Clinical course correlates poorly with muscle pathology in nemaline myopathy

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.

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

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab012 ◽

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.

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Alpha-actinin in nemaline bodies in congenital nemaline myopathy: immunological confirmation by light and electron microscopy

Neuromuscular Disorders ◽

10.1016/0960-8966(94)00035-8 ◽

1995 ◽

Vol 5 (2) ◽

pp. 93-104 ◽

Cited By ~ 39

Author(s):

Carina Wallgren-Pettersson ◽

Bharat Jasani ◽

Geoffrey R. Newman ◽

Glenn E. Morris ◽

Sally Jones ◽

...

Keyword(s):

Electron Microscopy ◽

Light And Electron Microscopy ◽

Nemaline Myopathy ◽

Nemaline Bodies

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An in vivo approach to characterize novel variants associated with musculoskeletal disorders

10.1101/2021.05.27.445925 ◽

2021 ◽

Author(s):

Aaron N Johnson ◽

Jennifer McAdow ◽

Shuo Yang ◽

Tiffany Ou ◽

Gary Huang ◽

...

Keyword(s):

Musculoskeletal Disorders ◽

Fiber Type ◽

Nemaline Myopathy ◽

Clinical Severity ◽

Actin Binding ◽

Pathogenic Variants ◽

Novel Variants ◽

Uncertain Significance ◽

Transient Overexpression

Pathogenic variants in Tropomyosin 2 (TPM2), which encodes a skeletal muscle specific actin binding protein essential for sarcomere function, cause a spectrum of musculoskeletal disorders including Nemaline Myopathy, Cap Myopathy, congenital fiber type disproportion, and distal arthrogrypsosis (DA). TPM2-related disorders have not been modeled in vivo, so we expressed a series of dominant, pathogenic TPM2 variants in Drosophila embryos and found two variants, K49Del and E122K, disrupted muscle morphogenesis and muscle function. Transient overexpression of K49Del and E122K also disrupted muscle morphogenesis in zebrafish. We further developed a benchmarked overexpression assay in zebrafish to characterize TPM2 variants that we identified in DA patients, and found these variants caused musculoskeletal defects similar to those of the known pathogenic variants. In addition, the severity of musculoskeletal phenotypes in zebrafish expressing TPM2 variants correlated with the severity of clinical phenotypes observed in DA patients. Our study establishes transient overexpression in zebrafish as an efficient platform to characterize variants of uncertain significance in vivo, and argues our assays can predict the clinical severity of musculoskeletal associated variants.

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

Journal of Histochemistry & Cytochemistry ◽

10.1177/30.1.7054271 ◽

1982 ◽

Vol 30 (1) ◽

pp. 1-11 ◽

Cited By ~ 42

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.

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Capillary beta-hydroxybutyrate levels reliably predicts clinical severity in established diabetes but not in first presentations of type 1 diabetes in children

Endocrine Abstracts ◽

10.1530/endoabs.36.oc6.5 ◽

2014 ◽

Author(s):

Chris Cooper ◽

Miriam Leach

Keyword(s):

Type 1 Diabetes ◽

Clinical Severity ◽

Beta Hydroxybutyrate

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Pre-training Skeletal Muscle Fiber Size and Predominant Fiber Type Best Predict Hypertrophic Responses to 6 Weeks of Resistance Training in Previously Trained Young Men

Frontiers in Physiology ◽

10.3389/fphys.2019.00297 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 17

Author(s):

Cody T. Haun ◽

Christopher G. Vann ◽

C. Brooks Mobley ◽

Shelby C. Osburn ◽

Petey W. Mumford ◽

...

Keyword(s):

Skeletal Muscle ◽

Resistance Training ◽

Muscle Fiber ◽

Fiber Type ◽

Young Men ◽

Skeletal Muscle Fiber ◽

Fiber Size

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Isolation and cloning of a papillomavirus from a North American porcupine by using multiply primed rolling-circle amplification: the Erethizon dorsatum papillomavirus type 1

Virology ◽

10.1016/j.virol.2004.10.033 ◽

2005 ◽

Vol 331 (2) ◽

pp. 449-456 ◽

Cited By ~ 28

Author(s):

Annabel Rector ◽

Ruth Tachezy ◽

Koenraad Van Doorslaer ◽

Tracey MacNamara ◽

Robert D. Burk ◽

...

Keyword(s):

North American ◽

Rolling Circle Amplification ◽

Rolling Circle ◽

Erethizon Dorsatum

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Skeletal muscle fiber size and fiber type distribution in human cancer: Effects of weight loss and relationship to physical function

Clinical Nutrition ◽

10.1016/j.clnu.2016.02.016 ◽

2016 ◽

Vol 35 (6) ◽

pp. 1359-1365 ◽

Cited By ~ 16

Author(s):

Michael J. Toth ◽

Damien M. Callahan ◽

Mark S. Miller ◽

Timothy W. Tourville ◽

Sarah B. Hackett ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Physical Function ◽

Muscle Fiber ◽

Human Cancer ◽

Fiber Type ◽

Skeletal Muscle Fiber ◽

Type Distribution ◽

Fiber Size ◽

Fiber Type Distribution

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Application of Epstein-Barr Virus Serology to the Diagnosis and Staging of North American Patients with Nasopharyngeal Carcinoma

Otolaryngology ◽

10.1177/019459988309100310 ◽

1983 ◽

Vol 91 (3) ◽

pp. 255-262 ◽

Cited By ~ 33

Author(s):

H. Bryan Neel ◽

Gary R. Pearson ◽

Louis H. Weiland ◽

William F. Taylor ◽

Helmut H. Goepfert ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

North American ◽

Epstein Barr Virus ◽

Geometric Mean ◽

World Health ◽

Barr Virus ◽

Staging Systems ◽

Antibody Titers ◽

Epstein Barr

From 1978 to 1981, 151 patients with nasopharyngeal carcinoma (NPC) were enrolled in a prospective, collaborative study of North American patients, most of them white. Thirty-seven had World Health Organization (WHO) type 1 tumors, and 114 had WHO types 2 and 3 tumors. The anti-Epstein-Barr virus (EBV) profile of elevated antibody titers directed against viral capsid antigen and early antigen was seen in 85% of the patients with WHO types 2 and 3 tumors but in only 16% of the patients with WHO type 1 tumors. Geometric mean titers tended to be higher in higher stages of the disease in several staging systems. Low antibody-dependent cellular cytotoxicity at diagnosis appears to reflect a poorer prognosis, and the determination of antibody titers by this assay may prove to be useful for identifying persons in whom recurrent disease is likely to develop after conventional therapy. Anti-EBV titers can aid in diagnosis and treatment planning in patients with NPC, particularly those with occult primary NPC.

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