A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency

Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene.     

Effect of verapamil on immediate recurrence of atrial fibrillation

INTRODUCTION: The purpose of this study was to assess the effect of verapamil on immediate recurrences of atrial fibrillation occurring after successful electrical cardioversion. METHODS AND RESULTS: The effect of verapamil on the recurrence of atrial fibrillation within 5 minutes after successful transthoracic cardioversion was assessed in 19 (5%) of 364 patients undergoing electrical cardioversion. The mean duration of atrial fibrillation was 4.44+/-3.0 months. In the 19 patients, cardioversion was successful after each of three consecutive cardioversion attempts per patient; however, atrial fibrillation recurred 0.4+/-0.3 minutes after cardioversion. Verapamil 10 mg was administered intravenously and a fourth cardioversion was performed. Cardioversion after verapamil was successful in each patient, and atrial fibrillation did not recur in 9 (47%) of 19 patients (P < 0.001 vs before verapamil). In the remaining 10 patients in whom atrial fibrillation recurred, the duration of sinus rhythm was significantly longer compared with before verapamil (3.6+/-2.4 min, P < 0.001). The density of atrial ectopy occurring after cardioversion was significantly less after verapamil (21+/-14 ectopic beats per min) compared with before verapamil (123+/-52 ectopic beats per min, P < 0.001). CONCLUSION: Among patients with immediate recurrence of atrial fibrillation after electrical cardioversion, acute calcium channel blockade by verapamil reduces recurrence of atrial fibrillation and extends the duration of sinus rhythm.     

The PCBP1 gene encoding poly(rc) binding protein i is recurrently mutated in Burkitt lymphoma

The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG‐MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole‐genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron‐less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K‐Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre‐mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20–40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis. © 2015 Wiley Periodicals, Inc.     

Diagnostic yield of bronchoscopy with bronchoalveolar lavage in febrile patients with hematologic malignancies and pulmonary infiltrates

Infectious complications are a major cause of morbidity and mortality in immunosuppressed patients. Febrile patients with hematologic malignancies and pulmonary infiltrates have high mortality rates, especially if mechanical ventilation is required. The diagnostic value of fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) in these patients is controversial. We retrospectively analyzed the microbiological results of BAL samples obtained during 249 FOB examinations from 199 febrile patients with hematologic malignancies and pulmonary infiltrates (underlying diseases: acute leukemia 103 patients, lymphoma 84 patients, other malignancies 12 patients). Two hundred forty-six examinations could be evaluated. Seventy-three out of 246 BAL samples were sterile; 55 samples showed microbiological findings classified as contamination or colonization. One hundred eighteen samples showed positive microbiological results of bacteria and/or fungi classified as causative pathogens. Thereof, in 70 samples, only bacterial pathogens were detectable (Gram-positive, 35; Gram-negative, 30; mixed Gram-positive and Gram-negative, 5). Thirteen samples showed both fungi and bacterial pathogens. In 33 samples, only fungi were detectable, thereof, in 15 samples Aspergillus species, in 16 samples Candida species, and in 2 both. In two samples, a viral pathogen could be detected. Three nonlethal complications (bleeding, arrhythmia) occurred that required early termination of FOB. In 94 (38.2%) patient episodes, antibiotic treatment was modified as a result of microbiological findings in BAL samples. Our results show that FOB with BAL is a valuable diagnostic tool with low complication rates in high-risk febrile patients with hematologic malignancies and pulmonary infiltrates, contributing crucial results for the individual case, and also improving epidemiologic knowledge.     

