Shift in hospital opioid use during the COVID-19 pandemic in Brazil: a time-series analysis of one million prescriptions.

The pronounced change in the profile of hospitalized patients during COVID-19 and the severe respiratory component of this disease, with a great need for mechanical ventilation, led to changes in the consumption pattern of some medicines and supplies. This time-series study analyzed the in-hospital consumption of opioids during the COVID-19 pandemic in 24 Brazilian hospitals compared to the pre-pandemic period. Data included 711,883 adult patients who had opioids prescribed. In 2020, the mean consumption was significantly higher compared to 2019 for parenteral fentanyl, enteral methadone, and parenteral methadone. It was significantly lower for parenteral morphine parenteral sufentanil, and parenteral tramadol. For remifentanil, it did not differ. The number of patients in 2020 was lower but the mean consumption was higher for fentanyl, parenteral methadone, and remifentanil. It was lower for enteral methadone and parenteral sufentanil. The consumption of parenteral morphine and parenteral tramadol was stable. There was a relevant increase in hospital consumption of some potent opioids during the COVID-19 pandemic in Brazil. These results reinforce the concern about epidemiological surveillance of opioid use after periods of increased hospital use since in-hospital consumption can be the gateway to the misuse or other than the prescribed use of opioids after discharge.

A Platform for Data-Centric, Continuous Epidemiological Analyses (EpiGraphHub): Descriptive Analysis.

BACKGROUND: Guaranteeing durability, provenance, accessibility, and trust in open data sets can be challenging for researchers and organizations that rely on public repositories of data critical for epidemiology and other health analytics. The required data repositories are often difficult to locate and may require conversion to a standard data format. Data-hosting websites may also change or become unavailable without warning. A single change to the rules in one repository can hinder updating a public dashboard reliant on data pulled from external sources. These concerns are particularly challenging at the international level, because policies on systems aimed at harmonizing health and related data are typically dictated by national governments to serve their individual needs. OBJECTIVE: In this paper, we introduce a comprehensive public health data platform, EpiGraphHub, that aims to provide a single interoperable repository for open health and related data. METHODS: The platform, curated by the international research community, allows secure local integration of sensitive data while facilitating the development of data-driven applications and reports for decision-makers. Its main components include centrally managed databases with fine-grained access control to data, fully automated and documented data collection and transformation, and a powerful web-based data exploration and visualization tool. RESULTS: EpiGraphHub is already being used for hosting a growing collection of open data sets and for automating epidemiological analyses based on them. The project has also released an open-source software library with the analytical methods used in the platform. CONCLUSIONS: The platform is fully open source and open to external users. It is in active development with the goal of maximizing its value for large-scale public health studies.

Leveraging human resources for outbreak analysis: lessons from an international collaboration to support the sub-Saharan African COVID-19 response.

Emerging infectious diseases are a growing threat in sub-Saharan African countries, but the human and technical capacity to quickly respond to outbreaks remains limited. Here, we describe the experience and lessons learned from a joint project with the WHO Regional Office for Africa (WHO AFRO) to support the sub-Saharan African COVID-19 response.In June 2020, WHO AFRO contracted a number of consultants to reinforce the COVID-19 response in member states by providing actionable epidemiological analysis. Given the urgency of the situation and the magnitude of work required, we recruited a worldwide network of field experts, academics and students in the areas of public health, data science and social science to support the effort. Most analyses were performed on a merged line list of COVID-19 cases using a reverse engineering model (line listing built using data extracted from national situation reports shared by countries with the Regional Office for Africa as per the IHR (2005) obligations). The data analysis platform The Renku Project ( https://renkulab.io ) provided secure data storage and permitted collaborative coding.Over a period of 6 months, 63 contributors from 32 nations (including 17 African countries) participated in the project. A total of 45 in-depth country-specific epidemiological reports and data quality reports were prepared for 28 countries. Spatial transmission and mortality risk indices were developed for 23 countries. Text and video-based training modules were developed to integrate and mentor new members. The team also began to develop EpiGraph Hub, a web application that automates the generation of reports similar to those we created, and includes more advanced data analyses features (e.g. mathematical models, geospatial analyses) to deliver real-time, actionable results to decision-makers.Within a short period, we implemented a global collaborative approach to health data management and analyses to advance national responses to health emergencies and outbreaks. The interdisciplinary team, the hands-on training and mentoring, and the participation of local researchers were key to the success of this initiative.

