Correction to: Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures.

The article "Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures".

Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures.

Epitranscriptomic systems enable post-transcriptional modifications of cellular RNA that are essential for regulating gene expression. Of the ~ 170 known RNA chemical modifications, methylation is among the most common. Loss of function mutations in NSUN3, encoding the 5-methylcytosine (m5C) methyltransferase NSun3, have been linked to multisystem mitochondrial disease associated with combined oxidative phosphorylation deficiency. Here, we report a patient with early-onset mitochondrial encephalomyopathy and seizures in whom the novel biallelic NSUN3 missense variants c.421G>C (p.A141P) and c.454T>A (p.C152S) were detected. Segregation studies and in silico functional analysis confirmed the likely pathogenic effects of both variants. These findings expand the molecular and phenotypic spectrum of NSUN3-related mitochondrial disease.

Homozygous R627W mutations in POLG cause mitochondrial DNA depletion leading to encephalopathy, seizures and stroke-like episodes.

Mutations in the mitochondrial DNA maintenance gene POLG (DNA Polymerase Gamma, Catalytic Subunit), encoding mitochondrial DNA polymerase gamma (pol γ), are associated with an extremely broad phenotypic spectrum. We identified homozygous POLG c.1879C>T; p.R627W mutations in two siblings from a consanguineous South Asian family following targeted resequencing of 75 nuclear-encoded mitochondrial genes. Both patients presented with encephalopathy, seizures and stroke-like episodes, and mitochondrial DNA depletion was confirmed in the proband's muscle tissue. Subsequent Sanger sequencing of POLG in a further 275 unrelated probands with genetically unconfirmed mitochondrial disease revealed a third unrelated proband with a similar phenotype harboring homozygous c.1879C>T; p.R627W mutations and a fourth patient, with a milder clinical disorder, harboring compound heterozygous POLG c.1879C>T; p.R627W and c.2341G>A; p.A781T mutations. Given endogamous practices in the Indian subcontinent, homozygous POLG c.1879C>T; p.R627W mutations should be excluded in South Asian patients presenting with encephalopathy, seizures and stroke-like episodes.

Correction to: Prediction of unfavorable outcomes in cryptococcal meningitis: results of the multicenter infectious Diseases International Research Initiative (ID-IRI) cryptococcal meningitis study.

In the original version of this article, Mustafa Sunbul was not included in the list of authors for this article. The name has been added accordingly.

Prediction of unfavorable outcomes in cryptococcal meningitis: results of the multicenter Infectious Diseases International Research Initiative (ID-IRI) cryptococcal meningitis study.

Cryptococcal meningitis (CM) is mostly seen in immunocompromised patients, particularly human immunodeficiency virus (HIV)-positive patients, but CM may also occur in apparently immunocompetent individuals. Outcome analyses have been performed in such patients but, due to the high prevalence of HIV infection worldwide, CM patients today may be admitted to hospitals with unknown HIV status, particularly in underdeveloped countries. The objective of this multicenter study was to analyze all types of CM cases in an aggregate cohort to disclose unfavorable outcomes. We retrospectively reviewed the hospitalized CM patients from 2000 to 2015 in 26 medical centers from 11 countries. Demographics, clinical, microbiological, radiological, therapeutic data, and outcomes were included. Death, neurological sequelae, or relapse were unfavorable outcomes. Seventy (43.8%) out of 160 study cases were identified as unfavorable and 104 (65%) were HIV infected. On multivariate analysis, the higher Glasgow Coma Scale (GCS) scores (p = 0.021), cerebrospinal fluid (CSF) leukocyte counts > 20 (p = 0.038), and higher CSF glucose levels (p = 0.048) were associated with favorable outcomes. On the other hand, malignancy (p = 0.026) was associated with poor outcomes. Although all CM patients require prompt and rational fungal management, those with significant risks for poor outcomes need to be closely monitored.

Co-occurrence of m.1555A>G and m.11778G>A mitochondrial DNA mutations in two Indian families with strikingly different clinical penetrance of Leber hereditary optic neuropathy.

BACKGROUND: Mitochondrial DNA (mtDNA) mutations are known to cause Leber hereditary optic neuropathy (LHON). However, the co-occurrence of double pathogenic mutations with different pathological significance in pedigrees is a rare event. METHODS: Detailed clinical investigation and complete mtDNA sequencing analysis was performed for two Indian families with LHON. The haplogroup was constructed based on evolutionarily important mtDNA variants. RESULTS: We observed the existence of double pathogenic mutations (m.11778G>A and m.1555A>G) in two Indian LHON families, who are from different haplogroup backgrounds (M5a and U2e1), with different clinical penetrance of the disease (visual impairment). The m.11778G>A mutation in the MT-ND4 gene is associated primarily with LHON; whereas, m.1555A>G in the 12S rRNA gene has been reported with aminoglycoside-induced non-syndromic hearing loss. CONCLUSIONS: The absence of hearing abnormality and widely varying clinical expression of LHON suggest additional nuclear modifier genes, environmental factors, and population heterogeneity might play an important role in the expression of visual impairment in these families.

Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India.

