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WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

Mitochondrial DNA (mtDNA) replication depends on the mitochondrial import of hundreds of nuclear encoded proteins that control the mitochondrial genome maintenance and integrity. Defects in these processes result in an expanding group of disorders called mtDNA maintenance defects that are characterized by mtDNA depletion and/or multiple mtDNA deletions with variable phenotypic manifestations. As it applies for mitochondrial disorders in general, current treatment options for mtDNA maintenance defects are limited. Lately, with the development of model organisms, improved understanding of the pathophysiology of these disorders, and a better knowledge of their natural history, the number of preclinical studies and existing and planned clinical trials has been increasing. In this review, we discuss recent preclinical studies and current and future clinical trials concerning potential therapeutic options for the different mtDNA maintenance defects.

Although vertebrate carcasses––particularly those assigned to fishes––are abundant in the fossil record, the literature rarely mentions fishes as trace producers. Herein we present evidence that was possibly overlooked in previous studies. Study of more than 100 large, shallow, teardrop-shaped, imprints that are aligned, with few overlapping each other, from early Paleozoic (probably Silurian based on trace fossils) outcrops in western Gondwana (southeastern Argentina), are identified as the oldest example of shoaling behavior. To understand the nature of the behavior, we considered analog (vertebrate and invertebrate) extant and extinct taxa. We compare and discuss the superficial similarities with certain traces, in particular Selenichnites isp. and erect a new ichnotaxon, Raederichnus dondasi isp. nov. for the Argentinian material. We report for the first time from the Balcarce Formation Psammichnites isp., in association with Herradurichnus scagliai, both forming minor components of the ichnoassemblage. Raederichnus dondasi and the accompanying traces are preserved in three-dimensional dunes, developed in a tide-dominated shallow marine environment. Given the morphological resemblance, and paleoecological context, we consider that Raederichnus dondasi might have been produced by fish while “resting”. Finally, this aggregation of trace fossils suggests shoaling related to feeding or breeding on the shallow marine bottom surface.

BackgroundCystinosis is a metabolic disease characterized by the accumulation of cystine most often presenting in an infantile nephropathic form caused by pathogenic variants in theCTNSgene. It is characterized by progressive loss of glomerular function leading to renal failure by the first decade of life, making early diagnosis crucial to improving outcomes. This study seeks to estimate the prevalence of cystinosis using a population genetics approach.MethodsThe Human Genome Mutation Database (HGMD) was used to identify known pathogenic variants inCTNS, and the 1000 Genomes (1KG) database was used to identifyCTNSvariants in a cohort representing a healthy population. These two databases were intersected to identify disease-causing variants and their carriers in the general population. The Hardy-Weinberg equilibrium was used to calculate expected carrier and affected rates for cystinosis.ResultsThe allele frequency for all disease-causing alleles was calculated to be 0.016. The predicted affected rate was calculated to be 0.00027 (approximately 1:3680), and the predicted carrier rate was 0.032 (approximately 1:30).ConclusionCompared to the reported clinical prevalence of between 1 in 100,000 to 1 in 200,000, the prevalence of cystinosis in this study was calculated to be 1 in 3,680. This significantly higher result may be due to the underdiagnosis of cystinosis or variable expressivity of variants presenting with a broad range of disease severity. These results support the proposal of newborn screening for early diagnosis and improved outcomes in infantile nephropathic cystinosis.

Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD; MIM #616084) is an autosomal recessive disorder of mitochondrial and cytosolic tRNA processing caused by pathogenic, biallelic variants in TRNT1. Other features of this disorder include central nervous system, renal, cardiac, ophthalmological features, and sensorineural hearing impairment. SIFD was first described in 2013 and to date, it has been reported in 46 patients. Herein, we review the literature and describe two siblings with SIFD and note the novel phenotype of hypoglycemia in the context of growth hormone (GH) deficiency. GH deficiency without hypoglycemia has previously been reported in three patients with SIFD, but GH deficiency had not been firmly ascribed to SIFD. We propose to expand the phenotype to include GH deficiency, hypoglycemia, and previously unreported dysmorphic features. Furthermore, we highlight the intrafamilial variability of the disease by the discordance of our patients' clinical phenotypes and biochemical profiles measured by untargeted metabolomics analysis. Several metabolomic abnormalities were observed in both patients, and these may represent a potential biochemical signature for SIFD.