An in-depth statistical analysis of the COVID-19 pandemic's initial spread in the WHO African region.

During the first wave of the COVID-19 pandemic, sub-Saharan African countries experienced comparatively lower rates of SARS-CoV-2 infections and related deaths than in other parts of the world, the reasons for which remain unclear. Yet, there was also considerable variation between countries. Here, we explored potential drivers of this variation among 46 of the 47 WHO African region Member States in a cross-sectional study. We described five indicators of early COVID-19 spread and severity for each country as of 29 November 2020: delay in detection of the first case, length of the early epidemic growth period, cumulative and peak attack rates and crude case fatality ratio (CFR). We tested the influence of 13 pre-pandemic and pandemic response predictor variables on the country-level variation in the spread and severity indicators using multivariate statistics and regression analysis. We found that wealthier African countries, with larger tourism industries and older populations, had higher peak (p<0.001) and cumulative (p<0.001) attack rates, and lower CFRs (p=0.021). More urbanised countries also had higher attack rates (p<0.001 for both indicators). Countries applying more stringent early control policies experienced greater delay in detection of the first case (p<0.001), but the initial propagation of the virus was slower in relatively wealthy, touristic African countries (p=0.023). Careful and early implementation of strict government policies were likely pivotal to delaying the initial phase of the pandemic, but did not have much impact on other indicators of spread and severity. An over-reliance on disruptive containment measures in more resource-limited contexts is neither effective nor sustainable. We thus urge decision-makers to prioritise the reduction of resource-based health disparities, and surveillance and response capacities in particular, to ensure global resilience against future threats to public health and economic stability.

Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease.

Mitochondrial disorders are clinically and genetically heterogeneous, with variants in mitochondrial or nuclear genes leading to varied clinical phenotypes. TAMM41 encodes a mitochondrial protein with cytidine diphosphate-diacylglycerol synthase activity: an essential early step in the biosynthesis of phosphatidylglycerol and cardiolipin. Cardiolipin is a mitochondria-specific phospholipid that is important for many mitochondrial processes. We report three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Whole exome and genome sequencing identified compound heterozygous variants in TAMM41 in each proband. Western blot analysis in fibroblasts showed a mild oxidative phosphorylation (OXPHOS) defect in only one of the three affected individuals. In skeletal muscle samples, however, there was severe loss of subunits of complexes I-IV and a decrease in fully assembled OXPHOS complexes I-V in two subjects as well as decreased TAMM41 protein levels. Similar to the tissue-specific observations on OXPHOS, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. To assess the functional impact of the TAMM41 missense variants, the equivalent mutations were modeled in yeast. All three mutants failed to rescue the growth defect of the Δtam41 strains on non-fermentable (respiratory) medium compared with wild-type TAM41, confirming the pathogenicity of the variants. We establish that TAMM41 is an additional gene involved in mitochondrial phospholipid biosynthesis and modification and that its deficiency results in a mitochondrial disorder, though unlike families with pathogenic AGK (Sengers syndrome) and TAFAZZIN (Barth syndrome) variants, there was no evidence of cardiomyopathy.

Risk of hospitalization and mortality due to COVID-19 in people with obesity: An analysis of data from a Brazilian state.

The aim of this article is to assess the odds ratio of hospitalization and mortality due to COVID-19 in people with obesity using data from residents of Espírito Santo, Brazil. An observational, quantitative, cross-sectional study was carried out from the database available on the official channel of the State Health Secretariat of Espírito Santo. Crude odds ratio estimates (ORs) referring to the association between variables were calculated, as well as adjusted odds ratios (adjusted odds ratios-OR adj.) and their respective 95% confidence intervals (CI 95%). The results indicate that men, non-white, no education or with lower education level and age over 40 years old were more likely to be hospitalized and died of COVID-19. People with obesity are at risk of hospitalization and death due to COVID-19 54% and 113% higher than people who do not have obesity. People with obesity had a higher chance of hospitalization when they were over 40 years old, had breathing difficulty, and the comorbidities diabetes (2.18 higher) and kidney disease (4.10 higher). The odds ratio of death for people with obesity over 60 years old was 12.51 higher, and those who were hospitalized was 17.9 higher compared to those who were not hospitalized.

