Search

Abstract Background RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE). Case presentation Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identified two variants in RARS2, c.36 + 1G > T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T > G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites. Conclusions Our work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.

Genetic variability persists across diverse populations, and it may impact the characterization of heritable diseases in different ancestral groups. Cystinosis is a metabolic disease caused by pathogenic variants in the CTNS gene causing the cellular accumulation of cystine. We attempted to assess the currently poorly characterized prevalence of cystinosis by employing a population genetics methodology. However, we encountered a significant challenge due to genetic variations across different populations, and the consideration of potential disparities in access to healthcare made our results inconclusive. Pathogenic CTNS variants were identified in a representative global population cohort using The Human Gene Mutation Database (HGMD) and the 1000 Genomes (1 KG) database. The c.124G>A (p.Val42Ile) variant was reported to be pathogenic based on an observation in the white population presenting with atypical phenotypes, but it would be reclassified as benign in the African ancestral group if applying the ACMG allele frequency guideline due to its high allele frequency specifically in this population. Inclusion or exclusion of this c.124G>A (p.Val42Ile) variant results in a significant change in estimated disease prevalence, which can impact the diagnosis and treatment of affected patients with a broad range of phenotypic presentations. This observation led us to postulate that pathogenic manifestations of the disease may be underdiagnosed due to variable expressivity and systemic inequities in access to care, specifically in the African subpopulation. We call for a more cautious and inclusive approach to achieve more equitable care across diverse populations.

Abstract Background Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.

Abstract Primary mitochondrial diseases (PMD) are genetic disorders with extensive clinical and molecular heterogeneity where therapeutic development efforts have faced multiple challenges. Clinical trial design, outcome measure selection, lack of reliable biomarkers, and deficiencies in long‐term natural history data sets remain substantial challenges in the increasingly active PMD therapeutic development space. Developing “FAIR” (findable, accessible, interoperable, reusable) data standards to make data sharable and building a more transparent community data sharing paradigm to access clinical research metadata are the first steps to address these challenges. This collaborative community effort describes the current landscape of PMD clinical research data resources available for sharing, obstacles, and opportunities, including ways to incentivize and encourage data sharing among diverse stakeholders. This work highlights the importance of, and challenges to, developing a unified system that enables clinical research structured data sharing and supports harmonized data deposition standards across clinical consortia and research groups. The goal of these efforts is to improve the efficiency and effectiveness of drug development and improve understanding of the natural history of PMD. This initiative aims to maximize the benefit for PMD patients, research, industry, and other stakeholders while acknowledging challenges related to differing needs and international policies on data privacy, security, management, and oversight.

This database is a geological and geochronological compilation made to study a small Archean/Paleoproterozoic block located in the centre of the Precambrian rock exposition of Uruguay. Petrographic and field outcrops data supporting the samples from which the zircons for textural analysis and U-Pb dating (LA-ICP-MS) come are presented at first with their descriptions. The first table (1) contains the new U-Pb isotopic data. The second table (2) presents a correlation of textures from different zircon samples. The last table (3) contains an inventory of different U-Pb ages found in antecedents. All these data are associated with the paper entitled: “The Archean Pavas Block in Uruguay: extension and tectonic evolution based on LA-ICP-MS U-Pb ages and airborne geophysics”.

Graft derived cell-free DNA was recently reported as a non-invasive biomarker to detect graft damage or rejection after liver transplantation. There are a number of methods for quantification of Gcf-DNA,3 including quantitative-PCR, digital droplet PCR and massively parallel sequencing (next generation sequencing). Here we present the NGS4 data and fragment size distribution of cell-free DNA in the plasma of patients with inborn errors of metabolism who underwent living-related liver transplantation. For more insights please see Analysis of fragment size distribution of cell-free DNA: a potential noninvasive marker to monitor graft damage in living-related liver transplantation for inborn errors of metabolism. [1]. Keywords: Graft derived cell-free DNA, Fragment size, Living-related liver transplantation, Inborn errors of metabolism

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.

Abstract Background The nuclear encoded gene RMND1 (Required for Meiotic Nuclear Division 1 homolog) has recently been linked to RMND1‐related mitochondrial disease (RRMD). This autosomal recessive condition characteristically presents with an infantile‐onset multisystem disease characterized by severe hypotonia, global developmental delay, failure to thrive, sensorineural hearing loss, and lactic acidosis. Renal disease, however, appears to be one of the more prominent features of RRMD, affecting patients at significantly higher numbers compared to other mitochondrial diseases. We report the clinical, histological, and molecular findings of four RRMD patients across three academic institutions with a focus on the renal manifestations. Methods Four patients were identified for the purpose of this study, all of whom had molecular confirmation at the time of inclusion, which included the common pathogenic variant c.713A>G (p.N238S) as well as the three rare variants: c.485delC (p.P162fs), c.533C>T (p.T178M), and c.1317 + 1G>C splice donor variant. Medical history and laboratory findings were collected from the medical records and medical providers. Results In this study, all four patients developed renal disease characterized as tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end‐stage renal disease (4/4) necessitating renal transplantation (2/4). Histological evaluation of renal biopsy specimens revealed generalized tubular atrophy and on electron microscopy, abundant mitochondria with pleomorphism and abnormal cristae. Conclusion Our experience with RRMD demonstrates a specific pattern of renal disease manifestations and clinical course. Patients are unlikely to respond to traditional chronic kidney disease (CKD) treatments, making early diagnosis and consideration of renal transplantation paramount to the management of RRMD.

