scholarly journals When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

2014 ◽  
Vol 72 (10) ◽  
pp. 803-811 ◽  
Author(s):  
Paulo José Lorenzoni ◽  
Rosana Herminia Scola ◽  
Cláudia Suemi Kamoi Kay ◽  
Carlos Eduardo S. Silvado ◽  
Lineu Cesar Werneck
Keyword(s):  
Muscle Biopsy ◽  
Morphological Changes ◽  
Mitochondrial Disorder ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Strong Reaction ◽  
Brain Images ◽  
Ragged Red Fibers ◽  
Myoclonus Epilepsy ◽  
Generalized Epilepsy

Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder. Diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia and ragged red fibers (RRF) on muscle biopsy. Clinical features of MERRF are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALys gene of the DNAmt, mainly A8344G, are responsible for almost 90% of MERRF cases. Morphological changes seen upon muscle biopsy in MERRF include a substantive proportion of RRF, muscle fibers showing a deficient activity of cytochrome c oxidase (COX) and the presence of vessels with a strong reaction for succinate dehydrogenase and COX deficiency. In this review, we discuss mainly clinical and laboratory manifestations, brain images, electrophysiological patterns, histology and molecular findings as well as some differential diagnoses and treatments.

scholarly journals When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

2015 ◽  
Vol 73 (11) ◽  
pp. 959-967 ◽  
Author(s):  
Paulo José Lorenzoni ◽  
Lineu Cesar Werneck ◽  
Cláudia Suemi Kamoi Kay ◽  
Carlos Eduardo Soares Silvado ◽  
Rosana Herminia Scola
Keyword(s):  
Lactic Acidosis ◽  
Morphological Changes ◽  
Mitochondrial Disorder ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Strong Reaction ◽  
Brain Images ◽  
Ragged Red Fibers ◽  
Diagnostic Criterion

ABSTRACTMitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.

scholarly journals In vitro analysis of mutations causing myoclonus epilepsy with ragged-red fibers in the mitochondrial tRNA(Lys)gene: two genotypes produce similar phenotypes.

1995 ◽  
Vol 15 (5) ◽  
pp. 2872-2881 ◽  
Author(s):  
J P Masucci ◽  
M Davidson ◽  
Y Koga ◽  
E A Schon ◽  
M P King
Keyword(s):  
Protein Synthesis ◽  
Molecular Genetic ◽  
Mitochondrial Disorder ◽  
Morphological Characteristics ◽  
Mitochondrial Translation ◽  
Mitochondrial Trna ◽  
Mtdna Mutations ◽  
Ragged Red Fibers ◽  
Myoclonus Epilepsy

Cytoplasts from patients with myoclonus epilepsy with ragged-red fibers harboring a pathogenic point mutation at either nucleotide 8344 or 8356 in the human mitochondrial tRNA(Lys) gene were fused with human cells lacking endogenous mitochondrial DNA (mtDNA). For each mutation, cytoplasmic hybrid (cybrid) cell lines containing 0 or 100% mutated mtDNAs were isolated and their genetic, biochemical, and morphological characteristics were examined. Both mutations resulted in the same biochemical and molecular genetic phenotypes. Specifically, cybrids containing 100% mutated mtDNAs, but not those containing the corresponding wild-type mtDNAs, exhibited severe defects in respiratory chain activity, in the rates of protein synthesis, and in the steady-state levels of mitochondrial translation products. In addition, aberrant mitochondrial translation products were detected with both mutations. No significant alterations were observed in the processing of polycistronic RNA precursor transcripts derived from the region containing the tRNA(Lys) gene. These results demonstrate that two different mtDNA mutations in tRNA(Lys), both associated with the same mitochondrial disorder, result in fundamentally identical defects at the cellular level and strongly suggest that specific protein synthesis abnormalities contribute to the pathogenesis of myoclonus epilepsy with ragged-red fibers.

scholarly journals Optimization of the pre-analytical stage of material processing for histochemical examination of skeletal muscle biopsies in the diagnosis of neuromuscular diseases

