy (CM) is a group of clinically and genetically heterogeneous muscle disorders, characterized by muscle weakness and hypotonia from birth. Currently, no definite treatment exists for CM. A de novo mutation in Tropomyosin 3-TPM3(E151G) was identified from a boy diagnosed with CM, previously TPM3(E151A) was reported to cause CM. However, the role of TPM3(E151G) in CM is unknown. Methods Histopathological, swimming behavior, and muscle endurance were monitored in TPM3 wild-type and mutant transgenic fish, modelling CM. Gene expression profiling of muscle of the transgenic fish were studied through RNAseq, and mitochondria respiration was investigated. Results While TPM3(WT) and TPM3(E151A) fish show normal appearance, amazingly a few TPM3(E151G) fish display either no tail, a crooked body in both F0 and F1 adults. Using histochemical staining for the muscle biopsy, we found TPM3(E151G) displays congenital fiber type disproportion and TPM3(E151A) resembles nemaline myopathy. TPM3(E151G) transgenic fish dramatically swimming slower than those in TPM3(WT) and TPM3(E151A) fish measured by DanioVision and T-maze, and exhibit weaker muscle endurance by swimming tunnel instrument. Interestingly, l-carnitine treatment on TPM3(E151G) transgenic larvae significantly improves the muscle endurance by restoring the basal respiration and ATP levels in mitochondria. With RNAseq transcriptomic analysis of the expression profiling from the muscle specimens, it surprisingly discloses large downregulation of genes involved in pathways of sodium, potassium, and calcium channels, which can be rescued by l-carnitine treatment, fatty acid metabolism was differentially dysregulated in TPM3(E151G) fish and rescued by l-carnitine treatment. Conclusions These results demonstrate that TPM3(E151G) and TPM3(E151A) exhibit different pathogenicity, also have distinct gene regulatory profiles but the ion channels were downregulated in both mutants, and provides a potential mechanism of action of TPM3 pathophysiology. Our results shed a new light in the future development of potential treatment for TPM3-related CM.

scholarly journals Z- and M-band appearance in different histochemically defined types of human skeletal muscle fibers.

1982 ◽  
Vol 30 (1) ◽  
pp. 1-11 ◽  
Author(s):  
M Sjöström ◽  
S Kidman ◽  
K H Larsén ◽  
K A Angquist
Keyword(s):  
Electron Microscopy ◽  
Skeletal Muscle ◽  
Band Structure ◽  
Human Skeletal Muscle ◽  
Enzyme Histochemistry ◽  
Fiber Type ◽  
Band Width ◽  
Type Indicator ◽  
Different Types

In order to define ultrastructural features, which alone or in combination with other features could be used to identify different types of fibers in human skeletal muscle, frozen biopsy specimens of m. tibialis anterior were serially sectioned. The thawed sections were prepared either for enzyme histochemistry or for electron microscopy. The same fiber was then identified in all serial sections and its ultrastructure examined under the electron microscope. A total of 75 fibers were included in this investigation. Specimens were also conventionally prepared for electron microscopy. Special interest was devoted to the appearance of the sarcomeric Z- and M-bands. In the same fiber, all myofibrils showed the same Z- as well as M-band structure. On the other hand, it was evident that these structures varied from one type of fiber to another in the same muscle and that their appearance were covariant to a great extent. Low level resolution of Type 1 fibers usually showed broad Z- and M-bands with five strong M-bridge lines. In Type 2A fibers intermediate Z-bands were observed. In the middle portion of the M-bands, three strong M-bridge lines were distinct while the two outer lines were relatively weak. Finally, Type 2B fibers usually appeared with narrow Z-bands. The three M-bridge lines in the middle were strong while the two outer ones were very weak, if seen at all. Discriminant analysis showed that about 70% of the fibers should have been correctly allocated on the basis of the Z-band width alone. When two independent observers classified the fibers on the basis of M-band appearance, more than 95% of the fibers were correctly classified. Thus, both the Z- and M-bands, alone or in combination, can be used as fiber type discriminators. However, the M-band structure proved to be more reliable than the Z-band width, and should therefore be used as the fiber type indicator when only one of these parameters is considered.

scholarly journals Comparison of Clinical Characteristics Between Congenital Fiber Type Disproportion Myopathy and Congenital Myopathy with Type 1 Fiber Predominance