Congenital disorders of glycosylation are a group of rare monogenic inborn errors of metabolism caused by defective glycoprotein and glycolipid glycan synthesis and attachment. Here, we present a patient with galactose epimerase deficiency, also known as GALE deficiency, accompanied by pancytopenia and immune dysregulation. She was first identified by an abnormal newborn screen for galactosemia with subsequent genetic evaluation due to pancytopenia and immune dysregulation. The evaluation ultimately revealed that her known diagnosis of GALE deficiency was the cause of her hematologic and immune abnormalities. These findings further expand the clinical spectrum of disease of congenital disorders of glycosylation.

TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delays, seizures, intermittent ataxia, hypothyroidism and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.Data were collected from an ongoing natural history study of TDD patients enrolled between February 2019 - May 2022. Data were obtained through phone-based parent interviews and medical record review.Data were collected from 73 patients (56% male) from 57 unrelated families in 17 different countries. The median age of participants at time of data collection was 9.0 years (IQR 5.3-15.9 years, range fetal - 31 years). A total of 24 different TANGO2 alleles were observed. Patients demonstrated normal development in early infancy with progressive delays in developmental milestones thereafter. Symptoms including ataxia, dystonia and speech difficulties typically starting between the ages of 1-3 years. A total of 48 (66%) patients suffered metabolic crises and, of these, 29/48 (73%) developed cardiac crises. Metabolic crises were significantly decreased after initiation of B-complex or multivitamins.We provide the most comprehensive review of natural history of TDD and provide important observational data suggesting B-complex or multivitamins may prevent metabolic crises.

Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by pathogenic biallelic variants in the ETHE1 gene. The phenotype of this disease has been attributed to deficiency in the mitochondrial sulfur dioxygenase leading to many downstream effects. Ethylmalonic encephalopathy classically presents with developmental regression, petechiae, acrocyanosis, and chronic diarrhea. The neurologic phenotype includes hypotonia, spastic diplegia, ataxia, and developmental delay. As more patients with this condition are described, the neurologic phenotype continues to expand. Although strokelike episodes or metabolic strokes have been studied in other mitochondrial disorders, they have not been thoroughly reported in this disorder. Herein, we describe 3 patients with ethylmalonic encephalopathy who presented clinically with strokelike episodes and strokelike abnormalities on brain magnetic resonance imaging in the setting of acute illness, and the long-term sequelae with evolution into cystic changes in one of these subjects.

OBJECTIVE: To harmonize terminology in mitochondrial medicine, we propose revised clinical criteria for primary mitochondrial syndromes. METHODS: The North American Mitochondrial Disease Consortium (NAMDC) established a Diagnostic Criteria Committee comprised of members with diverse expertise. It included clinicians, researchers, diagnostic laboratory directors, statisticians, and data managers. The Committee conducted a comprehensive literature review, an evaluation of current clinical practices and diagnostic modalities, surveys, and teleconferences to reach consensus on syndrome definitions for mitochondrial diseases. The criteria were refined after manual application to patients enrolled in the NAMDC Registry. RESULTS: By building upon published diagnostic criteria and integrating recent advances, NAMDC has generated updated consensus criteria for the clinical definition of classical mitochondrial syndromes. CONCLUSIONS: Mitochondrial diseases are clinically, biochemically, and genetically heterogeneous and therefore challenging to classify and diagnose. To harmonize terminology, we propose revised criteria for the clinical definition of mitochondrial disorders. These criteria are expected to standardize the diagnosis and categorization of mitochondrial diseases, which will facilitate future natural history studies and clinical trials.

