Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course.

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The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP). We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life. Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts. The enzyme defect was confirmed by complementation analysis in yeast. This is the first report of patients with mitochondrial phosphate-carrier deficiency.

Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.

Volcanic ash layers preserved within the geologic record represent precise time markers that correlate disparate depositional environments and enable the investigation of synchronous and/or asynchronous behaviors in Earth system and archaeological sciences. However, it is generally assumed that only exceptionally powerful events, such as supereruptions (≥450 km 3 of ejecta as dense-rock equivalent; recurrence interval of ~10 5 yr), distribute ash broadly enough to have an impact on human society, or allow us to address geologic, climatic, and cultural questions on an intercontinental scale. Here we use geochemical, age, and morphological evidence to show that the Alaskan White River Ash (eastern lobe; A.D. 833-850) correlates to the "AD860B" ash (A.D. 846-848) found in Greenland and northern Europe. These occurrences represent the distribution of an ash over 7000 km, linking marine, terrestrial, and ice-core records. Our results indicate that tephra from more moderate-size eruptions, with recurrence intervals of ~100 yr, can have substantially greater distributions than previously thought, with direct implications for volcanic dispersal studies, correlation of widely distributed proxy records, and volcanic hazard assessment.

Ambitious climate policies, as well as economic development, education, technological progress and less resource-intensive lifestyles, are crucial elements for progress towards the UN Sustainable Development Goals (SDGs). However, using an integrated modelling framework covering 56 indicators or proxies across all 17 SDGs, we show that they are insufficient to reach the targets. An additional sustainable development package, including international climate finance, progressive redistribution of carbon pricing revenues, sufficient and healthy nutrition and improved access to modern energy, enables a more comprehensive sustainable development pathway. We quantify climate and SDG outcomes, showing that these interventions substantially boost progress towards many aspects of the UN Agenda 2030 and simultaneously facilitate reaching ambitious climate targets. Nonetheless, several important gaps remain; for example, with respect to the eradication of extreme poverty (180 million people remaining in 2030). These gaps can be closed by 2050 for many SDGs while also respecting the 1.5 °C target and several other planetary boundaries.

Our findings establish MFF loss of function as a cause of disturbed mitochondrial and peroxisomal dynamics associated with early-onset Leigh-like basal ganglia disease. We suggest that, even if laboratory findings are not indicative of mitochondrial or peroxisomal dysfunction, the co-occurrence of optic and/or peripheral neuropathy with seizures warrants genetic testing for MFF mutations.

Objective To determine the frequency and clinicalradiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. Methods Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG-and AQP4-antibodies using live cell-based assays.Results 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course ( p=0.018) after one year, (2) presented with simultaneous ON and LETM ( p=0.004) and (3) were less likely to receive immunosuppressive therapies ( p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions ( p=0.001), (5) more often were unspecific ( p=0.004) and (6) resolved more frequently ( p=0.016). Conclusions 67% of all children presenting with NMO or limited forms tested positive for MOG-or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.