Increase in Hepatitis A Cases Linked to Imported Strains to Rio de Janeiro, Brazil: A Cross-Sectional Study.

This study aims to evaluate the epidemiological and molecular features associated with HAV transmission in adults in Rio de Janeiro during a period of increased registered cases of HAV (2017-2018). Socio-epidemiological data and serum samples from anti-HAV IgM+ individuals were obtained. HAV RNA was RT-PCR amplified and sequenced for further phylogenetic and phylogeographic analyses. From fifty-two HAV IgM+ individuals, most were men (78.85%; p = 0.024), aged 20-30 years old (84.61%; p < 0.001), resided in the Rio de Janeiro north zone (31/52; 59.62%; p = 0.001), and are men who have sex with men (MSM) (57.69%; p = 0.002). Sexual practices were more frequent (96%) than others risk factors (food-borne (44%), water-borne (42.31%), and parenteral (34.62%)). Individuals who traveled to endemic regions had a 7.19-fold (1.93-36.04; p < 0.01) increased risk of HAV. Phylogenetic analysis revealed four distinct clades of subgenotype IA, three of them comprised sequences from European/Asian MSM outbreaks and one from Brazilian endemic strains. Bayesian Inference showed that the imported strains were introduced to Brazil during large mass sportive events. Sexual orientation and sexual practices may play a role in acquiring HAV infection. Public policies targeting key populations must be implemented to prevent further dissemination of HAV and other STIs.

Manifestação de sintomas sugestivos de ansiedade e depressão durante a pandemia de covid-19 e associações com a prática de atividades físicas e fatores sociodemográficos no estado do Rio de Janeiro, Brasil / Manifestation of symptoms suggestive of anxiety and depression during the covid-19 pandemy and associations with the practice of physical activities and socio-demographic factors in the state of Rio de Janeiro, Brazil / Manifestación de síntomas que sugeren ansiedad y depresión durante la pandemia covid-19 y asociaciones con la práctica de actividades físicas y factores socio demográficos en el estado de Río de Janeiro, Brasil

Objetivo: verificar a prevalência de fatores sociodemográficos e da prática de atividade física com sintomas sugestivos de ansiedade e depressão em adultos durante a pandemia de Covid-19 no estado do Rio de Janeiro. Métodos: estudo observacional, transversal, com 1.019 participantes adultos residentes no estado do Rio de Janeiro, Brasil, realizado através de uma amostragem bola de neve. Resultados: sintomas de ansiedade estavam associados ao sexo feminino, em adultas jovens, com o ato de limpar/arrumar a residência e à inatividade física. Os sintomas de depressão associaram-se ao sexo feminino, à divisão da casa com outras pessoas que não eram familiares, grau de escolaridade, renda e à inatividade física. Conclusão: fatores sociodemográficos e a inatividade física estão associados com os sintomas de ansiedade e depressão durante a pandemia da COVID-19 (AU).

Objective: To analyze the prevalence of sociodemographic factors and the practice of physical activity with symptoms suggestive of anxiety and depression in adults during the Covid-19 pandemic, in the state of Rio de Janeiro. Methods: Observational, cross-sectional study with 1,019 adult participants residing in the state of Rio de Janeiro, Brazil carried out through a snowball sampling technique. Results: Anxiety symptoms were associated with being female, being young adults, cleaning/tidying the house, and physical inactivity. Depression symptoms were associated with female gender, sharing the house with other people who were not family members, level of education, income and physical inactivity. Conclusion: Sociodemographic factors and physical inactivity are associated with symptoms of anxiety and depression during the COVID-19 pandemic (AU).