The NAD(P)HX repair system is a metabolite damage repair mechanism responsible for restoration of NADH and NADPH after their inactivation by hydration. Deficiency in either of its two enzymes, NAD(P)HX dehydratase (NAXD) or NAD(P)HX epimerase (NAXE), causes a fatal neurometabolic disorder characterized by decompensations precipitated by inflammatory stress. Clinical findings include rapidly progressive muscle weakness, ataxia, ophthalmoplegia, and motor and cognitive regression, while neuroimaging abnormalities are subtle or nonspecific, making a clinical diagnosis challenging. During stress, nonenzymatic conversion of NAD(P)H to NAD(P)HX increases, and in the absence of repair, NAD(P)H is depleted, and NAD(P)HX accumulates, leading to decompensation; however, the contribution of each to the metabolic derangement is not established. Herein, we summarize the clinical knowledge of NAXE deficiency from 30 cases and lessons learned about disease pathogenesis from cell cultures and model organisms and describe a metabolomics signature obtained by untargeted metabolomics analysis in one case at the time of crisis and after initiation of treatment. Overall, biochemical findings support a model of acute depletion of NAD(+), signs of mitochondrial dysfunction, and altered lipidomics. These findings are further substantiated by untargeted metabolomics six months post-crisis showing that niacin supplementation reverses primary metabolomic abnormalities concurrent with improved clinical status.

Riboflavin transporter deficiency (RTD) (MIM #614707) is a neurogenetic disorder with its most common manifestations including sensorineural hearing loss, peripheral neuropathy, respiratory insufficiency, and bulbar palsy. Here, we present a 2-year-old boy whose initial presentation was severe macrocytic anemia necessitating multiple blood transfusions and intermittent neutropenia; he subsequently developed ataxia and dysarthria. Trio-exome sequencing detected compound heterozygous variants in SLC52A2 that were classified as pathogenic and a variant of uncertain significance. Bone marrow evaluation demonstrated megaloblastic changes. Notably, his anemia and neutropenia resolved after treatment with oral riboflavin, thus expanding the clinical phenotype of this disorder. We reiterate the importance of starting riboflavin supplementation in a young child who presents with macrocytic anemia and neurological features while awaiting biochemical and genetic work up. We detected multiple biochemical abnormalities with the help of untargeted metabolomics analysis associated with abnormal flavin adenine nucleotide function which normalized after treatment, emphasizing the reversible pathomechanisms involved in this disorder. The utility of untargeted metabolomics analysis to monitor the effects of riboflavin supplementation in RTD has not been previously reported.

Mitochondrial disorders comprise a molecular and clinically diverse group of diseases that are associated with mitochondrial dysfunction leading to multi-organ disease. With recent advances in molecular technologies, the understanding of the pathomechanisms of a growing list of mitochondrial disorders has been greatly expanded. However, the therapeutic approaches for mitochondrial disorders have lagged behind with treatment options limited mainly to symptom specific therapies and supportive measures. There is an increasing number of clinical trials in mitochondrial disorders aiming for more specific and effective therapies. This review will cover different treatment modalities currently used in mitochondrial disorders, focusing on recent and ongoing clinical trials.

We studied galactose supplementation in SLC35A2-congenital disorder of glycosylation (SLC35A2-CDG), caused by monoallelic pathogenic variants in SLC35A2 (Xp11.23), encoding the endoplasmic reticulum (ER) and Golgi UDP-galactose transporter. Patients present with epileptic encephalopathy, developmental disability, growth deficiency, and dysmorphism. Ten patients with SLC35A2-CDG were supplemented with oral D-galactose for 18 weeks in escalating doses up to 1.5 g/kg/day. Outcome was assessed using the Nijmegen Pediatric CDG Rating Scale (NPCRS, ten patients) and by glycomics (eight patients). SLC35A2-CDG patients demonstrated improvements in overall Nijmegen Pediatric CDG Rating Scale (NPCRS) score (P = 0.008), the current clinical assessment (P = 0.007), and the system specific involvement (P = 0.042) domains. Improvements were primarily in growth and development with five patients resuming developmental progress, which included postural control, response to stimuli, and chewing and swallowing amelioration. Additionally, there were improvements in gastrointestinal symptoms and epilepsy. One patient in our study did not show any clinical improvement. Galactose supplementation improved patients’ glycosylation with decreased ratios of incompletely formed to fully formed glycans (M-gal/disialo, P = 0.012 and monosialo/disialo, P = 0.017) and increased levels of a fully galactosylated N-glycan (P = 0.05). Oral D-galactose supplementation results in clinical and biochemical improvement in SLC35A2-CDG. Galactose supplementation may partially overcome the Golgi UDP-galactose deficiency and improves galactosylation. Oral galactose is well tolerated and shows promise as dietary therapy.

