RARE DISEASE
Mitochondrial neurogastrointestinal encephalomyopathy
Mitochondrial neurogastrointestinal encephalomyopathy
Mitochondrial neurogastrointestinal encephalomyopathy
Synonyms: MNGIE
Synonyms: MNGIE
Synonyms: MNGIE
Drug discovery
6
drugs
With orphan designations
Overview
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by TYMP mutations, resulting in thymidine phosphorylase deficiency. This leads to toxic thymidine/deoxyuridine accumulation, mitochondrial DNA instability, and multisystem degeneration. Key features include severe gastrointestinal dysmotility, cachexia, peripheral neuropathy, chronic progressive external ophthalmoplegia, and leukoencephalopathy. The disease is progressive, with mortality averaging 37 years due to malnutrition, infections, or gastrointestinal complications [1][2][3][14].
Burden
Fatal prognosis: Mean survival ~37 years; death often results from cachexia, sepsis, or intestinal perforation [3][11][14].
High morbidity: Chronic intestinal failure, progressive neurological decline, and dependency on parenteral nutrition [4][6][14].
Diagnostic delays: Frequent misdiagnosis (e.g., anorexia nervosa, inflammatory bowel disease) due to symptom overlap [14][17].
Therapies
Metabolic correction: Hemodialysis or peritoneal dialysis (temporary thymidine reduction) [3][15]; enzyme replacement (erythrocyte-encapsulated thymidine phosphorylase) [8].
Definitive treatments: Allogeneic hematopoietic stem cell transplantation or liver transplantation (restores thymidine phosphorylase activity) [3][8][14].
Supportive care: Parenteral nutrition, prokinetics, antibiotics for bacterial overgrowth, and pain management [4][17].
Categories: rare developmental anomalies during embryogenesis, rare gastroenterological diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
102 drug discovery papers about Mitochondrial neurogastrointestinal encephalomyopathy, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
102 drug discovery papers about Mitochondrial neurogastrointestinal encephalomyopathy, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-04-25 | Nutritional management in MNGIE disease: A case report
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive metabolic disorder characterized by thymidine phosphorylase deficiency. The progressive course of MNGIE increases the importance of early diagnosis and supportive treatment approaches. The disease usually presents with gastrointestinal dysmotility, neuropathy, hearing loss, cachexia, and nutritional disorders. In this case report, we present the nutritional management and follow-up of a 16-year-old male patient with MNGIE disease. The patient presented with a loss of nearly 40% of his total body weight, a BMI of 9.4 kg/m2 and severe nutritional deficiencies. Total parenteral nutrition was initiated in the first phase of nutritional treatment and then gradually transitioned to enteral nutrition. The patient’s nutritional status was improved with peptide-based formulas and pancreatic enzyme support. During the treatment process, energy and protein requirements were nearly met, weight gain was achieved and biochemical parameters were improved.
2025-03-20 | Multiscale Simulations and Profiling of Human Thymidine Phosphorylase Mutations: Insights into Structural, Dynamics, and Functional Impacts in Mitochondrial Neurogastrointestinal Encephalopathy.
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare metabolic disorder caused by missense mutations in the TYMP gene, leading to the loss of human thymidine phosphorylase (HTP) activity and subsequent mitochondrial dysfunction. Despite its well-characterized biochemical basis, the molecular mechanisms by which MNGIE-associated mutations alter HTP's structural stability, dynamics, and substrate (thymidine) binding remain unclear. In this study, we employ a multiscale computational approach, integrating AlphaFold2-based structural modeling, all-atom and coarse-grained molecular dynamics (MD) simulations, protein-ligand (HTP-thymidine) docking, HTP-thymidine complex simulations, binding free-energy landscape analysis, and systematic mutational profiling to investigate the impact of key MNGIE-associated mutations (R44Q, G145R, G153S, K222S, and E289A) on HTP function. Analyses of our long-duration multiscale simulations (comprising 9 μs coarse-grained, 1.2 μs all-atom apo HTP, and 1.2 μs HTP-thymidine complex MD simulations) and physicochemical properties reveal that while wild-type HTP maintains structural integrity and strong thymidine-binding affinity, MNGIE-associated mutations induce substantial destabilization, increased flexibility, and reduced enzymatic efficiency. Free-energy landscape analysis highlights a shift toward less stable conformational states in mutant HTPs, further supporting their functional impairment. Additionally, the G145R mutation introduces steric hindrance at the active site, preventing thymidine binding and causing off-site interactions. These findings not only provide fundamental insights into the physicochemical and dynamic alterations underlying HTP dysfunction in MNGIE but also establish a computational framework for guiding future experimental studies and the rational design of therapeutic interventions aimed at restoring HTP function.
