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Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ-KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition., Competing Interests: Declaration of interests R.W. is a consultant (equity) for Alamya Health., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

Purpose: Evaluate long-term efficacy and safety of elamipretide during the open-label extension (OLE) of the TAZPOWER trial in individuals with Barth syndrome (BTHS)., Methods: TAZPOWER was a 28-week randomized, double-blind, and placebo-controlled trial followed by a 168-week OLE. Patients entering the OLE continued elamipretide 40 mg subcutaneous daily. OLE primary endpoints were safety and tolerability; secondary endpoints included change from baseline in the 6-minute walk test (6MWT) and BarTH Syndrome Symptom Assessment (BTHS-SA) Total Fatigue score. Muscle strength, physician- and patient-assessed outcomes, echocardiographic parameters, and biomarkers, including cardiolipin (CL) and monolysocardiolipin (MLCL), were assessed., Results: Ten patients entered the OLE; 8 reached the week 168 visit. Elamipretide was well tolerated, with injection-site reactions being the most common adverse events. Significant improvements from OLE baseline on 6MWT occurred at all OLE time points (cumulative 96.1 m of improvement [week 168, P = .003]). Mean BTHS-SA Total Fatigue scores were below baseline (improved) at all OLE time points. Three-dimensional (3D) left ventricular stroke, end-diastolic, and end-systolic volumes improved, showing significant trends for improvement from baseline to week 168. MLCL/CL values showed improvement, correlating to important clinical outcomes., Conclusion: Elamipretide was associated with sustained long-term tolerability and efficacy, with improvements in functional assessments and cardiac function in BTHS., Competing Interests: Conflict of Interest Hilary J. Vernon and Frédéric M. Vaz have received research support from Stealth BioTherapeutics. Anthony Abbruscato, John Campbell, and Jim Carr are employees of Stealth BioTherapeutics. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Hypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes that increase myocyte energy demand and lead to cardiac hypertrophy. However, it is unknown whether a common metabolic trait underlies cardiac phenotype at the early disease stage. To address this question and define cardiac biochemical pathology in early-stage HCM, we studied two HCM mouse models that express pathogenic variants in cardiac troponin T ( Tnt2 ) or myosin heavy chain ( Myh6 ) genes, and have marked differences in cardiac imaging phenotype, mitochondrial function at early disease stage., Methods: We used a combination of echocardiography, transcriptomics, mass spectrometry-based untargeted metabolomics (GC-TOF, HILIC, CSH-QTOF), and computational modeling (CardioNet) to examine cardiac structural and metabolic remodeling at early disease stage (5 weeks of age) in R92W-TnT +/- and R403Q-MyHC +/- mutant mice. Data from mutants was compared with respective littermate controls (WT)., Results: Allele-specific differences in cardiac phenotype, gene expression and metabolites were observed at early disease stage. LV diastolic dysfunction was prominent in TnT mutants. Differentially-expressed genes in TnT mutant hearts were predominantly enriched in the Krebs cycle, respiratory electron transport, and branched-chain amino acid metabolism, whereas MyHC mutants were enriched in mitochondrial biogenesis, calcium homeostasis, and liver-X-receptor signaling. Both mutant hearts demonstrated significant alterations in levels of purine nucleosides, trisaccharides, dicarboxylic acids, acylcarnitines, phosphatidylethanolamines, phosphatidylinositols, ceramides and triglycerides; 40.4 % of lipids and 24.7 % of metabolites were significantly different in TnT mutants, whereas 10.4 % of lipids and 5.8 % of metabolites were significantly different in MyHC mutants. Both mutant hearts had a lower abundance of unsaturated long-chain acyl-carnitines (18:1, 18:2, 20:1), but only TnT mutants showed enrichment of FA18:0 in ceramide and cardiolipin species. CardioNet predicted impaired energy substrate metabolism and greater phospholipid remodeling in TnT mutants than in MyHC mutants., Conclusions: Our systems biology approach revealed marked differences in metabolic remodeling in R92W-TnT and R403Q-MyHC mutant hearts, with TnT mutants showing greater derangements than MyHC mutants, at early disease stage. Changes in cardiolipin composition in TnT mutants could contribute to impairment of energy metabolism and diastolic dysfunction observed in this study, and predispose to energetic stress, ventricular arrhythmias under high workloads such as exercise., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Establishing a molecular diagnosis of mitochondrial diseases due to pathogenic mitochondrial DNA (mtDNA) variants can be difficult because of varying levels of tissue heteroplasmy, and identifying these variants is important for clinical management. Here, we present clinical and molecular findings in 8 adult patients with classical features of mitochondrial ophthalmologic and/or muscle disease and multiple mtDNA deletions isolated to muscle., Methods: The patients were identified via a retrospective review of patients seen in both a tertiary ophthalmology center and a genetics clinic with a clinical diagnosis of chronic progressive external ophthalmoplegia, optic nerve abnormalities, and/or mitochondrial myopathy. Age at onset of symptoms ranged from 18 to 61 years. Ocular manifestations included bilateral optic neuropathy in one patient, bilateral optic disc cupping without optic neuropathy in 2 patients, ptosis in 4 patients, and ocular motility deficits in 2 patients. Five patients had generalized weakness., Results: Pathogenic variants in mtDNA were not found in the blood or buccal sample from any patient, but 7 of 8 patients had multiple mtDNA deletions identified in muscle tissue. One patient had a single mtDNA deletion identified in the muscle. Heteroplasmy was less than 15% for all of the identified deletions, with the exception of one deletion that had a heteroplasmy of 50%-60%. None of the patients were found to have a nuclear gene variant known to be associated with mitochondrial DNA maintenance., Conclusions: mtDNA deletions were identified in adult patients with ophthalmologic and/or musle abnormalities and may underlie their clinical presentations., Competing Interests: H. Cui, K. Allis, A. Balog, and R. Bai are employees of GeneDx in Gaithersburg, MD. All other authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.