We report two Hong Kong children with severe generalized epidermolysis bullosa simplex (EBS), the most severe form of EBS, without a family history of EBS. EBS is a rare genodermatosis usually inherited in an autosomal dominant fashion although rare autosomal recessive cases have been reported. Genetic studies in these patients showed that the first case was due to a novel de novo heterozygous variant, c.377T>G (NM_000526.5 (c.377T>G, p.Leu126Arg)) in the KRT14 gene and the second case was due to a rare de novo heterozygous variant c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser) in the KRT5 gene. To our knowledge, the c.377T>G variant in the KRT14 gene has not been previously reported, and the c.527A>G variant in the KRT5 gene is a rare cause of severe generalized EBS. In severe generalized EBS, infants exhibit severe symptoms at the onset; however, they tend to improve with time. A precise genetic diagnosis in these two cases aided in counseling the families concerning the prognosis in their affected children and the recurrence risk for future pregnancies.

ObjectiveTo investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.MethodsIn cohorts of 8–13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).ResultsNo differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, p = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, p = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, p = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, p = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.ConclusionsOmaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.Clinicaltrials.gov identifierNCT02255422.Classification of evidenceThis study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.

Purpose: The study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and to determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied through an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 48 (likely) pathogenic TRMU variants, of which, 18 were novel. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals, 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. Conclusion: In most patients, TRMU-associated ALF is a transient, reversible disease and cysteine supplementation improved survival. © 2022 The Authors, DMB-1805- 0002; 01GM1207; MR/S005021/1; G0800674; National Institutes of Health, NIH: 5U54-NS078059-11, 5U54-NS115198-02; Wellcome Trust, WT: 203105/Z/16/Z; PTC Therapeutics, PTC; Manchester Biomedical Research Centre, BRC; Medical Research Council, MRC: MR/W019027/1; Pathological Society of Great Britain and Ireland; National Health and Medical Research Council, NHMRC: GNT1155244, GNT1164479; Bundesministerium für Bildung und Forschung, BMBF: 01GM1906B, 01KU2016A; Newcastle upon Tyne Hospitals NHS Foundation Trust; State Government of Victoria; Astellas Pharma; Bundesministerium für Bildung und Frauen, BMBF; Medizinische Universität Innsbruck, MUI; King Salman Center for Disability Research, KSCDR: RG-2022-010; Lily Foundation, The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children’s HospitalFoundation The Royal Children's Hospital Foundation . We are grateful to the Crane, Perkins, and Miller families for their generous financial support. We thank the Kinghorn Centre for Clinical Genomics for assistance with production and processing of genome sequencing data. This project was supported by the funding from MitoCanada ( https://mitocanada.org ) as part of the Mitochondrial Functional and Integrative Next Generation Diagnostics (MITO-FIND) study. This work was supported by the European Reference Network for Hereditary Metabolic Disorders (MetabERN). S.W. received funding from ERAPERMED2019-310 Personalized Mitochondrial Medicine (PerMiM): Optimizing diagnostics and treatment for patients with mitochondrial diseases FWF 4704-B. F.S.A. is funded by the National Institutes of Health along with the North American Mitochondrial Disease Consortia (5U54-NS078059-11), the Frontiers of Congenital Disorders of Glycosylation Consortia (FCDGC, 5U54-NS115198-02), Mervar Foundation, Courage for a Cure Foundation , PTC Therapeutics , Astellas Pharma Inc, and Saol Therapeutics. R.M. and R.W.T. are funded by the Wellcome Trust Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (United Kingdom) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation , the UK NIHR Biomedical Research Centre for Ageing and Age-related Disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust , and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. R.W.T. also receives funding from the Pathological Society of Great Britain and Ireland. J.C. is supported by a New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant. We acknowledge funding from the National Health and Medical Research Council ( NHMRC ): project grant GNT1164479 (D.R.T.) and Principal Research Fellowship GNT1155244 (D.R.T.). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support program. This study was supported by BMBF (German Federal Ministry of Education and Research ) through the German Network for Mitochondrial Diseases ([mitoNET] grant number 01GM1906B), Personalized Mitochondrial Medicine (PerMiM) (grant number 01KU2016A), and E-Rare project GENOMIT (grant number 01GM1207) and the Bavarian State Ministry of Health and Care within its framework of DigiMed Bayern (grant number DMB-1805- 0002). The authors extend their appreciation to the King Salman Center For Disability Research for funding this work through research group number RG-2022-010 (to F.S.A.), The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children's HospitalFoundationThe Royal Children's Hospital Foundation. We are grateful to the Crane, Perkins, and Miller families for their generous financial support. We thank the Kinghorn Centre for Clinical Genomics for assistance with production and processing of genome sequencing data. This project was supported by the funding from MitoCanada (https://mitocanada.org) as part of the Mitochondrial Functional and Integrative Next Generation Diagnostics (MITO-FIND) study. This work was supported by the European Reference Network for Hereditary Metabolic Disorders (MetabERN). S.W. received funding from ERAPERMED2019-310 Personalized Mitochondrial Medicine (PerMiM): Optimizing diagnostics and treatment for patients with mitochondrial diseases FWF 4704-B. F.S.A. is funded by the National Institutes of Health along with the North American Mitochondrial Disease Consortia (5U54-NS078059-11), the Frontiers of Congenital Disorders of Glycosylation Consortia (FCDGC, 5U54-NS115198-02), Mervar Foundation, Courage for a CureFoundation, PTC Therapeutics, Astellas Pharma Inc, and Saol Therapeutics. R.M. and R.W.T. are funded by the Wellcome Trust Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (United Kingdom) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the LilyFoundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related Disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. R.W.T. also receives funding from the Pathological Society of Great Britain and Ireland. J.C. is supported by a New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant. We acknowledge funding from the National Health and Medical Research Council (NHMRC): project grant GNT1164479 (D.R.T.) and Principal Research Fellowship GNT1155244 (D.R.T.). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support program. This study was supported by BMBF (German Federal Ministry of Education and Research) through the German Network for Mitochondrial Diseases ([mitoNET] grant number 01GM1906B), Personalized Mitochondrial Medicine (PerMiM) (grant number 01KU2016A), and E-Rare project GENOMIT (grant number 01GM1207) and the Bavarian State Ministry of Health and Care within its framework of DigiMed Bayern (grant number DMB-1805- 0002). The authors extend their appreciation to the King Salman Center For Disability Research for funding this work through research group number RG-2022-010 (to F.S.A.), Conceptualization: G.F.V. S.W.; Data Curation: G.F.V. S.W. Y.M.-G. Y.E.L. R.G.F. J.A.M. H.B. L.D.S. H.Pr. A.Pec. F.S.A. J.J.B. G.B. I.B. N.B. B.B. J.C. E.C. D.C. A.M.D. N.D. A.D.M. F.D. E.A.E. M.E. W.F. P.G. R.D.G. E.G. C.H. J.H. V.K. M.Ko. M.Ke. A.K. D.L. R.M. M.G.M. K.Mo. T.M. K.Mu. E.N. A.Pen. H.Pe. D.P.-A. A.R. R.S. F.S. M.Sc. M.Shag. M.Shar. C.S.-A. C.S. I.S. M.St. R.W.T. D.R.T. E.L.T. J.-S.W. D.W.; Methodology: G.F.V. S.W. R.G.F. J.A.M.; Visualization: G.F.V. S.W. H.B. J.S.; Writing-original draft: G.F.V. S.W.; Writing-review and editing: G.F.V. S.W. Y.M.-G. Y.E.L. R.G.F. J.A.M. H.B. L.D.S. H.Pr. A.Pec. F.S.A. J.J.B. G.B. I.B. N.B. B.B. J.C. E.C. D.C. A.M.D. N.D. A.D.M. F.D. E.A.E. M.E. W.F. P.G. R.D.G. E.G. C.H. J.H. V.K. M.Ko. M.Ke. A.K. D.L. R.M. M.G.M. K.Mo. T.M. K.Mu. E.N. A.Pen. H.Pe. D.P.-A. A.R. R.S. F.S. M.Sc. M.Shag. M.Shar. C.S.-A. C.S. I.S. M.St. R.W.T. D.R.T. E.L.T. J.-S.W. D.W. This study was conducted in accordance with the guidelines of the Institutional Review Board of the Medical University of Innsbruck and the 1975 Declaration of Helsinki.29 Participants gave written informed consent for genetic investigations according to local regulations.