2019 ◽  
Vol 9 (2) ◽  
pp. 21-29
Author(s):  
A. M. Sycheva ◽  
V. D. Nazarova ◽  
S. V. Lapin ◽  
M. G. Rybakova ◽  
D. I. Rudenko
Keyword(s):  
Skeletal Muscle ◽  
Muscle Biopsy ◽  
Morphological Changes ◽  
Clinical Manifestations ◽  
Neuromuscular Diseases ◽  
Optimal Method ◽  
Tissue Samples ◽  
Important Place ◽  
Skeletal Muscle Biopsy ◽  
Muscle Biopsies

Diagnosis of neuromuscular diseases is complicated by the variety of clinical manifestations and requires the use of additional methods, an important place among which is the pathomorphological study of skeletal muscle biopsy. Despite the fact that the procedure for taking a muscle biopsy is not technically difficult, to obtain informative material a multitude of conditions must be observed at the stages of pre-analytical processing of the obtained tissue samples. Violation of the technology of taking, storing and fixing the material contributes to the formation of artifacts that limit the possibilities for further analysis of the morphological changes in tissue biopsy. A comparison was made of the effectiveness of various methods for cryoprocessing of muscle tissue samples and the manufacture of histological specimens with a subsequent assessment of morphological changes. As a result, the main causes of artifacts were identified. The optimal method for processing muscle biopsy specimens is indicated, which makes it possible to prevent the appearance of artifacts as much as possible and to ensure the preservation of tissue for research.

Clinical, morphological and biochemical signs of polymycotoxicosis in highly productive cows

2020 ◽  
pp. 14-17
Author(s):  
Irina A. Shkuratova ◽  
◽  
Lyudmila I. Drozdova ◽  
Aleksander I. Belousov ◽  
Keyword(s):  
Metabolic Disorders ◽  
Hepatorenal Syndrome ◽  
Morphological Changes ◽  
Clinical Manifestations ◽  
The Body ◽  
Feed Mixture ◽  
Milk Productivity ◽  
Structural Disorders ◽  
Increased Sensitivity ◽  
Penicillium Spp

Mycotoxicological monitoring of forages shows that the problem of mycotoxicosis has been relevant for several decades. Minimal doses of mycotoxins in feed lead to a decrease in milk productivity, increased sensitivity to infectious and non-infectious diseases. When several mycotoxins enter the body simultaneously, a synergistic effect develops, causing a significant increase in toxicity. Feed contaminated with several types of fungi and their toxins is dangerous for dairy cattle. It was found that the feed mixture contained the types of associations of Aspergillus spp. fungi + Fusarium; Aspergillus spp. + Penicillium spp. + Mucor spp; Fusarium + Penicillium; Mucor spp. + Fusarium + Ustilaginales. Pathogenetic features of metabolic and morphological changes in highly productive cows with polymycotoxicosis were studied. Feeding food contaminated with various metabolites of mold fungi leads to the development of signs of chronic toxemia in animals. Clinical manifestations are the development of diarrhea and dehydration, with a decrease in milk productivity. Metabolic disorders feature the development of an inflammatory process, metabolic acidosis, hyperfermentonemia, with an increase in the amount of creatinine and urea in the blood serum. Metabolic signs indicate the development of hepatorenal syndrome due to structural disorders of the liver and kidneys. Histological signs of polymicotoxicosis are intracapillary and hemorrhagic glomerulonephritis, hepatocyte micronecrosis, and proliferation of connective tissue stroma cells, which leads to the development of atrophic cirrhosis in the interstitial and circular phases.

scholarly journals Caspase-mediated Cleavage of p130cas in Etoposide-induced Apoptotic Rat-1 Cells