2024-03-08 | P059: Late onset lipid storage myopathy caused by synergistic heterozygosity in ETFDH and TYMP genes
Electron transfer flavoprotein dehydrogenase (ETFDH) gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. The mutations in ETFDH have been associated with autosomal recessive multiple acyl-CoA dehydrogenase deficiency (MADD). In the late-onset MADD, patients usually present with muscle weakness, exercise intolerance, muscle pain and lipid storage in muscle fibers that can be corrected by riboflavin treatment. TYMP gene encodes thymidine phosphorylase (TP), a cytosolic enzyme that catalyzes the phosphorylation of thymidine or deoxyuridine to thymine or uracil and is thus essential for the nucleotide salvage pathway. Absence or reduced activity of TP alters mitochondrial nucleoside and nucleotide pools, leading to impaired mitochondrial DNA replication and/or repair and cause mitochondrial DNA (mtDNA) defects. Mutations in TYMP have been associated with autosomal recessive mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In the late-onset form of MNGIE, patients may manifest mainly isolated mitochondrial myopathy. A 34-year-old female developed profound proximal weakness of the upper and lower extremities for one year. She could not hold her head up and felt very weak. At times, she had word finding difficulties and slurred speech, difficulty swallowing and short of breath. Her CK was mildly elevated. She was wheelchair bound. She has a history of hypertension, high cholesterol, hypothyroidism and anxiety and depression. Subsequent evaluation included an EMG/nerve conduction study and laboratory studies consistent with myopathy. Muscle biopsy revealed lipid droplets in muscle. Plasma acylcarnitine profile shows consistent elevation from C6-carnitine to C16:1-carnitine with C6 and C8 about two times higher than upper limit of normal. Urinary organic acids by gas chromatography-mass spectrometry (GC-MS) reveled mild elevation of ethylmalonic acid 12.38 (nl <7.01 mg/g creatinine) and glutaric acid 1.61 (nl<1.17 mg/g creatinine). These findings are consistent with late-onset MADD (LO-MADD). Urine deoxythymidine and deoxyuridine were normal. Sequence analysis and deletion/duplication testing of the 211 genes (comprehensive neuromuscular disorders panel including FLAD1 gene) studies identified heterozygous mutations in the ETFDH gene (c.51dul (Ala18Cys*fs) and the TYMP gene (c. 11del (p. Leu4*). Both are pathogenic. She started riboflavin therapy with apparent resolution of symptoms. We herein report a case of late onset lipid storage myopathy. Double Heterozygote pathogenic mutations were found in ETFDH and TYMP genes. Both genes can cause mitochondrial dysfunction, such as mitochondrial energetic impairment and impaired mitochondrial DNA replication and/or repair. Both late-onset MADD and MNGIE can present with myopathy. Therefore, we speculate that potential explanation for this case is due to synergistic heterozygosity effects of ETFDH and TYMP genes in mitochondria. This patient was treated with riboflavin and showed apparent resolution of symptoms. This case highlights the points that it is critical to look beyond a simple genotype and consider synergistic heterozygosity effects and to treat the clinical phenotype, especially with abnormal biochemical findings and not just the genotype.
2022-11-07 | Case report: A patient with mitochondrial neurogastrointestinal encephalomyopathy and chronic intestinal failure
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare disorder commonly diagnosed in later disease stages when it prominently manifests as malnutrition. We report on a female patient diagnosed with MNGIE at the age of 36. She was severely malnourished due to loss of resorptive surface after several surgical procedures, gastrointestinal dysmotility, and small intestinal bacterial overgrowth. Therefore, early and aggressive total parenteral nutrition was introduced. Although no reports have shown that nutritional support can modify the clinical outcome, this case suggests that adequate nutritional support, particularly parenteral nutrition, supervised by an experienced nutritional team, may prolong the lifespan of patients with MNGIE.
2022-03-21 | Intensive nutrition support may benefit patients with a rare mitochondrial disorder.
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare, inherited, multisystemic autosomal recessive disorder caused by mutations in the nuclear TYMP gene. This syndrome is characterized by ptosis, external ophthalmoplegia, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Our case illustrates a patient diagnosed with MNGIE and cachexia who has benefited from the initiation and maintenance of parenteral nutrition. We highlight the benefits of receiving long-term supplementary home parenteral nutrition under close monitoring for patients with this neurogastrointestinal disease in order to gain weight and maintain good health.
cell therapies
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.