Preeclampsia, characterized by the onset of hypertension with significant proteinuria after 20 weeks’ gestation, is one of the leading causes of maternal and perinatal morbidity and mortality. Prophylactic low-dose aspirin treatment reduces the rate of preterm preeclampsia in high-risk women, but a significant proportion still develops preeclampsia. The mechanism of the prophylactic response is unknown. Here, the untargeted metabolomics analysis of 144 plasma samples from high-risk pregnant women before (11–13 weeks) and after (20–23 weeks) aspirin/placebo treatment elucidated metabolic effects of aspirin and metabolic differences potentially associated with the variation of the treatment response. We demonstrated that aspirin treatment resulted in a strong drug-associated metabolomics signature and that the preeclamptic or nonpreeclamptic outcome in response to treatment was significantly associated with the level of internal aspirin exposure ascertained from metabolomics data ( t test, P =0.0083). Comparing women with and without preeclampsia after aspirin treatment, differences in 73 metabolites were detected, some of which involve pathways whose regulation is of importance in pregnancy and placental functions, such as glycerophospholipids metabolism, polyunsaturated fatty acid metabolism, and steroid hormone biosynthesis. To further examine the hypothesis that aspirin delays gestational age advancement and thus the onset of preeclampsia, we constructed a metabolic clock on pretreatment and placebo-treated samples that estimated gestational age with high accuracy and found that aspirin significantly decelerated metabolic gestational age by 1.27 weeks (95% CI, 0.66–1.88 weeks), and partially reversed one-fourth of the metabolites changed over gestational age advancement, suggesting that aspirin treatment slowed down the metabolic clock of gestation.

Purpose: Untargeted metabolomic analysis is increasingly being used in the screening and management of individuals with inborn errors of metabolism (IEM). We aimed to test whether untargeted metabolomic analysis in plasma might be useful for monitoring the disease course and management of urea cycle disorders (UCDs). Methods: Untargeted mass spectrometry-based metabolomic analysis was used to generate z-scores for more than 900 metabolites in plasma from 48 individuals with various UCDs. Pathway analysis was used to identify common pathways that were perturbed in each UCD. Results: Our metabolomic analysis in plasma identified multiple potentially neurotoxic metabolites of arginine in arginase deficiency and, thus, may have utility in monitoring the efficacy of treatment in arginase deficiency. In addition, we were also able to detect multiple biochemical perturbations in all UCDs that likely reflect clinical management, including metabolite alterations secondary to dietary and medication management. Conclusions: In addition to utility in screening for IEM, our results suggest that untargeted metabolomic analysis in plasma may be beneficial for monitoring efficacy of clinical management and off-target effects of medications in UCDs and potentially other IEM.

Autosomal recessive COX4I1 deficiency has been previously reported in a single individual with a homozygous pathogenic variant in COX4I1, who presented with short stature, poor weight gain, dysmorphic features, and features of Fanconi anemia. COX4I1 encodes subunit 4, isoform 1 of cytochrome c oxidase. Cytochrome c oxidase is a respiratory chain enzyme that plays an important role in mitochondrial electron transport and reduces molecular oxygen to water leading to the formation of ATP. Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome. Here, we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh-syndrome, and a novel homozygous variant on COX4I1, expanding the known clinical phenotype associated with pathogenic variants in COX4I1.