PURPOSE: To investigate the clinical and mitochondrial DNA (mtDNA) haplogroup background of Indian Leber hereditary optic neuropathy (LHON) patients carrying the m.14484T>C mutation. METHODS: Detailed clinical investigation and complete mtDNA sequencing analysis was carried out for eight Indian LHON families with the m.14484T>C mutation. Haplogroup was constructed based on the evolutionarily important mtDNA variants. RESULTS: In the present study, we characterized eight unrelated probands selected from 187 LHON cases. The overall penetrance of the disease was estimated to be 19.75% (16/81) in eight pedigrees with the m.14484T>C mutation and showed substantially higher sex bias (male: female = 13:3). The mtDNA haplogrouping revealed that they belong to diverse haplogroups; i.e., F1c1, M31a, U2a, M*, I1, M6, M3a1, and R30a. Interestingly, we did not find an association of the m.14484T>C mutation with any specific haplogroup within the Indian population. We also did not find any secondary mutation(s) in these pedigrees, which might affect the clinical expression of LHON. CONCLUSIONS: Contrary to earlier reports showing preferential association of the m.14484T>C mutation with western Eurasian haplogroup J and increased clinical penetrance when present in J1 subhaplogroup background, the present study shows that m.14484T>C arose independently in a different mtDNA haplogroup and ethnic background in India, which may influence the clinical expression of the disease.

Genome-wide analysis of the intrinsic terminators of transcription across the genus Mycobacterium.

Termination of transcription in eubacteria is achieved by a region of the nascent transcript. In Escherichia coli, this intrinsic terminator consists of a hairpin followed by a U-stretch. Absence of the typical terminators in several genes of Mycobacterium tuberculosis led us to develop an accurate and efficient algorithm to identify putative terminators in all sequenced microbial genomes. In addition to the typical Escherichia coli type of terminators, several variant terminator structures were predicted by the algorithm and their existence was experimentally verified. We have now analysed 17 Mycobacterium genomes to obtain a comprehensive picture of the transcription terminators in mycobacteria. Our results show that the terminators that lack a U-trail, variant from the typical E. coli intrinsic terminators, are overwhelmingly predominant in all members of the genus. Most terminator structures are concentrated within 50 base pairs downstream of the stop codon. A large number of these terminators occur at the end of experimentally verified or predicted transcription units. We have observed inter-species variations in DeltaG and positioning of the terminators downstream of specific genes amongst closely related mycobacterial species suggesting differences in gene expression. The analysis would be useful in furthering our understanding of genome organization and gene expression in mycobacteria, in addition to the improvement in the annotation of the new genomes.

Modified double-disc test for detection of extended-spectrum beta-lactamases in Escherichia coli and Klebsiella pneumoniae.

This study evaluates the performance of a modified double-disc test (MDDT) for the detection of extended-spectrum beta-lactamases (ESBLs) in clinical isolates of Escherichia coli and Klebsiella pneumoniae. Ninety-six isolates of E. coli and 40 K. pneumoniae are studied for ESBL production by the National Committee for Clinical Laboratory Standards (NCCLS) combination disc tests and MDDT A total of 112 (82%) isolates (80 [83%] E. coli, 32 [80%] K. pneumoniae) were positive for ESBL by MDDT compared to 102 (75%; 72 [75%] E. coli and 30 [75%] K. pneumoniae) by the NCCLS method. In 10 (7.4%) isolates, ESBLs were detected only by MDDT Twenty-four (17.6%) isolates were negative for ESBL by both methods. The protocol described in this study provides a more sensitive approach than does the NCCLS method for ESBL detection in E. coli and K. pneumoniae.

Prevalence of extended spectrum beta-lactamase among multidrug resistant gram-negative isolates from a general hospital in Saudi Arabia.

OBJECTIVE: To determine the prevalence of extended spectrum beta-lactamase (ESBL) among multidrug resistant isolates of enterobacteriaceae and non-fermenting gram-negative bacilli. METHODS: This study was carried out at the Almana General Hospital, Eastern Province, Kingdom of Saudi Arabia, during the period March 2002 through to June 2003. Multidrug resistant gram-negative isolates from patients admitted to the surgical, medical, pediatric, long-term care and intensive care units were studied for the presence of the ESBL enzyme. RESULTS: A total of 3231 gram-negative organisms were studied for the presence of multidrug resistance and ESBLs. Of these, 197 (6%) isolates were multidrug resistant (MDR), and 156 (4.8%) were positive for ESBL. Seventy nine percent of the MDR strains were positive for ESBL. The most frequent isolates were Escherichia coli (1116) and Klebsiella pneumoniae (687) and ESBL was detected in 72 (6.5%) and 37 (5.4%) of these isolates. The MDR strains that produced ESBL were most commonly isolated from surgical care patients with diabetic fascitis (83%) and patients with indwelling Foley's catheter (79%). Extended spectrum beta-lactamase producing strains showed the highest susceptibility to imipenem and meropenem (86%). The non-beta-lactam antibiotics with greatest activity against these ESBL strains in vitro were ciprofloxacin (72%), amikacin (70%), tobramycin (67%) and gentamicin (56%). CONCLUSION: The majority (79%) of the MDR enterobacteriaceae and non-fermenting gram-negative bacilli tested over 15-months were positive for ESBL. Imipenem, meropenem, ciprofloxacin and amikacin showed the highest activity against these ESBL-producing organisms. Due to the growing problem of infection with ESBL-producing bacteria, which are frequently resistant to many classes of antibiotics resulting in difficult-to-treat infections, clinicians need to be familiar with the clinical significance of these enzymes and potential strategies for dealing with them.