Temporäre mechanische Linksherzentlastung

Zusammenfassung Hintergrund  Die Implantation eines mechanischen Herzunterstützungssystem (MCSS) bei Patienten mit idiopathischer dilatativer Kardiomyopathie im Endstadium kann zu einer Verbesserung der Herzfunktion führen und die Explantation des Systems erlauben. Wir berichten über die Effekte der ventrikul?ren Entlastung auf die Herzfunktion, die humoralen Anti-β₁-Adrenozeptor-Autoantik?rper (A-β₁-AAK) sowie die myokardiale Fibrose. Methoden  13 Patienten mit nichtisch?mischer dilatativer Kardiomyopathie im Endstadium (NYHA IV-D) erhielten ein monoventrikul?res (zw?lf Patienten) oder ein biventrikul?res (ein Patient) Herzentlastungssystem. Alle hatten zur Zeit der Implantation einen Cardiac Index <1,61·min⁻¹·m² K?rperoberfl?che, eine linksventrikul?re Auswurffraktion (LVEF) von <16%, einen linksventrikul?ren enddiastolischen Diameter (LVEDd)>68 mm und einen positiven A-β₁-AAK-Nachweis. Echokardiographische Auswertungen, Serumtests auf A-β₁-AAK und histologische Untersuchungen hinsichtlich myokardialer Fibrose wurden vor und nach Implantation eines MCSS durchgeführt. Ergebnisse  Die durchschnittliche Unterstützungsdauer betrug 236±201 Tage (30 bis 794 Tage). Innerhalb dieses Zeitraums verbesserte sich die LVEF von ≤15 auf im Durchschnitt 46% und der LVEDd von 74 auf 56 mm. Die A-β₁-AAK waren nach im Mittel 11,7 Wochen im Serum nicht mehr nachweisbar. Ein Wiederanstieg konnte auch nach Explantation bei keinem Patienten beobachtet werden. Ein hochpathologischer Fibroseanteil im Myokard war etwa ein Jahr nach Explantation ebenfalls nicht mehr zu beobachten. Ein Patient dekompensierte sechs Monate nach Explantation und wurde daraufhin mit einem externen monoventrikul?ren System unterstützt. Die nachfolgende Transplantation verlief erfolgreich. Ein weiterer Patient starb unmittelbar nach Explantation an der Folge einer an?sthesiologischen Komplikation. Die mittlere Nachbeobachtungsdauer bei elf Patienten nach Explantation betr?gt (Stand 31. 5. 1997) 12,6±9,77 Monate (drei bis 26 Monate). Kumulativ konnten 139 Patientenmonate nachbeobachtet werden. Schlu?folgerung  Bei ausgew?hlten Patienten mit terminaler idiopathischer dilatativer Kardiomyopathie kann durch eine tempor?re mechanische Herzunterstützung eine weitgehende Normalisierung der Herzfunktion erreicht werden. Die pr?operative myokardiale Fibrose ist ein Jahr nach Explantation nicht mehr nachweisbar. Die A-β₁-AAK verschwinden in der Phase der mechanischen Entlastung des Herzens und treten nach Explantation des Systems nicht mehr auf. “Weaning” von der mechanischen Herzunterstützung kann eine Alternative zur Herztransplantation darstellen.      

Functional characterization of antineutrophil cytoplasmic antibodies in patients with cocaine-induced midline destructive lesions

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) binding to neutrophil elastase (NE) and proteinase 3 (PR3) are detectable in most patients with cocaine-induced midline destructive lesions (CIMDL), but the pathogenic role and antigen specificity of these antibodies are unknown. This study was undertaken to assess the effects of NE ANCA on the enzymatic activity of NE, to determine whether these antibodies interfere with the physiologic effect of secretory leukoprotease inhibitor (SLPI), and to investigate the antigen specificity of both NE and PR3 ANCA in patients with CIMDL. We also compared the binding of PR3 ANCA in patients with CIMDL with that in patients with Wegener's granulomatosis (WG). METHODS: PR3 ANCA and NE ANCA were detected by capture enzyme-linked immunosorbent assays (ELISAs) and by indirect immunofluorescence. IgG was purified from the patients' sera, and the influence of NE ANCA on the enzymatic activity of NE and on the inhibitory activity of SLPI was investigated by determining the hydrolysis of N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide by NE. RESULTS: IgG from NE ANCA-positive sera of patients with CIMDL inhibited the enzymatic activity of NE and did not interfere with the activity of SLPI. In contrast to the findings in WG sera, measurement of PR3 ANCA in CIMDL sera showed only fair to moderate concordance between the 2 different capture ELISAs. Cross-inhibition experiments demonstrated that NE ANCA and PR3 ANCA represent distinct autoantibodies in patients with CIMDL. CONCLUSION: The functional effects of NE ANCA on the enzymatic activity of NE or on the activity of SLPI cannot be implicated in the pathogenesis of CIMDL. The autoimmune reaction that targets neutrophil serine proteases in patients with CIMDL is frequently directed against more than one antigen. The ANCA response, including the reactivity of PR3 ANCA, in patients with CIMDL differs from what has been described in patients with WG.     

Beteiligung und Unterstützung klinischer Studien und anderer wissenschaftlicher Untersuchungen

Clinical studies and preclinical investigations are essential in order to test new therapies and diagnostics with the aim of sustained improvement in the treatment of patients. Fortunately, the number of clinical studies is continuously increasing and pathology and tissue-based research are included more often. The German Society for Pathology (DGP) and the pathologists it represents want to and can support this process and our clinical partners as best as possible as an equal partner. With our technologies and our specific expertise we can make a substantial contribution to the quality and the success of preclinical investigations, clinical studies and implementation of the results into clinical pathological diagnostics. In order to support this process the DGP has formulated a statement on the participation and support of clinical studies and other scientific investigations.