Objetivo: Analizar la asociación entre síntomas de ansiedad y depresión, durante la pandemia COVID-19, con la práctica de actividades físicas y factores sociodemográficos. Métodos: Estudio observacional, transversal con 1.019 participantes adultos residentes en el estado de Río de Janeiro, Brasil, realizado a través de un muestreo de bola de nieve. Resultados: Síntomas de ansiedad asociados con mujeres, adultos jóvenes, con el acto de limpiar / ordenar la casa e inactividad física. Los síntomas depresivos se asociaron con el género femenino, compartir la casa con otras personas que no eran familiares, nivel de educación, ingresos e inactividad física. Conclusión: Los factores sociodemográficos y la inactividad física se asocian con síntomas de ansiedad y depresión durante una pandemia de COVID-19 (AU).

Manifestação de sintomas sugestivos de ansiedade e depressão durante a pandemia de covid-19 e associações com a prática de atividades físicas e fatores sociodemográficos no estado do Rio de Janeiro, Brasil / Manifestation of symptoms suggestive of anxiety and depression during the covid-19 pandemy and associations with the practice of physical activities and socio-demographic factors in the state of Rio de Janeiro, Brazil / Manifestación de síntomas que sugeren ansiedad y depresión durante la pandemia covid-19 y asociaciones con la práctica de actividades físicas y factores socio demográficos en el estado de Río de Janeiro, Brasil

Objetivo: verificar a prevalência de fatores sociodemográficos e da prática de atividade física com sintomas sugestivos de ansiedade e depressão em adultos durante a pandemia de Covid-19 no estado do Rio de Janeiro. Métodos: estudo observacional, transversal, com 1.019 participantes adultos residentes no estado do Rio de Janeiro, Brasil, realizado através de uma amostragem bola de neve. Resultados: sintomas de ansiedade estavam associados ao sexo feminino, em adultas jovens, com o ato de limpar/arrumar a residência e à inatividade física. Os sintomas de depressão associaram-se ao sexo feminino, à divisão da casa com outras pessoas que não eram familiares, grau de escolaridade, renda e à inatividade física. Conclusão: fatores sociodemográficos e a inatividade física estão associados com os sintomas de ansiedade e depressão durante a pandemia da COVID-19.

Objective: To analyze the prevalence of sociodemographic factors and the practice of physical activity with symptoms suggestive of anxiety and depression in adults during the Covid-19 pandemic, in the state of Rio de Janeiro. Methods: Observational, cross-sectional study with 1,019 adult participants residing in the state of Rio de Janeiro, Brazil carried out through a snowball sampling technique. Results: Anxiety symptoms were associated with being female, being young adults, cleaning/tidying the house, and physical inactivity. Depression symptoms were associated with female gender, sharing the house with other people who were not family members, level of education, income and physical inactivity. Conclusion: Sociodemographic factors and physical inactivity are associated with symptoms of anxiety and depression during the COVID-19 pandemic.

Objetivo: Analizar la asociación entre síntomas de ansiedad y depresión, durante la pandemia COVID-19, con la práctica de actividades físicas y factores sociodemográficos. Métodos: Estudio observacional, transversal con 1.019 participantes adultos residentes en el estado de Río de Janeiro, Brasil, realizado a través de un muestreo de bola de nieve. Resultados: Síntomas de ansiedad asociados con mujeres, adultos jóvenes, con el acto de limpiar / ordenar la casa e inactividad física. Los síntomas depresivos se asociaron con el género femenino, compartir la casa con otras personas que no eran familiares, nivel de educación, ingresos e inactividad física. Conclusión: Los factores sociodemográficos y la inactividad física se asocian con síntomas de ansiedad y depresión durante una pandemia de COVID-19.

Fatores associados à prática de atividades físicas durante a pandemia da COVID-19 no estado do Rio de Janeiro, Brasil / Factors associated with physical activity during the COVID-19 pandemic in Rio de Janeiro, Brazil