2000 ◽  
Vol 11 (3) ◽  
pp. 929-939 ◽  
Author(s):  
Seunghyi Kook ◽  
Sang Ryeol Shim ◽  
Soo Jeon Choi ◽  
Joohong Ahnn ◽  
Jae Il Kim ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Focal Adhesion ◽  
Caspase 3 ◽  
Morphological Changes ◽  
Point Mutations ◽  
Membrane Blebbing ◽  
Adhesion Sites ◽  
Focal Adhesion Proteins ◽  
Induced Apoptosis

Apoptosis causes characteristic morphological changes in cells, including membrane blebbing, cell detachment from the extracellular matrix, and loss of cell–cell contacts. We investigated the changes in focal adhesion proteins during etoposide-induced apoptosis in Rat-1 cells and found that during apoptosis, p130cas (Crk-associated substrate [Cas]) is cleaved by caspase-3. Sequence analysis showed that Cas contains 10 DXXD consensus sites preferred by caspase-3. We identified two of these sites (DVPD416G and DSPD748G) in vitro, and point mutations substituting the Asp of DVPD416G and DSPD748G with Glu blocked caspase-3-mediated cleavage. Cleavage at DVPD416G generated a 74-kDa fragment, which was in turn cleaved at DSPD748G, yielding 47- and 31-kDa fragments. Immunofluorescence microscopy revealed well-developed focal adhesion sites in control cells that dramatically declined in number in etoposide-treated cells. Cas cleavage correlated temporally with the onset of apoptosis and coincided with the loss of p125FAK (focal adhesion kinase [FAK]) from focal adhesion sites and the attenuation of Cas–paxillin interactions. Considering that Cas associates with FAK, paxillin, and other molecules involved in the integrin signaling pathway, these results suggest that caspase-mediated cleavage of Cas contributes to the disassembly of focal adhesion complexes and interrupts survival signals from the extracellular matrix.

scholarly journals Neonatal Hemolytic Anemia Due to Inherited Harderoporphyria: Clinical Characteristics and Molecular Basis

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1453-1457 ◽  
Author(s):  
J. Lamoril ◽  
H. Puy ◽  
L. Gouya ◽  
R. Rosipal ◽  
V. Da Silva ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Neuropsychiatric Symptoms ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Neurological Dysfunction ◽  
Compound Heterozygous ◽  
Variant Form ◽  
Functional Protein ◽  
Main Site ◽  
Skin Photosensitivity

Abstract Porphyrias, a group of inborn errors of heme synthesis, are classified as hepatic or erythropoietic according to clinical data and the main site of expression of the specific enzymatic defect. Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase (COX). Typical clinical manifestations of the disease are acute attacks of neurological dysfunction; skin photosensitivity may also be present. We report a variant form of HC characterized by a unifying syndrome in which hematologic disorders predominate: harderoporphyria. Harderoporphyric patients exhibit jaundice, severe chronic hemolytic anemia of early onset associated with hepatosplenomegaly, and skin photosensitivity. Neither abdominal pain nor neuropsychiatric symptoms are observed. COX activity is markedly decreased. In a first harderoporphyric family, with three affected siblings, a homozygous K404E mutation has been previously characterized. In the present study, molecular investigations in a second family with neonatal hemolytic anemia and harderoporphyria revealed two heterozygous point mutations in the COX gene. One allele bore the missense mutation K404E previously described. The second allele bore an A→G transition at the third position of the donor splice site in intron 6. This new COX gene mutation resulted in exon 6 skipping and the absence of functional protein production. In contrast with other COX gene defects that produce the classical hepatic porphyria presentation, our data suggest that the K404E substitution (either in the homozygous or compound heterozygous state associated with a mutation leading to the absence of functional mRNA or protein) is responsible for the specific hematologic clinical manifestations of harderoporphyria.

scholarly journals Morphological changes in human neural cells following tick-borne encephalitis virus infection