Classification of the extinct South American native ungulates (SANUs) has posed a challenge given the absence of close, surviving relatives. Here, Westburyet al. sequence the mitochondrial genome of the extinct SANU Macrauchenia patachonicaand reconstruct the evolutionary history of the lineage.

Early recognition of rare mitochondrial respiratory chain defects has become readily available with the routine use of whole exome sequencing. Patients with oxidative phosphorylation defects present with a heterogenous phenotype, often rapidly progressive, and lethal. Clinicians aim for prompt identification of the specific molecular defect to provide timely management, decrease morbidity, and potentially improve survival rates. More recently, bi-allelic pathogenic variants in the TRMU gene responsible for encoding the mitochondrial tRNA-specific 2-thiouridylase were found in a syndrome characterized by infantile hepatopathy due to a mitochondrial translation defect (OMIM# 613070). This nuclear encoded enzyme catalyzes the addition of a sulfur-containing thiol group to the wobble position of mitochondrial specific tRNAs. TRMU deficiency is characterized by a combined respiratory chain deficiency without associated mitochondrial DNA depletion. This mitochondrial tRNA-modifying enzyme requires sulfur for its activity. Previous cellular models have suggested supplementation with cysteine, one of the sulfur containing amino acids, may play a role in increasing thiouridylation levels of mt-tRNAs by increasing sulfur availability for TRMU activity. Cysteine is considered a conditional essential amino acid due to limited availability in infants caused by immature cystathionine gamma-lyase (cystathionase) enzyme activity. The potential benefit of L-cysteine supplementation in TRMU deficiency has been previously proposed to ameliorate the severity and insidious course of the disease. Here we report the clinical, biochemical, and genetic findings of two siblings presenting with hepatopathy associated with hyperlactatemia due to bi-allelic pathogenic variants in TRMU. One patient died due to related complications. The other case was diagnosed prenatally allowing early implementation of L-cysteine supplementation, recovery of liver function, and avoidance of liver transplantation. Keywords: TRMU, mitochondrial, cysteine, hepatopathy, liver transplant

ABSTRACT IMPACT: Alterations in mitochondrial metabolism affect any tissue, especially those with the highest demand for energy. As the symptoms and clinical manifestations are heterogenous, disease diagnosis is challenging. The implementation of genetic-first approach in the diagnosis of mitochondrial diseases will expedite confirmation, treatment, management, and counseling of affected Puerto Rican individuals. OBJECTIVES/GOALS: Mitochondrial diseases are rare, and diagnosis is complex due to the heterogeneity of clinical manifestations. We aim to develop and implement a testing algorithm using a genetics-first approach, facilitating the identification of variants that contribute to mitochondrial disease’s etiology and influence onset and progression in Puerto Ricans. METHODS/STUDY POPULATION: This is a cross-sectional study for characterizing clinical laboratory results from profiles used to evaluate metabolic diseases in individuals with suspected mitochondrial disorders from 2018 to 2021. A subset of 25 individuals from biochemical profile will be recruited to analyze their medical and family history, metabolic biomarkers in blood and urine, hearing test, imaging and chromosomal microarray. The implementation of a genetic testing algorithm using whole exome and mitochondrial DNA sequencing will be performed in a subset of 11 randomized individuals. Descriptive analysis will be reported, including a catalog of all variants. Multivariate analysis will be performed to estimate the statistical association between variants and phenotypes reported and adjusting for potential confounders. RESULTS/ANTICIPATED RESULTS: The biochemical profile of pediatric Puerto Rican individuals suspected of having mitochondrial diseases will be altered and can be used to differentiate among other metabolic causes. We expect to find altered levels of lactate, pyruvate and carnitines in serum, as well as altered organic acids in urine. The implementation of a testing algorithm using both, mitochondrial DNA and whole exome sequencing as first approach will be enabling the identification of disease-causing variants, thus enhancing and confirming the diagnosis of mitochondrial disease in Puerto Ricans. We will be able to identify rare/novel variants specific to our Hispanic population, for both nuclear and mitochondrial DNA. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study will help to characterize the metabolic profile of pediatric Puerto Ricans. No previous study has been reported that describes testing algorithms for genetic diagnosis of mitochondrial disease in our population. Variants found will contribute to a deep understanding of the genetic contribution to phenotypes and disease susceptibility.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disease with a broad spectrum of manifestations. In addition to impaired energy production, nitric oxide (NO) deficiency occurs in MELAS syndrome and leads to impaired blood perfusion in microvasculature that can contribute to several complications including stroke-like episodes, myopathy, and lactic acidosis. The supplementation of NO precursors, L-arginine and L-citrulline, increases NO production and hence can potentially have therapeutic utility in MELAS syndrome. L-citrulline raises NO production to a greater extent than L-arginine; therefore, L-citrulline may have a better therapeutic effect. The clinical effect of L-citrulline has not yet been studied and clinical studies on L-arginine, which are limited, only evaluated the stroke-like episodes’ aspects of the disease. Controlled studies are still needed to assess the clinical effects of L-arginine and L-citrulline on different aspects of MELAS syndrome.