A relação entre os determinantes sociais e a prática de atividade física em um período de distanciamento social ainda é desconhecida. O presente estudo teve como objetivo analisar os fatores associados à prática de atividade física durante o distanciamento social induzido pela pandemia da COVID-19. Foi realizado um estudo observacional do tipo transversal com indivíduos maiores de 18 anos. A coleta de dados foi realizada de 28 de abril a 11 de maio de 2020 por meio de um questionário eletrônico online. Participaram da pesquisa 1.138 indivíduos residentes do estado do Rio de Janeiro. A maior parte dos indivíduos eram do sexo feminino (63,1%), brancos (61,9%) e estavam na faixa etária de 18 a 39 anos (60,5%). A prática de atividades físicas foi relatada por 66,1% dos entrevistados. Foram analisadas, via modelos de regressão logístico e logístico ordinal variáveis sociodemográficas, participação em atividades físicas e a frequência desta prática. As variáveis associadas com a maior chance de praticar atividades físicas durante o distanciamento foram o sexo masculino, idade acima de 40 anos, maior escolaridade, não ser profissional de serviço essencial e não ter filhos. As chances de praticar atividades físicas com maior frequência também esteve associada ao sexo masculino, a idade acima de 40 anos, não ser profissional de serviço essencial e não ter filhos. Conclui-se que a prática de atividades físicas durante o período de distanciamento social está associada aos determinantes sociais. Assim, recomendamos que políticas de promoção de atividades físicas tenham um olhar prioritário para os grupos de maior vulnerabilidade

The relationship between social determinants and the practice of physical activity in a period of social distance is still unknown. The present study aimed to analyze the factors associated with the practice of physical activ-ity during the social distance induced by the pandemic of COVID-19. An observational cross-sectional study was conducted with individuals over 18 years of age. Data collection was carried out from April 28 to May 11, 2020 through an online electronic questionnaire. Participated in the research 1,138 individuals residing of the state of Rio de Janeiro. Most individuals were female (63.1%), white (61.9%) and were aged between 18 and 39 years (60.5%). The practice of physical activities was reported by 66.1% of respondents. Sociodemo-graphic variables, participation in physical activities and the frequency of this practice were analyzed using logistic regression and ordinal logistic models. Individuals who had a higher chance of practicing physical activity during the pandemic were greater chance of practicing physical activities during the distance were male, aged over 40 years, who had higher education, not being an essential service professional and not having children. The chances of practicing physical activities more frequently were also associated with men, being over 40 years old, not being an essential service professional and not having children. It is concluded that the practice of physical activities during the period of social distance is associated with social determinants. Therefore, we recommend that policies to promote physical activities prioritize the most vulnerable groups

Six hundred years of South American tree rings reveal an increase in severe hydroclimatic events since mid-20th century.

South American (SA) societies are highly vulnerable to droughts and pluvials, but lack of long-term climate observations severely limits our understanding of the global processes driving climatic variability in the region. The number and quality of SA climate-sensitive tree ring chronologies have significantly increased in recent decades, now providing a robust network of 286 records for characterizing hydroclimate variability since 1400 CE. We combine this network with a self-calibrated Palmer Drought Severity Index (scPDSI) dataset to derive the South American Drought Atlas (SADA) over the continent south of 12°S. The gridded annual reconstruction of austral summer scPDSI is the most spatially complete estimate of SA hydroclimate to date, and well matches past historical dry/wet events. Relating the SADA to the Australia-New Zealand Drought Atlas, sea surface temperatures and atmospheric pressure fields, we determine that the El Niño-Southern Oscillation (ENSO) and the Southern Annular Mode (SAM) are strongly associated with spatially extended droughts and pluvials over the SADA domain during the past several centuries. SADA also exhibits more extended severe droughts and extreme pluvials since the mid-20th century. Extensive droughts are consistent with the observed 20th-century trend toward positive SAM anomalies concomitant with the weakening of midlatitude Westerlies, while low-level moisture transport intensified by global warming has favored extreme rainfall across the subtropics. The SADA thus provides a long-term context for observed hydroclimatic changes and for 21st-century Intergovernmental Panel on Climate Change (IPCC) projections that suggest SA will experience more frequent/severe droughts and rainfall events as a consequence of increasing greenhouse gas emissions.

A nonlinear mixed-effects modeling approach for ecological data: Using temporal dynamics of vegetation moisture as an example.

