Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features

Giordano, Carla; Perli, Elena; Orlandi, Maurizia; Pisano, Annalinda; Tuppen, Helen A.L.; He, Langping; Ierinó, Rocco; Petruzziello, Luciano; Terzi, Amedeo; Autore, Camillo; Petrozza, Vincenzo; Gallo, Pietro; Taylor, Robert W.; d’Amati, Giulia

doi:10.1016/j.humpath.2012.10.011

Cited by 33 publications

(25 citation statements)

References 22 publications

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“…By PAS we noticed increased in the reaction in methotrxate treated group especially around the nucleus which may explained the perinuclear vacuolation. A previous study proved that mitochondrial disorders of cardiac muscles is a leading factor for accumulation of glycogen in perinuclear region and associated with hypertrophic cardiomyopathies due accumulation of free radicals [22] .…”

Section: Discussionmentioning

confidence: 97%

Histological and immunohistochemical study of the possible protective effect of folic acid on the methotrexate- induced cardiac muscle toxicity in male albino rats

Mohamed

Nor-Eldin

2018

Egyptian Journal of Histology

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Introduction: Methotrexate is widely used as a chemotherapeutic agent in cancers, ectopic pregnancies and rheumatic arthritis. Folic acid is found in dark green leafy vegetables. Methotrexate is folic acid antagonist that prevents its conversion to tetrahydro folic acid. Aim: This research aimed to study the protective effect of folic acid on the histological changes produced by methotrexate in cardiac muscles. Materials and Methods: Thirty adult male albino rats were divided into three equal groups. Group I (control group) 10 rats injected intraperitoneally with saline. Group II rats were intraperitoneally injected with methotrexate at a dose of 5mg/kg/day for one month. Group III: were intraperitoneally injected with methotrexate at a dose of (5mg/kg/day) with concomitant oral folic acid at a dose of (0.1mg/kg/day) for one month. After 24 hrs of the last dose, the animals were dissected. Hearts were processed for haematoxyline and eosine stain, immunohistochemical stains and electron microscopic examination. Results: Both degenerative and apoptotic changes were observed in the cardiac muscles in the methotrexte-treated group, these changes were attenuated by administration of folic acid. Conclusion: Folic acid is beneficial to the cardiac muscles during methotrexate treatment and should be used concomitant with methotrexate treatment.

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Section: Discussionmentioning

confidence: 97%

Histological and immunohistochemical study of the possible protective effect of folic acid on the methotrexate- induced cardiac muscle toxicity in male albino rats

Mohamed

Nor-Eldin

2018

Egyptian Journal of Histology

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“…For patients carrying these A4300G and C4277T mt-tRNA Ile mutations, the only symptom was hypertrophic cardiomyopathy. However, detailed immunohistochemistry and biochemical studies on the hearts of patients after transplant surgery indicated a large proportion of COX-deficient cardiomyocytes and defects in activity for respiratory chain complexes I, III, and IV (Giordano et al, 2013). Also, there appeared to be reduced expression of mt-tRNA Ile in both left and right ventricle samples from two patients compared with control mt-tRNA Leu .…”

Section: Mitochondrial Trna Mutations and Diseasementioning

confidence: 99%

Transfer RNA and human disease

2014

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Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are “hotspots” for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

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“…Although neither skin nor muscle biopsies were performed, a normal lactate (pre and post-operative period) helped exclude some mitochondrial oxidative phosphorylation defects [1]. Genetic testing for certain mitochondrial transfer RNA mutations [21] was also negative. As this child’s development is progressing well, a mitochondrial cytopathy is not so far suspected.…”

Section: Discussionmentioning

confidence: 99%

Combined obstructive hypertrophic cardiomyopathy and double outlet right ventricle in an infant with Down syndrome

2013

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Patient: Male, 2Final Diagnosis: Obstructive hypertrophic cardiomyopathySymptoms: Congestive heart failureMedication: —Clinical Procedure: Left ventricular septal myectomy • repair of congenital heart diseaseSpecialty: CardiologyObjective:Rare diseaseBackground:Hypertrophic cardiomyopathy (HCM) is uncommon in Down syndrome (DS). When combined with congenital heart disease (CHD) both morbidity and mortality may be greater compared to CHD alone. Whether HCM in DS patients is related to having trisomy 21 versus a second site mutation is unknown.Case Report:We report a case of severe HCM in an infant with DS in combination with double outlet right ventricle (DORV) who required surgery for relive of sub-aortic obstruction and congestive heart failure. We predicted that this infant would have a second site mutation involving either a sarcomeric protein or metabolic disorder as a cause for his HCM. Using current genetic and metabolic testing as well as histologic assessment of excised cardiac tissue we sought to further characterize the nature of the HCM. A successful resection of sub-aortic stenosis and DORV repair was performed. Genetic and metabolic testing was negative for gene defects and/or syndromes commonly associated with familial HCM. Excised cardiac tissue from the ventricular septum exhibited myocyte hypertrophy and sub-endocardial fibrosis but no sarcomeric disarray, myocyte fibrosis or glycogen storage. Metabolic testing for common forms of mitochondrial disease was negative. Post-operative echocardiograms show persistent, non-obstructive septal hypertrophy.Conclusions:Unlike prior reports, this child required a surgical intervention to relieve his sub-aortic obstruction. Thus, HCM in this population can be more serious that previously suspected. Although testing did not reveal the cause of his HCM, we still suggest screening for known causes of HSC until the etiology of the HCM in DS is well understood.

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Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features

Cited by 33 publications

References 22 publications

Histological and immunohistochemical study of the possible protective effect of folic acid on the methotrexate- induced cardiac muscle toxicity in male albino rats

Histological and immunohistochemical study of the possible protective effect of folic acid on the methotrexate- induced cardiac muscle toxicity in male albino rats

Transfer RNA and human disease

Combined obstructive hypertrophic cardiomyopathy and double outlet right ventricle in an infant with Down syndrome

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