2026-06-18 | Association of a Homozygous TYMP c.131G>C Variant With MNGIE in a Chinese Pedigree: Insights From Genetic Analysis and Computational Modeling.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in TYMP, which disrupt thymidine metabolism. This study aimed to characterize a novel homozygous TYMP variant and provide insights into its potential structural and functional consequences through bioinformatic analyses. We identified a homozygous TYMP variant (c.131G>C, p.R44P) in a proband with MNGIE using whole-exome sequencing and Sanger sequencing. Computational structural analyses and molecular modeling were performed to predict the impact of the R44P substitution on thymidine phosphorylase (TP) stability, homodimerization, catalytic activity, and substrate binding. The homozygous TYMP c.131G>C variant was confirmed in the proband. Computational analyses suggested that the p.R44P substitution may destabilize TP and potentially impair homodimerization. Molecular modeling further predicted altered thymidine binding and disrupted active-site geometry. These predicted perturbations are hypothesized to contribute to defective nucleotide metabolism, thymidine accumulation, and deoxynucleotide triphosphate pool imbalance, which may ultimately result in mitochondrial genomic instability manifesting as mitochondrial DNA deletions and depletion. Our findings report the TYMP c.131G>C variant in a homozygous configuration, extending beyond a recently described compound heterozygous case. The bioinformatic predictions support the classification of this variant as likely pathogenic in MNGIE, though functional studies are warranted to validate these findings.
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2026-05-07 | Ultrasound assessment of diaphragmatic structure and function before and after orthotopic liver transplantation in MNGIE.
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder caused by thymidine phosphorylase (TP) deficiency, leading to systemic nucleoside accumulation and multisystemic dysfunction. While respiratory failure is not a primary feature, severe cachexia, sarcopenia, and respiratory muscle weakness may contribute to morbidity, particularly during acute illnesses. Orthotopic liver transplantation (OLT) has emerged as a disease-modifying therapy, restoring TP activity and normalizing circulating nucleosides, though its impact on respiratory muscle function remains largely unexplored. Diaphragmatic ultrasound offers a noninvasive tool to monitor respiratory muscle structure and function longitudinally. We report a 27 year-old male with genetically confirmed MNGIE who underwent OLT while severely cachectic (BMI 13.4 kg/m2). Pre-transplant diaphragmatic ultrasound demonstrated severe atrophy (thickness 1 mm) and dysfunction (thickening fraction < 10%). Seven years after OLT, diaphragmatic trophism and contractility had markedly improved (thickness 2.3 mm; thickening fraction 31%), whereas peripheral skeletal muscle recovery remained limited. During a subsequent septic episode, the patient required only brief mechanical ventilation, reflecting enhanced respiratory resilience. Orthotopic liver transplantation provides sustained metabolic correction in MNGIE, facilitating significant recovery of diaphragmatic structure and function, even in patients with advanced disease. Diaphragmatic ultrasound proved invaluable for the noninvasive assessment of respiratory muscle trophism and contractility, guiding ventilatory management and long-term follow-up. Importantly, this case demonstrates a dissociation between peripheral and diaphragmatic muscle recovery, suggesting differential responsiveness to post-transplant metabolic normalization. These results underscore the potential of diaphragmatic ultrasound as a sensitive functional biomarker in MNGIE, although larger studies are warranted to establish its prognostic and clinical relevance.
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2025-12-26 | Sequential development of three syndromes in a patient with m.3243A>G mutation: a case report.
Mitochondrial disorders are highly heterogeneous and can manifest as a spectrum of clinically heterogeneous disorders that affect multiple organ systems. Herein, we report a Chinese female patient carrying mitochondrial DNA m.3243A>G mutation who sequentially experienced myoclonic epilepsy with ragged red fibers, mitochondrial neurogastrointestinal encephalomyopathy, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. This report expands the current understanding of phenotypic heterogeneity in mitochondrial disorders.
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2025-10-16 | Expansion of the Phenotypic Spectrum of MNGIE: Lipodystrophy and Metabolic Alterations Associated with a p.Arg393_Val400dup TYMP Variant.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in the TYMP gene, typically characterized by severe and progressive gastrointestinal and neurological manifestations. Recent reports have identified a subset of patients presenting with generalized lipodystrophy and metabolic abnormalities, suggesting that adipose tissue involvement may be an underrecognized feature of the disease. Herein, we report the case of a 16-year-old female carrying a previously described homozygous TYMP variant (c.1178_1201dup; p.Arg393_Val400dup), who presented during adolescence with generalized lipodystrophy, insulin resistance, hypertriglyceridemia, hepatic steatosis, and other metabolic complications. At diagnosis, she exhibited no overt neurological or gastrointestinal symptoms; however, electroneurography revealed subclinical peripheral neuropathy. This case broadens the phenotypic spectrum of TYMP-related disease by documenting a lipodystrophic and metabolic presentation associated with the p.Arg393_Val400dup variant. While TYMP mutations have been linked to lipodystrophy in rare cases, this specific variant had previously been reported only in the context of classical MNGIE, with no documented evidence of adipose tissue or metabolic derangement. Our findings highlight the importance of considering TYMP involvement in the differential diagnosis of atypical lipodystrophy syndromes, particularly when features suggest underlying mitochondrial dysfunction.
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2025-08-08 | Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy.
Ex situ normothermic machine perfusion (NMP) is rapidly emerging as a novel platform for testing therapeutics in human donor livers. Recently, perfusion of explanted patient livers was achieved, raising the possibility of using these diseased organs to increase the fidelity and resolution of drug testing and development. Here, we provide proof-of-principle for the feasibility of this approach in the context of gene therapy. We report the first successful administration of adeno-associated virus serotype 8 (AAV8) vector treatment in the explanted liver of a 34-year-old patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), using machine perfusion. MNGIE is caused by mutations in the thymidine phosphorylase (TYMP) gene, leading to nucleoside accumulation. The patient's liver was split into anatomical left and right lobes and perfused using separate machine perfusion devices. Prior to treatment, nucleoside accumulation was observed in the perfusate of both lobes, recapitulating the cardinal feature of MNGIE. An AAV8 vector carrying the human TYMP gene was administered in the left lobe with the right serving as a control. AAV8 gene therapy resulted in successful vector uptake, with complete nucleoside clearance within 6 days of administration. Our results constitute the first demonstration of the efficacy of gene therapy for MNGIE in a human organ and provide proof-of-principle for using machine perfusion as a new strategy for disease modelling and testing novel therapeutics, e.g. gene therapy, in explanted livers.
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