Increasingly, often ecologist collects data with nonlinear trends, heterogeneous variances, temporal correlation, and hierarchical structure. Nonlinear mixed-effects models offer a flexible approach to such data, but the estimation and interpretation of these models present challenges, partly associated with the lack of worked examples in the ecological literature.We illustrate the nonlinear mixed-effects modeling approach using temporal dynamics of vegetation moisture with field data from northwestern Patagonia. This is a Mediterranean-type climate region where modeling temporal changes in live fuel moisture content are conceptually relevant (ecological theory) and have practical implications (fire management). We used this approach to answer whether moisture dynamics varies among functional groups and aridity conditions, and compared it with other simpler statistical models. The modeling process is set out "step-by-step": We start translating the ideas about the system dynamics to a statistical model, which is made increasingly complex in order to include different sources of variability and correlation structures. We provide guidelines and R scripts (including a new self-starting function) that make data analyses reproducible. We also explain how to extract the parameter estimates from the R output.Our modeling approach suggests moisture dynamic to vary between grasses and shrubs, and between grasses facing different aridity conditions. Compared to more classical models, the nonlinear mixed-effects model showed greater goodness of fit and met statistical assumptions. While the mixed-effects approach accounts for spatial nesting, temporal dependence, and variance heterogeneity; the nonlinear function allowed to model the seasonal pattern.Parameters of the nonlinear mixed-effects model reflected relevant ecological processes. From an applied perspective, the model could forecast the time when fuel moisture becomes critical to fire occurrence. Due to the lack of worked examples for nonlinear mixed-effects models in the literature, our modeling approach could be useful to diverse ecologists dealing with complex data.

Mutations in the MRPS28 gene encoding the small mitoribosomal subunit protein bS1m in a patient with intrauterine growth retardation, craniofacial dysmorphism and multisystemic involvement.

Mitochondria contain a dedicated translation system, which is responsible for the intramitochondrial synthesis of 13 mitochondrial DNA (mtDNA)-encoded polypeptides essential for the biogenesis of oxidative phosphorylation (OXPHOS) complexes I and III-V. Mutations in nuclear genes encoding factors involved in mitochondrial translation result in isolated or multiple OXPHOS deficiencies and mitochondrial disease. Here, we report the identification of disease-causing variants in the MRPS28 gene, encoding the small mitoribosomal subunit (mtSSU) protein bS1m in a patient with intrauterine growth retardation, craniofacial dysmorphism and developmental delay. Whole exome sequencing helped identify a seemingly homozygous missense variant NM_014018.2:c.356A>G, p.(Lys119Arg) which affected a highly conserved lysine residue. The variant was present in the mother in a heterozygous state, but not in the father who likely carried a large deletion spanning exon 2 and parts of introns 1 and 2 that could account for the apparent homozygosity of the patient. Polymerase chain reaction (PCR) amplification and Sanger sequencing of MRPS28 cDNA from patient fibroblasts revealed the presence of a truncated MRPS28 transcript, which lacked exon 2. Molecular and biochemical characterization of patient fibroblasts revealed a decrease in the abundance of the bS1m protein, decreased abundance of assembled mtSSU and inhibited mitochondrial translation. Consequently, OXPHOS biogenesis and cellular respiration were compromised in these cells. Expression of wild-type MRPS28 restored mitoribosomal assembly, mitochondrial translation and OXPHOS biogenesis, thereby demonstrating the deleterious nature of the identified MRPS28 variants. Thus, MRPS28 joins the increasing number of nuclear genes encoding mitoribosomal structural proteins linked to mitochondrial disease.

Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy.

BACKGROUND: Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin. METHODS: We used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica. RESULTS: We identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively. CONCLUSIONS: Biallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function.

Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency.

Mitochondrial complex I deficiency results in a plethora of often severe clinical phenotypes manifesting in early childhood. Here, we report on three complex-I-deficient adult subjects with relatively mild clinical symptoms, including isolated, progressive exercise-induced myalgia and exercise intolerance but with normal later development. Exome sequencing and targeted exome sequencing revealed compound-heterozygous mutations in TMEM126B, encoding a complex I assembly factor. Further biochemical analysis of subject fibroblasts revealed a severe complex I deficiency caused by defective assembly. Lentiviral complementation with the wild-type cDNA restored the complex I deficiency, demonstrating the pathogenic nature of these mutations. Further complexome analysis of one subject indicated that the complex I assembly defect occurred during assembly of its membrane module. Our results show that TMEM126B defects can lead to complex I deficiencies and, interestingly, that symptoms can occur only after exercise.