2009 ◽  
Vol 90 (7) ◽  
pp. 1649-1658 ◽  
Author(s):  
Daniel Růžek ◽  
Marie Vancová ◽  
Martina Tesařová ◽  
Arunee Ahantarig ◽  
Jan Kopecký ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Lines ◽  
Morphological Changes ◽  
Neuroblastoma Cells ◽  
Clinical Manifestations ◽  
Neural Cell ◽  
Neural Cells ◽  
Tick Borne Encephalitis ◽  
Tbev Infection ◽  
Neural Cell Lines

Tick-borne encephalitis (TBE) is one of the leading and most dangerous human viral neuroinfections in Europe and north-eastern Asia. The clinical manifestations include asymptomatic infections, fevers and debilitating encephalitis that might progress into chronic disease or fatal infection. To understand TBE pathology further in host nervous systems, three human neural cell lines, neuroblastoma, medulloblastoma and glioblastoma, were infected with TBE virus (TBEV). The susceptibility and virus-mediated cytopathic effect, including ultrastructural and apoptotic changes of the cells, were examined. All the neural cell lines tested were susceptible to TBEV infection. Interestingly, the neural cells produced about 100- to 10 000-fold higher virus titres than the conventional cell lines of extraneural origin, indicating the highly susceptible nature of neural cells to TBEV infection. The infection of medulloblastoma and glioblastoma cells was associated with a number of major morphological changes, including proliferation of membranes of the rough endoplasmic reticulum and extensive rearrangement of cytoskeletal structures. The TBEV-infected cells exhibited either necrotic or apoptotic morphological features. We observed ultrastructural apoptotic signs (condensation, margination and fragmentation of chromatin) and other alterations, such as vacuolation of the cytoplasm, dilatation of the endoplasmic reticulum cisternae and shrinkage of cells, accompanied by a high density of the cytoplasm. On the other hand, infected neuroblastoma cells did not exhibit proliferation of membranous structures. The virions were present in both the endoplasmic reticulum and the cytoplasm. Cells were dying preferentially by necrotic mechanisms rather than apoptosis. The neuropathological significance of these observations is discussed.

scholarly journals Clinicopathologic and molecular profiles of Duchenne and Becker muscular dystrophy

2019 ◽  
Vol 59 (5) ◽  
pp. 257-64
Author(s):  
Ery Kus Dwianingsih ◽  
Meydita Fuzia Putri Insani ◽  
Linda Pratiwi ◽  
Irianiwati Widodo ◽  
Rusdy Ghazali Malueka
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Biopsy ◽  
Clinical Manifestations ◽  
Becker Muscular Dystrophy ◽  
High Serum ◽  
Molecular Profile ◽  
Molecular Profiles ◽  
Weak Expression ◽  
Dmd Gene ◽  
Histopathological Grading

Background Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive diseases caused by mutations in the dystrophin (DMD) gene. To our knowledge, molecular analysis to differentiate between DMD and BMD has never been performed in Indonesia. Objective To elaborate the clinicopathologic and molecular profiles of DMD/BMD patients in Yogyakarta, Indonesia. Methods Eighteen muscle biopsy specimens of patients clinically suspected to have DMD/BMD were collected. Possible associations of clinical manifestations, histopathological grading, and immunohistochemistry (IHC) results were analyzed. Polymerase chain reaction (PCR) was performed to identify mutations in exon 52. Results. Positive Gower’s sign and high serum creatine kinase (CK) were observed in most patients. The IHC of dystrophin in two female patients suggested that they were manifesting carriers. Of the 16 male patients, 12 showed negative IHC staining, indicating DMD, while 4 patients demonstrated weak expression of dystrophin, indicating BMD. There was a significant association between high CK level and IHC results (P=0.005), indicating higher CK level in DMD patients. Histopathological grading of muscle biopsy was significantly associated with diagnosis of DMD/BMD using IHC (P=0.01), showing more severe tissue damage in DMD patients. None of the subjects had the single exon 52 deletion. Conclusion This is the first report of a clinicopathologic and molecular profile of DMD/BMD in an Indonesian population. Serum CK level and histopathological grading of muscle biopsy are useful in distinguishing DMD from BMD in settings where an IHC assay is not available.

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