Micronutrients: Speculation on Inborn Errors, Nutrigenomics, Evolution, the Microbiome, and Nutritional Immunity

Many micronutrients or cofactors derived from micronutrients are highly reactive, hence their role in catalysis of reactions by enzymes. The concentration of cofactors has to be kept low to avoid unwanted reactions while allowing them to bind to the (apo)enzymes that need them. A new disorder causing B6-responsive epilepsy (proline synthetase cotranscribed bacterial homologue deficiency) is probably due to the absence of an important intracellular pyridoxal phosphate chaperone. The availability of some micronutrients varies by orders of magnitude in different geographical areas. Selenium is both essential and toxic, and during evolution, different populations have had to adapt to this differing availability. An “inborn error of metabolism (IEM)” in a low selenium area of China may be a selective advantage in a high selenium area and vice versa; the concept of nutrigenomics is an important one for micronutrients. The gut flora may make an important contribution to vitamin synthesis. This is difficult to study, but experiments can be undertaken with the nematode, Caenorhabditis elegans (with or without an IEM) and a single clone of Escherichia coli (with or without an IEM) as food and gut flora. This model shows that the gut microbiome can have profound influences on the folate cycle and associated vitamins. Our innate immune system makes use of the micronutrient requirements of pathogens and can deprive a pathogen of essential micronutrient(s) or expose it to toxic levels. It is not surprising, therefore, that some mutations affecting the way the host handles micronutrients can confer an advantage in resistance to infection and this may have acted as a selective advantage during evolution. This will be discussed by reference to the relationship of inborn errors to resistance to malaria. Conversely, other inborn errors of micronutrient metabolism are likely to make it more difficult for the host to use nutritional immunity to fight infection; this probably accounts for the list of infections that are more serious in patients with hereditary haemochromatosis

Cerebrospinal fluid neurofilament light levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment [version 1; peer review: 1 approved with reservations]

Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT

RARS2 mutations in a sibship with infantile spasms

Pontocerebellar hypoplasia is a group of heterogeneous neurodevelopmental disorders characterized by reduced volume of the brainstem and cerebellum. We report two male siblings who presented with early infantile clonic seizures, and then developed infantile spasms associated with prominent isolated cerebellar hypoplasia/atrophy on magnetic resonance imaging (MRI). Using whole exome sequencing techniques, both were found to be compound heterozygotes for one previously reported and one novel mutation in the gene encoding mitochondrial arginyl-tRNA synthetase 2 (RARS2). Mutations in this gene have been classically described in pontocerebellar hypoplasia type six (PCH6), a phenotype characterized by early (often intractable) seizures, profound developmental delay, and progressive pontocerebellar atrophy. The electroclinical spectrum of PCH6 is broad and includes a number of seizure types: myoclonic, generalized tonic-clonic, and focal clonic seizures. Our report expands the characterization of the PCH6 disease spectrum and presents infantile spasms as an associated electroclinical phenotype

SLC39A14 Deficiency

SLC39A14 deficiency is characterized by evidence between ages six months and three years of delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance). Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor. By the end of the first decade they develop severe, generalized, pharmaco-resistant dystonia, limb contractures, and scoliosis, and lose independent ambulation. Cognitive impairment appears to be less prominent than motor disability. Some affected children have succumbed in their first decade due to secondary complications such as respiratory infections.The diagnosis of SLC39A14 deficiency is established in a proband with progressive dystonia-parkinsonism (often combined with other signs such as spasticity and parkinsonian features), characteristic neuroimaging findings, hypermanganesemia, and biallelic pathogenic variants in SLC39A14 on molecular genetic testing.Treatment of manifestations: Symptomatic treatment includes physiotherapy and orthopedic management to prevent contractures and maintain ambulation; use of adaptive aids (walker or wheelchair) for gait abnormalities; and use of assistive communication devices. Support by a speech and language/feeding specialist and nutritionist to assure adequate nutrition and to reduce the risk of aspiration. When an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. Antispasticity medications (baclofen and botulinum toxin) and L-dopa have had limited success. While chelation therapy with intravenous administration of disodium calcium edetate early in the disease course shows promise, additional studies are warranted. Prevention of primary manifestations: Unknown, but disodium calcium edetate chelation therapy shows promise; additional studies are warranted. Surveillance: Routine monitoring of: Height and weight using age- and gender-appropriate growth charts; Swallowing and diet to assure adequate nutrition; Ambulation and speech; Whole-blood manganese levels and brain MRI to assess treatment response and disease progression. Agents/circumstances to avoid: Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations). High manganese content of total parenteral nutrition. Foods very high in manganese, including: cloves; saffron; nuts; mussels; dark chocolate; pumpkin, sesame, and sunflower seeds. Evaluation of relatives at risk: Molecular genetic testing for the familial SLC39A14 pathogenic variants of apparently asymptomatic younger sibs of an affected individual allows early identification of sibs who would benefit from prompt initiation of treatment and preventive measures.SLC39A14 deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC39A14 pathogenic variants have been identified in an affected family member, carrier testing of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible

Anthropogenic-scale CO2 degassing from the Central Atlantic Magmatic Province as a driver of the end-Triassic mass extinction

The climatic and environmental impact of exclusively volcanic CO2 emissions is assessed during the main effusive phase of the Central Atlantic Magmatic Province (CAMP), which is synchronous with the end-Triassic mass extinction. CAMP volcanism occurred in brief and intense eruptive pulses each producing extensive basaltic lava flows. Here, CAMP volcanic CO2 injections into the surface system are modelled using a biogeochemical box model for the carbon cycle. Our modelling shows that, even if positive feedback phenomena may be invoked to explain the carbon isotope excursions preserved in end-Triassic sedimentary records, intense and pulsed volcanic activity alone may have caused repeated temperature increases and pH drops, up to 5 °C and about 0.2 log units respectively. Hence, rapid and massive volcanic CO2 emissions from CAMP, on a similar scale to current anthropogenic emissions, severely impacted on climate and environment at a global scale, leading to catastrophic biotic consequences

An enormous sulfur isotope excursion indicates marine anoxia during the end-Triassic mass extinction

The role of ocean anoxia as a cause of the end-Triassic marine mass extinction is widely debated. Here, we present carbonate-associated sulfate δ³⁴S data from sections spanning the Late Triassic–Early Jurassic transition, which document synchronous large positive excursions on a global scale occurring in ~50 thousand years. Biogeochemical modeling demonstrates that this S isotope perturbation is best explained by a fivefold increase in global pyrite burial, consistent with large-scale development of marine anoxia on the Panthalassa margin and northwest European shelf. This pyrite burial event coincides with the loss of Triassic taxa seen in the studied sections. Modeling results also indicate that the pre-event ocean sulfate concentration was low (<1 millimolar), a common feature of many Phanerozoic deoxygenation events. We propose that sulfate scarcity preconditions oceans for the development of anoxia during rapid warming events by increasing the benthic methane flux and the resulting bottom-water oxygen demand

TRNT1 deficiency: clinical, biochemical and molecular genetic features

BACKGROUND: TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs). RESULTS: We investigated four patients from two families with infantile-onset cyclical, aseptic febrile episodes with vomiting and diarrhoea, global electrolyte imbalance during these episodes, sideroblastic anaemia, B lymphocyte immunodeficiency, retinitis pigmentosa, hepatosplenomegaly, exocrine pancreatic insufficiency and renal tubulopathy. Other clinical features found in children include sensorineural deafness, cerebellar atrophy, brittle hair, partial villous atrophy and nephrocalcinosis. Whole exome sequencing and bioinformatic filtering were utilised to identify recessive compound heterozygous TRNT1 mutations (missense mutation c.668T>C, p.Ile223Thr and a novel splice mutation c.342+5G>T) segregating with disease in the first family. The second family was found to have a homozygous TRNT1 mutation (c.569G>T), p.Arg190Ile, (previously published). We found normal mitochondrial translation products using passage matched controls and functional perturbation of 3' CCA addition to mitochondrial tRNAs (tRNA(Cys), tRNA(LeuUUR) and tRNA(His)) in fibroblasts from two patients, demonstrating a pathomechanism affecting the CCA addition to mt-tRNAs. Acute management of these patients included transfusion for anaemia, fluid and electrolyte replacement and immunoglobulin therapy. We also describe three-year follow-up findings after treatment by bone marrow transplantation in one patient, with resolution of fever and reversal of the abnormal metabolic profile. CONCLUSIONS: Our report highlights that TRNT1 mutations cause a spectrum of disease ranging from a childhood-onset complex disease with manifestations in most organs to an adult-onset isolated retinitis pigmentosa presentation. Systematic review of all TRNT1 cases and mutations reported to date revealed a distinctive phenotypic spectrum and metabolic and other investigative findings, which will facilitate rapid clinical recognition of future cases