2024-02-01 | Successful Sequential Liver and Isolated Intestine Transplantation for Mitochondrial Neurogastrointestinal Encephalopathy Syndrome: A Case Report
Background:Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is an autosomal recessive disease caused by thymidine phosphorylase deficiency leading to progressive gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy.Although liver transplantation corrects thymidine phosphorylase deficiency, intestinal deficiency of the enzyme persists.Retrospective chart review was carried out to obtain clinical, biochemical, and pathological details. Case Report:We present a case of liver and subsequent intestine transplant in a 28-year-old man with MNGIE syndrome with gastrointestinal dysmotility, inability to walk, leukoencephalopathy, ptosis, cachexia, and elevated serum thymidine.To halt progression of neurologic deficit, he first received a left-lobe partial liver transplantation.Although his motor deficit improved, gastrointestinal dysmotility persisted, requiring total parenteral nutrition.After exhaustive intestinal rehabilitation, he was listed for intestine transplantation.Two-and-half years after liver transplantation, he received an intestine transplant.At 4 years after LT and 20 months after the intestine transplant, he remains off parenteral nutrition and is slowly gaining weight. Conclusions:This is the first reported case of mitochondrial neurogastrointestinal encephalomyopathy to undergo successful sequential liver and intestine transplantation.
2023-04-12 | Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome
Abstract Background Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT). Procedure In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center. Results A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan‐based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant. Conclusions Treosulfan‐based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.
2021-10-14 | Hematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalopathy: A single-center experience underscoring the multiple factors involved in the prognosis.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive autosomal recessive disorder characterized by cachexia, gastrointestinal (GI) dysmotility, ptosis, peripheral neuropathy, and brain magnetic resonance imaging (MRI) white matter changes. Bi-allelic TYMP mutations lead to deficient thymidine phosphorylase (TP) activity, toxic accumulation of plasma nucleosides (thymidine and deoxyuridine), nucleotide pool imbalances, and mitochondrial DNA (mtDNA) instability. Death is mainly due to GI complications: intestinal perforation, peritonitis, and/or liver failure. Based on our previous observations in three patients with MNGIE that platelet infusions resulted in a transient 40% reduction of plasma nucleoside levels, in 2005 we performed the first hematopoietic stem cell transplantation (HSCT) worldwide as a life-long source of TP in a patient with MNGIE. HSCT was performed in a total of six patients with MNGIE. The multiple factors involved in the prognosis of this cohort were analyzed and compared to the literature experience. Cell source was bone marrow in five patients and peripheral stem cells in one, all from fully human leukocyte antigen (HLA)-matched related donors, including four who were TYMP mutation carriers. Four of six (66%) survived compared to the 37% survival rate in the literature. Reduced intensity conditioning regimen contributed to secondary graft failure in two patients. Fifteen years post HSCT, the first transplanted patient is seemingly cured. Severe GI symptoms before transplantation were mostly irreversible and were poor prognostic factors. Allogenic HSCT could constitute a curative therapeutic option for carefully selected, young, presymptomatic, or mildly affected patients. Timing, donor selection, and optimal conditioning protocol are major determinants of outcome. HSCT is inadvisable in patients with advanced MNGIE disease.
2021-06-18 | Liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical long-term follow-up and pathogenic implications.
We report the longest follow-up of clinical and biochemical features of two previously reported adult mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients treated with liver transplantation (LT), adding information on a third, recently transplanted, patient. All three patients overcame the early post-operative period and tolerated immunosuppressive therapy. Plasma nucleoside levels dramatically decreased, with evidence of clinical improvement of ambulation and neuropathy. Conversely, other features of MNGIE, as gastrointestinal dysmotility, low weight, ophthalmoparesis, and leukoencephalopathy were essentially unchanged. A similar picture characterized two patients treated with allogenic hematopoietic stem cell transplantation (AHSCT). In conclusion, LT promptly and stably normalizes nucleoside imbalance in MNGIE, stabilizing or improving some clinical parameters with marginal periprocedural mortality rate as compared to AHSCT. Nevertheless, restoring thymidine phosphorylase (TP) activity, achieved by both LT and AHSCT, does not allow a full clinical recovery, probably due to consolidated cellular damage and/or incomplete enzymatic tissue replacement.
gene therapies
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.
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.
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.
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.