We report a patient harboring a de novo m.5540G>A mutation affecting the MT-TW gene coding for the mitochondrial tryptophan-transfer RNA. This patient presented with atonic–myoclonic epilepsy, bilateral sensorineural hearing loss, ataxia, motor regression, ptosis, and pigmentary retinopathy. Our proband had an earlier onset and more severe phenotype than the first reported patient harboring the same mutation. We discuss her clinical presentation and compare it with the only previously published case.

Mitochondria are found in all nucleated human cells and perform a variety of essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small fraction of their proteins are encoded by mitochondrial DNA (mtDNA) while more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs of various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20-40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular noncompaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain (ETC) complexes subunits and their assembly factors, mitochondrial tRNAs, rRNAs, ribosomal proteins, and translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia.

The San Gregorio de Polanco Dike Swarm (Tacuarembó Department, Uruguay) is the southernmost set of dikes in the Paraná Magmatic Province of Uruguay. Five major dikes have been identified with two main structural trends: N140º–N170º and N50º–N80º. The dikes have tholeiitic affinities and are composed of plagioclase (An55), augite and augite-pigeonite, relicts of olivine and opaque minerals. These rocks have high contents of Fe–Ti oxides (titanomagnetites), the mineralogical and textural characteristics of which have been studied using scanning electron microscopy and energy dispersive spectrometry techniques (SEM – EDS). These features, along with other mineralogical and textural relationships, have been used to propose the following crystallization sequence for the dikes: (i) crystallization of olivine, plagioclase and Ca-rich pyroxene phenocrysts; (ii) precipitation of the first population of Ti-magnetite; (iii) crystallization of plagioclase and pyroxene in the groundmass; (iv) partial dissolution of Ti-magnetite by reaction with magmatic fluids; (v) crystallization of the second population of Ti-magnetite and finally, (vi) crystallization of interstitial barite. Resumen El Haz de Diques de San Gregorio de Polanco (Departamento de Tacuarembó, Uruguay) es la ocurrencia más meridional de diques pertenecientes a la Provincia Magmática Paraná en Uruguay. Fueron identificados cinco 5 diques principales con dos direcciones estructurales principales: N140º - N170º y N50º - N80º, respectivamente. Son diques de afinidad tholeítica compuestos por plagioclasa (An55), augita y augita-pigeonita, relictos de olivina y minerales opacos. Estos diques se caracterizan por el alto contenido de óxidos de Fe y Ti (titanomagnetitas), cuyas características mineralógicas y texturales fueron estudiadas con microscopio electrónico de barrido y espectrometría de energía dispersiva (SEM-EDS), incluyendo mapeos composicionales. Estas características junto con otras relaciones mineralógico-texturales presentes en estas rocas permitieron proponer la siguiente secuencia de cristalización: (i) cristalización de fenocristales de olivina, plagioclasa y piroxenos cálcicos; (ii) precipitación de una primera población de titanomagnetita, (iii) cristalización de plagioclasa y piroxenos conformando la matriz; (iv) disolución parcial de la primera población de titanomagnetitas por reacción con fluidos magmáticos; (v) cristalización de la segunda población de titanomagnetitas y finalmente, (vi) cristalización de barita intersticial.

ABSTRACT: This work is the result of a multiyear effort to use field geology to describe lithologies, to establish contact relationships and to create a sketch of the tectonic evolution of the Meso- to Neoproterozoic metasedimentary successions within the Schist Belt of the Dom Feliciano Belt. This low-grade metamorphic cover rests on the high-grade metamorphic basement of the La China and Las Tetas complexes. This basement is Archean-Paleoproterozoic in age. The Schist Belt is overlapped unconformably by the Barriga Negra formation. The Lavalleja complex and the Barriga Negra formation both deformed together during the D2 deformation event (~ 570 -540 Ma), but the Barriga Negra only partially recorded the D2 transpressive event, whereas the Lavalleja complex was affected by both the D1 tangential event and the D2 event. Event D1 would have developed a fold nappe with vergence to the south. This hypothesis is supported by different structures: (i) recumbent and upright folds oriented E-W, (ii) subhorizontal mylonitic foliation in marbles (calc-schists), (iii) stretching lineations plunging towards the SW in metaconglomerates of the Las Tetas Complex, and (iv) a reworking of the subhorizontal foliation parallel to the Sarandí del Yí strike-slip shear zone.