Autosomal Recessive Atrial Dilated Cardiomyopathy With Standstill Evolution Associated With Mutation of Natriuretic Peptide Precursor A

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Mitochondrial cardiomyopathies: how to identify candidate pathogenic mutations by mitochondrial DNA sequencing, MITOMASTER and phylogeny

Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathy and heart failure. Owing to a high mutation rate, mtDNA defects may occur at any nucleotide in its 16 569 bp sequence. Complete mtDNA sequencing may detect pathogenic mutations, which can be difficult to interpret because of normal ethnic/geographic-associated haplogroup variation. Our goal is to show how to identify candidate mtDNA mutations by sorting out polymorphisms using readily available online tools. The purpose of this approach is to help investigators in prioritizing mtDNA variants for functional analysis to establish pathogenicity. We analyzed complete mtDNA sequences from 29 Italian patients with mitochondrial cardiomyopathy or suspected disease. Using MITOMASTER and PhyloTree, we characterized 593 substitution variants by haplogroup and allele frequencies to identify all novel, non-haplogroup-associated variants. MITOMASTER permitted determination of each variant's location, amino acid change and evolutionary conservation. We found that 98% of variants were common or rare, haplogroup-associated variants, and thus unlikely to be primary cause in 80% of cases. Six variants were novel, non-haplogroup variants and thus possible contributors to disease etiology. Two with the greatest pathogenic potential were heteroplasmic, nonsynonymous variants: m.15132T>C in MT-CYB for a patient with hypertrophic dilated cardiomyopathy and m.6570G>T in MT-CO1 for a patient with myopathy. In summary, we have used our automated information system, MITOMASTER, to make a preliminary distinction between normal mtDNA variation and pathogenic mutations in patient samples; this fast and easy approach allowed us to select the variants for traditional analysis to establish pathogenicity

Genetic Basis of Myocarditis: Myth or Reality?

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Mitochondrial cardiomyopathies: how to identify candidate pathogenic mutations by mitochondrial DNA sequencing, MITOMASTER and phylogeny.

Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathy and heart failure. Owing to a high mutation rate, mtDNA defects may occur at any nucleotide in its 16 569 bp sequence. Complete mtDNA sequencing may detect pathogenic mutations, which can be difficult to interpret because of normal ethnic/geographic-associated haplogroup variation. Our goal is to show how to identify candidate mtDNA mutations by sorting out polymorphisms using readily available online tools. The purpose of this approach is to help investigators in prioritizing mtDNA variants for functional analysis to establish pathogenicity. We analyzed complete mtDNA sequences from 29 Italian patients with mitochondrial cardiomyopathy or suspected disease. Using MITOMASTER and PhyloTree, we characterized 593 substitution variants by haplogroup and allele frequencies to identify all novel, non-haplogroup-associated variants. MITOMASTER permitted determination of each variant's location, amino acid change and evolutionary conservation. We found that 98% of variants were common or rare, haplogroup-associated variants, and thus unlikely to be primary cause in 80% of cases. Six variants were novel, non-haplogroup variants and thus possible contributors to disease etiology. Two with the greatest pathogenic potential were heteroplasmic, nonsynonymous variants: m.15132T>C in MT-CYB for a patient with hypertrophic dilated cardiomyopathy and m.6570G>T in MT-CO1 for a patient with myopathy. In summary, we have used our automated information system, MITOMASTER, to make a preliminary distinction between normal mtDNA variation and pathogenic mutations in patient samples; this fast and easy approach allowed us to select the variants for traditional analysis to establish pathogenicity

The mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNA(Leu(CUN)) and is associated with dilated cardiomyopathy

Mitochondrial DNA (mtDNA) mutations have been causally linked with cardiomyopathies, both dilated (DCM) and hypertrophic. We identified the T12297C mutation in the mtDNA-tRNA(Leu(CUN)) of a 36-year-old male patient diagnosed with DCM. The mutation was heteroplasmic, with high amount (88%) of mutant DNA in the myocardium, and was absent in normal (n = 120) and disease (n = 150) controls. It affects a highly conserved nucleotide (adjacent to the anticodon triplet) that allows the phospho-ribose backbone to turn and form the loop. The potential pathological role of T12297C mutation is further supported by its recent identification in another unrelated Italian family with DCM associated with endocardial fibroelastosis. In the variable loop of the same tRNA, our patient also carried the A12308G transition that is debated as pathological mutation or neutral polymorphism in progressive external ophthalmoplegia: the two defects could exert a synergistic effect on the tRNA structure and function. The endomyocardial biopsy study showed abnormal ring-like mitochondria and occasional cytochrome c oxydase negative myocytes. Overall, the heteroplasmy, the highly conserved position of the mutated nucleotide, the absence of the mutation in large series of diseased and normal controls, and the cardiac mitochondrial changes support a causative link of the mutation with the disease

[18F]-FDG PET/CT for suspected lymphoma relapse in a patient with concomitant pneumococcal pneumonia during COVID-19 outbreak: unexpected SARS-Cov-2 co-infection despite double RT-PCR negativity

During COVID-19 outbreak (March 2020), a local 78-year-old male patient, with a history of treated non-Hodgkin lymphoma, was admitted to the hospital (day 1) with persistent fever, cough, and dyspnea. Thorax high-resolution computed tomography (HRCT) suspected viral lung infection and incidentally detected enlarged axillary and mediastinal lymphadenopathies. Reverse transcriptase-polymerase chain reaction (RTPCR) on pharyngeal swab yielded negative results for SARS-CoV-2 infection, both at patient admission and 2 days after (days 1 and 3). Subsequently (day 5), Streptococcus pneumoniae urinary antigen was found positive; therefore, the patient was immediately referred to high-dose antibiotics administration for pneumonia and to [18F]-FDG PET-CT for suspected lymphoma relapse. The scan (day 6) demonstrated multiple FDG avid lymphadenopathies above and below the diaphragm and increased diffuse uptake in the spleen in keeping with NHL progression and suspected bowel involvement. Furthermore, concomitant pneumonia was confirmed due to faint and diffuse uptake within a left inferior lobe consolidation and a single non-FDG-avid peripheral rounded ground-glass opacity (GGO) in the right upper lobe. A follow-up (day 11) HRCT demonstrated GGO small reduction, further extension of left basal consolidation, and new periscissural thickening in the right apex. Then, a third RT-PCR test (day 12) finally revealed COVID-19. Two weeks later, despite hydroxychloroquine and azithromycin, clinical and radiological worsening was documented (day 26) showing extensive interstitial viral involvement throughout both lungs. The patient started tocilizumab and required CPAP ventilation. Although RT-PCR remains the gold standard for COVID-19 diagnosis, false-negative/delayed results are not uncommon. The routine method for screening, diagnosis, and monitoring is HRCT. [18F]-FDG PET/CT is not specific, and differential diagnosis of lung infections is challenging [1\u20134]. According to this single experience, we suppose that co-infection with other pathogens (i.e., S. pneumoniae) might influence RT-PCR test accuracy; when clinical and CT features are highly suggestive for suspected COVID-19 pneumonia, precautions in patients management are recommended even in case of first RT-PCR negativities; during COVID-19 pandemic, incidental findings detected by a nuclear medicine physician at lung window CT component of PET/CT studies might be extremely relevant. [5