2025-07-01 | AAV8 gene therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) in a patient's liver maintained ex situ for 9 days
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder caused by mutations in TYMP . 1 This results in nucleoside accumulation, mitochondrial damage and progressive gastrointestinal and neurological dysfunction leading to cachexia and death before 40 years. No established treatment exists. Liver transplantation restores nucleoside levels, but is not indicated in all patients (eg, severely malnourished patients) and is associated with complications. 1 Adeno-associated virus (AAV) gene therapy offers an attractive therapeutic alternative, which is already clinically approved for other genetic diseases and has been successful in MNGIE animal models. 2 Nevertheless, it has not been tested in human and, because of the rarity of MNGIE (<200 cases described), obtaining sufficient numbers for robust AAV trials is challenging. Ex situ machine perfusion (ESMP) maintains organs in near-physiological conditions before transplantation and is emerging as a new avenue to trial novel therapies in the liver with the potential to address this limitation. 3–7 However, until now only donor livers, not affected by disease, have been used for these studies, preventing testing of treatment efficacy. Our aim was to test AAV gene therapy for MNGIE in the explanted liver of a patient transplanted for this disease, which was maintained on ESMP. A 34-year-old patient with MNGIE underwent liver transplantation as enzyme replacement therapy. The explanted liver was divided into anatomical right and left lobe and perfused ex situ using two XVIVO LiverAssist devices for 9 days. Nucleoside levels in the perfusate were measured with mass spectrometry. An AAV serotype 8 encoding for TYMP was used at a dose of 10 11 viral genomes/kg of liver. PCR, qPCR and immunofluorescence for TYMP were used to assess treatment efficacy. Perfusion parameters (flow and pressure), biochemistry (ALT, pH and glucose) and histology were used to assess treatment toxicity. Within 24 h of perfusion, nucleosides accumulated in the perfusate, recapitulating key features of MNGIE. Subsequently, one lobe received AAV8-TYMP, while the other served as an internal control and received carrier injection. The viral vector was taken up by hepatocytes and TYMP expression was restored in the treated lobe within 3 days. Importantly, AAV8-TYMP treatment resulted in clearance of nucleoside from the perfusate, which recapitulated nucleoside clearance from the patient’s blood following liver transplant. Furthermore, long-term ESMP of the two liver lobes revealed no evidence of hepatotoxicity following AAV8 gene therapy, including normal ALT. Our report provides the first demonstration of the safety and efficacy of AAV gene therapy for MNGIE in a human liver, paving the road for clinical trials. We describe the first UK perfusion of a patient's organ, shifting the paradigm of using ESMP exclusively for donor livers to patient explanted pathological livers as a novel platform for drug testing. Using ESMP to test promising novel therapeutic candidates could offer an intermediate platform bridging the gap between animal studies and clinical trials. Finally, our study provides proof of principle for the efficacy of AAV gene therapy for treating diseased livers on ESMP, which could be applied to various other liver diseases.
proteins
2025-07-01 | A Novel Case of Mitochondrial Neurogastrointestinal Encephalopathy with Growth Hormone Deficiency: A Case Report
Background: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultrarare autosomal recessive metabolic disorder caused by mutations in the TYMP gene. The reported endocrine manifestations include diabetes, hyperlipidemia, and hypertriglyceridemia. However, growth hormone deficiency has not been previously described in the literature. Case presentation: This case describes a 19-year-old male with genetically confirmed MNGIE who presented with severe malnutrition (BMI 10.9 kg/m²) requiring total parenteral nutrition (TPN). Initially, he was developing normally, then the patient began experiencing chronic abdominal pain, vomiting, and diarrhea at age 11, along with noticeable short stature. Despite normal insulin-like growth factor 1 (IGF-1) levels, growth hormone deficiency was diagnosed through suboptimal responses to glucagon and clonidine stimulation tests. At age 13, he underwent duodenojejunostomy for superior mesenteric artery (SMA) syndrome, but symptoms persisted. Diagnostic workup, including endoscopy, imaging, and serological tests, excluded inflammatory bowel disease and celiac disease. Genetic testing confirmed a homozygous pathogenic mutation in the TYMP gene (p.Gly145Arg). Brain MRI revealed leukoencephalopathy with T2 and FLAIR hyperintensities in the centrum semiovale and parietal regions, which was consistent with MNGIE. Despite TPN therapy, the patient’s condition continues to progress, highlighting the need for early diagnosis and multidisciplinary management in MNGIE. Conclusion: This case highlights a novel presentation of growth hormone deficiency in MNGIE, offering new insights into its endocrine involvement. Despite treatment with somatotropin and TPN, patients’ nutritional improvement has remained limited, underscoring the need for more targeted therapies. Future research should focus on the link between mitochondrial dysfunction and endocrine abnormalities in MNGIE.