TRMU is a nuclear gene crucial for mitochondrial DNA translation by encoding tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, which thiolates mitochondrial tRNA. Biallelic pathogenic variants in TRMU are associated with transient infantile liver failure. Other less common presentations such as Leigh syndrome, myopathy, and cardiomyopathy have been reported. Recent studies suggested that provision of exogenous L-cysteine or N-acetylcysteine may ameliorate the effects of disease-causing variants and improve the natural history of the disease. Here, we report six infants with biallelic TRMU variants, including four previously unpublished patients, all treated with exogenous cysteine. We highlight the first report of an affected patient undergoing orthotopic liver transplantation, the long-term effects of cysteine supplementation, and the ability of the initial presentation to mimic multiple inborn errors of metabolism. We propose that TRMU deficiency should be suspected in all children presenting with persistent lactic acidosis and hypoglycemia, and that combined N-acetylcysteine and L-cysteine supplementation should be considered prior to molecular diagnosis, as this is a low-risk approach that may increase survival and mitigate the severity of the disease course.

International audience; The Pavas Block is an Archean/Paleoproterozoic inlier located in the central segment of Uruguay's Precambrian exposition. A new insight initiated due to the acquisition of airborne geophysical data and new U–Pb zircon dating. The correlation of Archean crustal inliers in the amalgamation of the South American Platform is one of the main objectives in the Precambrian geological investigation. Although Ediacaran lateral strike-slip shear zones controlled the Pavas Block, their ultimate boundaries are not clear. Furthermore, a pre-Neoproterozoic metasedimentary succession discordant on this block is often confused with Neoproterozoic ones. Correctly identifying these limits is a necessary task to modify wrong tectono-stratigraphic models. The airborne total count radiometric imaging and the horizontal derivative of the total magnetic field anomaly reduced to the pole at 1000 m elevation led to establishing the Pavas Block's dimensions, based on new structural interpretation. The filtered magnetic anomaly is concordant with the previous Bouguer anomaly indicating a westward virgation of the Pavas Block in the north. This inlier narrows through the Minas city and along the Sarandí del Yí shear zone. The Sierra de Sosa and Sierra Ballena shear zones were confirmed as lateral limits. The total count radiometric map highlights the presence of brittle-fault reactivation. The Archean La China Complex containing zircons from three periods (∼3.3–3.1 Ga; 3.0; 2.8–2.7 Ga) is in the Pavas Block's centre. New U–Pb zircon geochronology provided six samples from different metagranitoids that yielded LA-ICPMS U–Pb zircon ages ranging between 3353 ± 9 Ma and 1839 ± 2 Ma. Its southern periphery shows more recent Archean and Orosirian metagranitoids. These rocks were later partially affected by Neoproterozoic deformation. The preservation of igneous textures, field relationships, and zircon textures suggested that younger Neoarchean intrusive granitoids emplaced within the basal granitic gneiss “La China” complex. The pre-Neoproterozoic metasedimentary cover intercalates with Neoproterozoic successions until the southern end of the Pavas Block against the Sarandí del Yí Shear Zone. Finally, one granitoid devoid of Archean inherited zircons yielded a concordant 207Pb/206Pb zircon age of 1999 ± 3 Ma (MSWD = 8.1) interpreted as magmatic crystallisation. This Orosirian K-feldspar granite is likely to set the southern border of the block in a transitional crust. The Pavas Block is limited from the Villa Serrana Block by a schist belt of Mesoproterozoic protoliths, and reports enough information to be interpreted as a suspect terrane.

