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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.

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.

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.

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.