small molecules
2025-04-25 | Nutritional management in MNGIE disease: A case report
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive metabolic disorder characterized by thymidine phosphorylase deficiency. The progressive course of MNGIE increases the importance of early diagnosis and supportive treatment approaches. The disease usually presents with gastrointestinal dysmotility, neuropathy, hearing loss, cachexia, and nutritional disorders. In this case report, we present the nutritional management and follow-up of a 16-year-old male patient with MNGIE disease. The patient presented with a loss of nearly 40% of his total body weight, a BMI of 9.4 kg/m2 and severe nutritional deficiencies. Total parenteral nutrition was initiated in the first phase of nutritional treatment and then gradually transitioned to enteral nutrition. The patient’s nutritional status was improved with peptide-based formulas and pancreatic enzyme support. During the treatment process, energy and protein requirements were nearly met, weight gain was achieved and biochemical parameters were improved.
2025-03-20 | Multiscale Simulations and Profiling of Human Thymidine Phosphorylase Mutations: Insights into Structural, Dynamics, and Functional Impacts in Mitochondrial Neurogastrointestinal Encephalopathy.
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare metabolic disorder caused by missense mutations in the TYMP gene, leading to the loss of human thymidine phosphorylase (HTP) activity and subsequent mitochondrial dysfunction. Despite its well-characterized biochemical basis, the molecular mechanisms by which MNGIE-associated mutations alter HTP's structural stability, dynamics, and substrate (thymidine) binding remain unclear. In this study, we employ a multiscale computational approach, integrating AlphaFold2-based structural modeling, all-atom and coarse-grained molecular dynamics (MD) simulations, protein-ligand (HTP-thymidine) docking, HTP-thymidine complex simulations, binding free-energy landscape analysis, and systematic mutational profiling to investigate the impact of key MNGIE-associated mutations (R44Q, G145R, G153S, K222S, and E289A) on HTP function. Analyses of our long-duration multiscale simulations (comprising 9 μs coarse-grained, 1.2 μs all-atom apo HTP, and 1.2 μs HTP-thymidine complex MD simulations) and physicochemical properties reveal that while wild-type HTP maintains structural integrity and strong thymidine-binding affinity, MNGIE-associated mutations induce substantial destabilization, increased flexibility, and reduced enzymatic efficiency. Free-energy landscape analysis highlights a shift toward less stable conformational states in mutant HTPs, further supporting their functional impairment. Additionally, the G145R mutation introduces steric hindrance at the active site, preventing thymidine binding and causing off-site interactions. These findings not only provide fundamental insights into the physicochemical and dynamic alterations underlying HTP dysfunction in MNGIE but also establish a computational framework for guiding future experimental studies and the rational design of therapeutic interventions aimed at restoring HTP function.
2024-03-08 | P059: Late onset lipid storage myopathy caused by synergistic heterozygosity in ETFDH and TYMP genes
Electron transfer flavoprotein dehydrogenase (ETFDH) gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. The mutations in ETFDH have been associated with autosomal recessive multiple acyl-CoA dehydrogenase deficiency (MADD). In the late-onset MADD, patients usually present with muscle weakness, exercise intolerance, muscle pain and lipid storage in muscle fibers that can be corrected by riboflavin treatment. TYMP gene encodes thymidine phosphorylase (TP), a cytosolic enzyme that catalyzes the phosphorylation of thymidine or deoxyuridine to thymine or uracil and is thus essential for the nucleotide salvage pathway. Absence or reduced activity of TP alters mitochondrial nucleoside and nucleotide pools, leading to impaired mitochondrial DNA replication and/or repair and cause mitochondrial DNA (mtDNA) defects. Mutations in TYMP have been associated with autosomal recessive mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In the late-onset form of MNGIE, patients may manifest mainly isolated mitochondrial myopathy. A 34-year-old female developed profound proximal weakness of the upper and lower extremities for one year. She could not hold her head up and felt very weak. At times, she had word finding difficulties and slurred speech, difficulty swallowing and short of breath. Her CK was mildly elevated. She was wheelchair bound. She has a history of hypertension, high cholesterol, hypothyroidism and anxiety and depression. Subsequent evaluation included an EMG/nerve conduction study and laboratory studies consistent with myopathy. Muscle biopsy revealed lipid droplets in muscle. Plasma acylcarnitine profile shows consistent elevation from C6-carnitine to C16:1-carnitine with C6 and C8 about two times higher than upper limit of normal. Urinary organic