2006 ◽  
Vol 47 (4) ◽  
pp. 513 ◽  
Author(s):  
Sang-Jun Na ◽  
Woo-Kyung Kim ◽  
Tai-Seung Kim ◽  
Seong-Woong Kang ◽  
Eun-Young Lee ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Fiber Type ◽  
Congenital Myopathy

scholarly journals Centronuclear myopathy: histopathological aspects in ten patients with chilfhood onset

1998 ◽  
Vol 56 (1) ◽  
pp. 01-08 ◽  
Author(s):  
EDMAR ZANOTELI ◽  
ACARY SOUZA BULLE OLIVEIRA ◽  
BEATRIZ HITOMI KIYOMOTO ◽  
BENY SCHMIDT ◽  
ALBERTO ALAIN GABBAI
Keyword(s):  
Ultrastructural Study ◽  
Fiber Type ◽  
Signs And Symptoms ◽  
Congenital Myopathy ◽  
Great Variability ◽  
Type I ◽  
Centronuclear Myopathy ◽  
Adult Onset ◽  
Childhood Onset

Centronuclear myopathy is a rare congenital myopathy. According to the period of onset of signs and symptoms and the degree of muscular involvement three clinical forms are distinguished: severe neonatal; childhood onset; and adult onset. We describe herein the muscle biopsy findings of ten patients with the childhood onset form of the disease including three cases with ultrastructural study. The biopsies disclosed increased nuclear centralization that varied from 25 to 90% of the fibers, type 1 predominance, great variability in fiber diameters, involvement in the internal fiber's architecture, and focal areas of myofilament disorganization. The main histopathologic differential diagnoses included type I fiber predominance, congenital fiber type disproportion, and myotonic dystrophy. The histologic abnormalities in centronuclear myopathy may be due to an arrest of maturation on the fetal myotubular stage. The cause of this arrest remains elusive.

Two- or three-way observations of the identical cell elements within the same sections by LM, TEM and/or SEM

1978 ◽  
Vol 36 (2) ◽  
pp. 82-83 ◽  
Author(s):  
Nakazo Watari ◽  
Yasuaki Hotta ◽  
Yoshio Mabuchi
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Fine Structure ◽  
Light Microscopy ◽  
Thin Sections ◽  
Transmission Electron ◽  
Identical Cell ◽  
Electron Microscopes ◽  
Scanning Electron

It is very useful if we can observe the identical cell elements within the same sections by light microscopy (LM), transmission electron microscopy (TEM) and/or scanning electron microscopy (SEM) sequentially, because, the cell fine structure can not be indicated by LM, while the color is; on the other hand, the cell fine structure can be very easily observed by EM, although its color properties may not. However, there is one problem in that LM requires thick sections of over 1 μm, while EM needs very thin sections of under 100 nm. Recently, we have developed a new method to observe the same cell elements within the same plastic sections using both light and transmission (conventional or high-voltage) electron microscopes.In this paper, we have developed two new observation methods for the identical cell elements within the same sections, both plastic-embedded and paraffin-embedded, using light microscopy, transmission electron microscopy and/or scanning electron microscopy (Fig. 1).

Tumor Diagnosis

1982 ◽  
Vol 40 ◽  
pp. 262-265
Author(s):  
Bruce Mackay
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Differential Diagnosis ◽  
Light Microscopy ◽  
Clinical Examination ◽  
Ultrastructural Study ◽  
Diagnostic Procedures ◽  
Specific Diagnosis ◽  
Transmission Electron ◽  
Microscopic Diagnosis

The broadest application of transmission electron microscopy (EM) in diagnostic medicine is the identification of tumors that cannot be classified by routine light microscopy. EM is useful in the evaluation of approximately 10% of human neoplasms, but the extent of its contribution varies considerably. It may provide a specific diagnosis that can not be reached by other means, but in contrast, the information obtained from ultrastructural study of some 10% of tumors does not significantly add to that available from light microscopy. Most cases fall somewhere between these two extremes: EM may correct a light microscopic diagnosis, or serve to narrow a differential diagnosis by excluding some of the possibilities considered by light microscopy. It is particularly important to correlate the EM findings with data from light microscopy, clinical examination, and other diagnostic procedures.

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