Deep CO₂ in the end-Triassic Central Atlantic Magmatic Province

Large Igneous Province eruptions coincide with many major Phanerozoic mass extinctions, suggesting a cause-effect relationship where volcanic degassing triggers global climatic changes. In order to fully understand this relationship, it is necessary to constrain the quantity and type of degassed magmatic volatiles, and to determine the depth of their source and the timing of eruption. Here we present direct evidence of abundant CO2 in basaltic rocks from the end-Triassic Central Atlantic Magmatic Province (CAMP), through investigation of gas exsolution bubbles preserved by melt inclusions. Our results indicate abundance of CO2 and a mantle and/or lower-middle crustal origin for at least part of the degassed carbon. The presence of deep carbon is a key control on the emplacement mode of CAMP magmas, favouring rapid eruption pulses (a few centuries each). Our estimates suggest that the amount of CO2 that each CAMP magmatic pulse injected into the end-Triassic atmosphere is comparable to the amount of anthropogenic emissions projected for the 21st century. Such large volumes of volcanic CO2 likely contributed to end-Triassic global warming and ocean acidification

Iraq War mortality estimates: A systematic review

<p>Abstract</p> <p>Background</p> <p>In March 2003, the United States invaded Iraq. The subsequent number, rates, and causes of mortality in Iraq resulting from the war remain unclear, despite intense international attention. Understanding mortality estimates from modern warfare, where the majority of casualties are civilian, is of critical importance for public health and protection afforded under international humanitarian law. We aimed to review the studies, reports and counts on Iraqi deaths since the start of the war and assessed their methodological quality and results.</p> <p>Methods</p> <p>We performed a systematic search of 15 electronic databases from inception to January 2008. In addition, we conducted a non-structured search of 3 other databases, reviewed study reference lists and contacted subject matter experts. We included studies that provided estimates of Iraqi deaths based on primary research over a reported period of time since the invasion. We excluded studies that summarized mortality estimates and combined non-fatal injuries and also studies of specific sub-populations, e.g. under-5 mortality. We calculated crude and cause-specific mortality rates attributable to violence and average deaths per day for each study, where not already provided.</p> <p>Results</p> <p>Thirteen studies met the eligibility criteria. The studies used a wide range of methodologies, varying from sentinel-data collection to population-based surveys. Studies assessed as the highest quality, those using population-based methods, yielded the highest estimates. Average deaths per day ranged from 48 to 759. The cause-specific mortality rates attributable to violence ranged from 0.64 to 10.25 per 1,000 per year.</p> <p>Conclusion</p> <p>Our review indicates that, despite varying estimates, the mortality burden of the war and its sequelae on Iraq is large. The use of established epidemiological methods is rare. This review illustrates the pressing need to promote sound epidemiologic approaches to determining mortality estimates and to establish guidelines for policy-makers, the media and the public on how to interpret these estimates.</p

Middle Permian organic carbon isotope stratigraphy and the origin of the Kamura Event

Large carbon cycle perturbations associated with the Middle Permian (Capitanian) mass extinction have been widely reported, but their causes and timing are still in dispute. Low resolution carbon isotope records prior to this event also limit the construction of a Middle Permian chemostratigraphic framework and global or local stratigraphic correlation, and hence limit our understanding of carbon cycle and environmental changes. To investigate these issues, we analyzed the 13Corg values from the Middle Permian chert-mudstone sequence (Gufeng Formation) in the Lower Yangtze deep-water basin (South China) and compared them with published records to build a chemostratigraphic scheme and discuss the underlying environmental events. The records show increased δ13Corg values from late Kungurian to early Guadalupian, followed by a decrease to the late Wordian/early Capitanian. The early-mid Capitanian was characterized by elevated δ13Corg values suggesting the presence of the “Kamura Event”: an interval of heavy positive values seen in the δ13Ccarb record. We propose that these heavy Capitanian δ13C values may be a response to a marked decline in chemical weathering rates on Pangea and associated reduction in carbonate burial, which we show using a biogeochemical model. The subsequent negative δ13C excursion seen in some carbonate records, especially in shallower-water sections (and in a muted expression in organic carbon) coincide with the Capitanian mass extinction may be caused by the input of isotopically-light carbon sourced from the terrestrial decomposition of organic matter