acids by gas chromatography-mass spectrometry (GC-MS) reveled mild elevation of ethylmalonic acid 12.38 (nl <7.01 mg/g creatinine) and glutaric acid 1.61 (nl<1.17 mg/g creatinine). These findings are consistent with late-onset MADD (LO-MADD). Urine deoxythymidine and deoxyuridine were normal. Sequence analysis and deletion/duplication testing of the 211 genes (comprehensive neuromuscular disorders panel including FLAD1 gene) studies identified heterozygous mutations in the ETFDH gene (c.51dul (Ala18Cys*fs) and the TYMP gene (c. 11del (p. Leu4*). Both are pathogenic. She started riboflavin therapy with apparent resolution of symptoms. We herein report a case of late onset lipid storage myopathy. Double Heterozygote pathogenic mutations were found in ETFDH and TYMP genes. Both genes can cause mitochondrial dysfunction, such as mitochondrial energetic impairment and impaired mitochondrial DNA replication and/or repair. Both late-onset MADD and MNGIE can present with myopathy. Therefore, we speculate that potential explanation for this case is due to synergistic heterozygosity effects of ETFDH and TYMP genes in mitochondria. This patient was treated with riboflavin and showed apparent resolution of symptoms. This case highlights the points that it is critical to look beyond a simple genotype and consider synergistic heterozygosity effects and to treat the clinical phenotype, especially with abnormal biochemical findings and not just the genotype.
2022-11-07 | Case report: A patient with mitochondrial neurogastrointestinal encephalomyopathy and chronic intestinal failure
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare disorder commonly diagnosed in later disease stages when it prominently manifests as malnutrition. We report on a female patient diagnosed with MNGIE at the age of 36. She was severely malnourished due to loss of resorptive surface after several surgical procedures, gastrointestinal dysmotility, and small intestinal bacterial overgrowth. Therefore, early and aggressive total parenteral nutrition was introduced. Although no reports have shown that nutritional support can modify the clinical outcome, this case suggests that adequate nutritional support, particularly parenteral nutrition, supervised by an experienced nutritional team, may prolong the lifespan of patients with MNGIE.
2022-03-21 | Intensive nutrition support may benefit patients with a rare mitochondrial disorder.
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare, inherited, multisystemic autosomal recessive disorder caused by mutations in the nuclear TYMP gene. This syndrome is characterized by ptosis, external ophthalmoplegia, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Our case illustrates a patient diagnosed with MNGIE and cachexia who has benefited from the initiation and maintenance of parenteral nutrition. We highlight the benefits of receiving long-term supplementary home parenteral nutrition under close monitoring for patients with this neurogastrointestinal disease in order to gain weight and maintain good health.
cell therapies
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.
2024-02-01 | Successful Sequential Liver and Isolated Intestine Transplantation for Mitochondrial Neurogastrointestinal Encephalopathy Syndrome: A Case Report
Background:Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is an autosomal recessive disease caused by thymidine phosphorylase deficiency leading to progressive gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy.Although liver transplantation corrects thymidine phosphorylase deficiency, intestinal deficiency of the enzyme persists.Retrospective chart review was carried out to obtain clinical, biochemical, and pathological details. Case Report:We present a case of liver and subsequent intestine transplant in a 28-year-old man with MNGIE syndrome with gastrointestinal dysmotility, inability to walk, leukoencephalopathy, ptosis, cachexia, and elevated serum thymidine.To halt progression of neurologic deficit, he first received a left-lobe partial liver transplantation.Although his motor deficit improved, gastrointestinal dysmotility persisted, requiring total parenteral nutrition.After exhaustive intestinal rehabilitation, he was listed for intestine transplantation.Two-and-half years after liver transplantation, he received an intestine transplant.At 4 years after LT and 20 months after the intestine transplant, he remains off parenteral nutrition and is slowly gaining weight. Conclusions:This is the first reported case of mitochondrial neurogastrointestinal encephalomyopathy to undergo successful sequential liver and intestine transplantation.
2023-04-12 | Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome
Abstract Background Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT). Procedure In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center. Results A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan‐based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant. Conclusions Treosulfan‐based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.