International audience; La Provincia Magmática Paraná-Etendeka (Cretácico inferior, Peate, 1997), está representada en Uruguay por términos efusivos (basalto-andesitas) comprendidos bajo la Formación Arapey (Bossi 1966) y por términos intrusivos asociados (originalmente asignados a la Formación Cuaró; Preciozzi et al., 1985), ambos de carácter básico, subalcalinos y con improntas geoquímicas de tipo Gramado (Muzio et al., 2017). Los intrusivos (diques y sills) afloran en la porción centro-noreste de Uruguay, abarcando los Departamentos de Durazno, Tacuarembó y Cerro Largo (Masquelin et al., 2009). El área de estudio se encuentra dentro del Departamento de Cerro Largo y limíta con Brasil hacia el este; coordenadas 32°17’01’’S-32°26’43’’S y 54°10’34’’-53°38’58’’O. En general, los diques expuestos al oeste de la Ciudad de Melo (Capital Departamental de Cerro Largo), poseen orientaciones predominantes N290° a E-W y longitudes que pueden alcanzar hasta 100km de manera discontinua (Masquelin et al., 2009). Los cuerpos intrusivos Mesozoicos (Fm. Cuaró) sólo habían sido relevados en la Cuenca Norte (de Santa Ana et al., 2006), y no al este de la Ciudad de Melo donde se encuentra expuesto el basamento cristalino (Cinturón Orogénico Dom Feliciano; Fragoso César, 1980) y por ende no han sido cartografiados anteriormente a este trabajo. En el presente estudio fue reprocesada la Magnetometría de la Hoja 38 Melo (escala 1:100.000) obtenida por la Dirección Nacional de Minería y Geología utilizando el software Oasis Montaj 8.3.3. Los datos magnetométricos fueron reducidos al polo (RTP), por lo que las anomalías resultantes estarían sobre los cuerpos causantes; siendo una imagen de mayor confianza para la cartografía de los cuerpos ígneos básicos. El análisis e interpretación de los datos magnetométricos, en conjunto con los de su derivada segunda, permitió identificar al menos dos diques principales (denominados A y B), con valores de intensidad del campo magnético de entre 95 a 120nT, cuyas orientaciones varían entre N100° en la porción oeste del área de estudio y luego se flexionan hacia el noreste en la porción este del área, alcanzado direcciones de N65°-70° para el dique A , y N80° para el dique B. Ambos diques presentan longitudes de hasta 50km, incluso con bifurcaciones como es el caso del Dique B. Si bien los diques afloran de forma discontinua pueden ser visualizados y reconocidos fácilmente mediante imágenes satelitales en solapamiento con las imágenes geofísicas procesadas. Las características geométricas de estos cuerpos son típicas de emplazamientos magmáticos siguiendo estructuras pre-existentes del basamento cristalino, en dos direcciones conjugadas, SW-NE y N-S, observándose en algunos sectores un cambio brusco, por ejemplo dirección N50°E. Los diques Mesozoicos continuarían en el subsuelo del territorio brasileño (Estado del Rio Grande del Sur), con dirección noreste. Por ende, se deja plasmado en el presente trabajo el primer relevamiento cartográfico en detalle de los diques Mesozoicos al este de la Ciudad de Melo.

Glutaric acidemia type 2 (GA2), also called multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4–C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin-containing dehydrogenases to Coenzyme Q(10) (CoQ(10)) of the mitochondrial electron transport chain (ETC). We report a patient who was originally reported as the first case with primary myopathic CoQ(10) deficiency when he presented at 11.5 years with exercise intolerance and myopathy that improved after treatment with ubiquinone and carnitine. At age 23, his symptoms relapsed despite increasing doses of ubiquinone and he was shown to have biallelic mutations in the ETFDH gene. Treatment with riboflavin was started and ubiquinone was changed to ubiquinol. After 4 months, the patient recovered his muscle strength with normalization of laboratory exams and exercise tolerance. Functional studies on fibroblasts revealed decreased levels of ETFDH as well as of very long-chain acyl-CoA dehydrogenase and trifunctional protein α. In addition, the mitochondrial mass was decreased, with increased formation of reactive oxygen species and oxygen consumption rate, but with a decreased spared respiratory capacity, and decreased adenosine triphosphate level. These findings of widespread dysfunction of fatty acid oxidation and ETC enzymes support the impairment of a larger mitochondrial ETC supercomplex in our patient.