2021-10-14 | Hematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalopathy: A single-center experience underscoring the multiple factors involved in the prognosis.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive autosomal recessive disorder characterized by cachexia, gastrointestinal (GI) dysmotility, ptosis, peripheral neuropathy, and brain magnetic resonance imaging (MRI) white matter changes. Bi-allelic TYMP mutations lead to deficient thymidine phosphorylase (TP) activity, toxic accumulation of plasma nucleosides (thymidine and deoxyuridine), nucleotide pool imbalances, and mitochondrial DNA (mtDNA) instability. Death is mainly due to GI complications: intestinal perforation, peritonitis, and/or liver failure. Based on our previous observations in three patients with MNGIE that platelet infusions resulted in a transient 40% reduction of plasma nucleoside levels, in 2005 we performed the first hematopoietic stem cell transplantation (HSCT) worldwide as a life-long source of TP in a patient with MNGIE. HSCT was performed in a total of six patients with MNGIE. The multiple factors involved in the prognosis of this cohort were analyzed and compared to the literature experience. Cell source was bone marrow in five patients and peripheral stem cells in one, all from fully human leukocyte antigen (HLA)-matched related donors, including four who were TYMP mutation carriers. Four of six (66%) survived compared to the 37% survival rate in the literature. Reduced intensity conditioning regimen contributed to secondary graft failure in two patients. Fifteen years post HSCT, the first transplanted patient is seemingly cured. Severe GI symptoms before transplantation were mostly irreversible and were poor prognostic factors. Allogenic HSCT could constitute a curative therapeutic option for carefully selected, young, presymptomatic, or mildly affected patients. Timing, donor selection, and optimal conditioning protocol are major determinants of outcome. HSCT is inadvisable in patients with advanced MNGIE disease.
2021-06-18 | Liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical long-term follow-up and pathogenic implications.
We report the longest follow-up of clinical and biochemical features of two previously reported adult mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients treated with liver transplantation (LT), adding information on a third, recently transplanted, patient. All three patients overcame the early post-operative period and tolerated immunosuppressive therapy. Plasma nucleoside levels dramatically decreased, with evidence of clinical improvement of ambulation and neuropathy. Conversely, other features of MNGIE, as gastrointestinal dysmotility, low weight, ophthalmoparesis, and leukoencephalopathy were essentially unchanged. A similar picture characterized two patients treated with allogenic hematopoietic stem cell transplantation (AHSCT). In conclusion, LT promptly and stably normalizes nucleoside imbalance in MNGIE, stabilizing or improving some clinical parameters with marginal periprocedural mortality rate as compared to AHSCT. Nevertheless, restoring thymidine phosphorylase (TP) activity, achieved by both LT and AHSCT, does not allow a full clinical recovery, probably due to consolidated cellular damage and/or incomplete enzymatic tissue replacement.
gene therapies
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.
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.
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.
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.
2025-07-01 | AAV8 gene therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) in a patient's liver maintained ex situ for 9 days
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder caused by mutations in TYMP . 1 This results in nucleoside accumulation, mitochondrial damage and progressive gastrointestinal and neurological dysfunction leading to cachexia and death before 40 years. No established treatment exists. Liver transplantation restores nucleoside levels, but is not indicated in all patients (eg, severely malnourished patients) and is associated with complications. 1 Adeno-associated virus (AAV) gene therapy offers an attractive therapeutic alternative, which is already clinically approved for other genetic diseases and has been successful in MNGIE animal models. 2 Nevertheless, it has not been tested in human and, because of the rarity of MNGIE (<200 cases described), obtaining sufficient numbers for robust AAV trials is challenging. Ex situ machine perfusion (ESMP) maintains organs in near-physiological conditions before transplantation and is emerging as a new avenue to trial novel therapies in the liver with the potential to address this limitation. 3–7 However, until now only donor livers, not affected by disease, have been used for these studies, preventing testing of treatment efficacy. Our aim was to test AAV gene therapy for MNGIE in the explanted liver of a patient transplanted for this disease, which was maintained on ESMP. A 34-year-old patient with MNGIE underwent liver transplantation as enzyme replacement therapy. The explanted liver was divided into anatomical right and left lobe and perfused ex situ using two XVIVO LiverAssist devices for 9 days. Nucleoside levels in the perfusate were measured with mass spectrometry. An AAV serotype 8 encoding for TYMP was used at a dose of 10 11 viral genomes/kg of liver. PCR, qPCR and immunofluorescence for TYMP were used to assess treatment efficacy. Perfusion parameters (flow and pressure), biochemistry (ALT, pH and glucose) and histology were used to assess treatment toxicity. Within 24 h of perfusion, nucleosides accumulated in the perfusate, recapitulating key features of MNGIE. Subsequently, one lobe received AAV8-TYMP, while the other served as an internal control and received carrier injection. The viral vector was taken up by hepatocytes and TYMP expression was restored in the treated lobe within 3 days. Importantly, AAV8-TYMP treatment resulted in clearance of nucleoside from the perfusate, which recapitulated nucleoside clearance from the patient’s blood following liver transplant. Furthermore, long-term ESMP of the two liver lobes revealed no evidence of hepatotoxicity following AAV8 gene therapy, including normal ALT. Our report provides the first demonstration of the safety and efficacy of AAV gene therapy for MNGIE in a human liver, paving the road for clinical trials. We describe the first UK perfusion of a patient's organ, shifting the paradigm of using ESMP exclusively for donor livers to patient explanted pathological livers as a novel platform for drug testing. Using ESMP to test promising novel therapeutic candidates could offer an intermediate platform bridging the gap between animal studies and clinical trials. Finally, our study provides proof of principle for the efficacy of AAV gene therapy for treating diseased livers on ESMP, which could be applied to various other liver diseases.
proteins
2025-07-01 | A Novel Case of Mitochondrial Neurogastrointestinal Encephalopathy with Growth Hormone Deficiency: A Case Report
Background: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultrarare autosomal recessive metabolic disorder caused by mutations in the TYMP gene. The reported endocrine manifestations include diabetes, hyperlipidemia, and hypertriglyceridemia. However, growth hormone deficiency has not been previously described in the literature. Case presentation: This case describes a 19-year-old male with genetically confirmed MNGIE who presented with severe malnutrition (BMI 10.9 kg/m²) requiring total parenteral nutrition (TPN). Initially, he was developing normally, then the patient began experiencing chronic abdominal pain, vomiting, and diarrhea at age 11, along with noticeable short stature. Despite normal insulin-like growth factor 1 (IGF-1) levels, growth hormone deficiency was diagnosed through suboptimal responses to glucagon and clonidine stimulation tests. At age 13, he underwent duodenojejunostomy for superior mesenteric artery (SMA) syndrome, but symptoms persisted. Diagnostic workup, including endoscopy, imaging, and serological tests, excluded inflammatory bowel disease and celiac disease. Genetic testing confirmed a homozygous pathogenic mutation in the TYMP gene (p.Gly145Arg). Brain MRI revealed leukoencephalopathy with T2 and FLAIR hyperintensities in the centrum semiovale and parietal regions, which was consistent with MNGIE. Despite TPN therapy, the patient’s condition continues to progress, highlighting the need for early diagnosis and multidisciplinary management in MNGIE. Conclusion: This case highlights a novel presentation of growth hormone deficiency in MNGIE, offering new insights into its endocrine involvement. Despite treatment with somatotropin and TPN, patients’ nutritional improvement has remained limited, underscoring the need for more targeted therapies. Future research should focus on the link between mitochondrial dysfunction and endocrine abnormalities in MNGIE.
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Drug Discovery Landscape
6 orphan drug designations for Mitochondrial neurogastrointestinal encephalomyopathy.
6 orphan drug designations for Mitochondrial neurogastrointestinal encephalomyopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-associated virus vector serotype 8 containing the human TYMP gene (CpG-depleted) | gene therapies | EMA | 2024-07-25 | — | Fundacio Hospital Universitari Vall D’Hebron Institut De Recerca |
Thymidine phosphorylase-cCPP-PEG | proteins | FDA | 2020-03-30 | — | Pierrepont Therapeutics, Inc. |
Adenoassociated virus vector (AAV) carrying a modified AAV serotype 2 backbone and coding sequence of human thymidine phosphorylase preceded by a human thyroxin-binding globulin promoter | gene therapies | FDA | 2014-09-04 | — | Columbia University Medical Center |
Vector based on an adeno-associated virus serotype 2 backbone, pseudo-serotyped with a type 8 capsid, which carries the coding sequence of the human TYMP gene under the control of the human thyroxine binding globulin promoter | gene therapies | EMA | 2014-08-22 | — | Vall d'Hebron Institute of Research |
Recombinant thymidine phosphorylase encapsulated in autologous erythrocytes | proteins | EMA | 2011-04-15 | — | St George's University of London |
recombinant thymidine phosphorylase encapsulated with autologous erythrocytes | proteins | FDA | 2010-12-13 | — | St. George's University of London |
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