Mitochondrial Neurogastrointestinal Encephalomyopathy: Novel Pathogenic Mutation in Thymidine Phosphorylase Gene in a Patient from Cape Verde Islands

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in the gene encoding the Thymidine Phosphorylase (TP). It is clinically characterized by severe gastrointestinal dysmotility, cachexia, palpebral ptosis, ophthalmoparesis, sensorimotor polyneuropathy and leukoencephalopathy. The diagnosis is established by the presence of typical clinical and neuroimaging features, positive family history, and abnormal genetic test. A 19-year-old Cape Verdean patient with a history since childhood of recurrent episodes of nausea, vomiting, diarrhoea and painful abdominal distension associated with progressive motor disability with difficulty in climbing stairs and running and clumsiness with her hands. The diagnostic workup was suggestive of MNGIE. Genetic screening of the TYMP gene identified a novel mutation (c. 1283 G>A). Patients with MNGIE have significant comorbidity and mortality, and they are frequently misdiagnosed. A better acknowledgment of this disorder is essential to permit an earlier diagnosis and to improve disease management.

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Mitochondrial Neurogastrointestinal Encephalomyopathy Disease in Three Siblings from Pakistan with a Novel Mutation

Journal of Pediatric Genetics ◽

10.1055/s-0038-1661411 ◽

2018 ◽

Vol 08 (01) ◽

pp. 015-019

Author(s):

Sana Durrani ◽

Bee Chen ◽

Yusnita Yakob ◽

Lua Hian ◽

Bushra Afroze

Keyword(s):

Thymidine Phosphorylase ◽

Autosomal Recessive ◽

Novel Mutation ◽

Gastrointestinal Symptoms ◽

Autosomal Recessive Disorder ◽

Homozygous Mutation ◽

Pakistani Family ◽

Mitochondrial Neurogastrointestinal Encephalomyopathy ◽

Intestinal Dysmotility ◽

Sensorineural Hearing Impairment

AbstractMitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem autosomal recessive disorder. The disease is clinically heterogeneous with gastrointestinal symptoms of intestinal dysmotility and cachexia as well as neurological symptoms of ophthalmoplegia, neuropathy, sensorineural hearing impairment, and diffuse leukoencephalopathy being most prominent. MNGIE is caused by mutations in TYMP, a gene that encodes thymidine phosphorylase (TP)—a cytosolic enzyme. Mutations in TYMP lead to very low TP catalytic activity, resulting in dramatically increased thymidine and deoxyuridine in plasma. We describe the clinical, biochemical, and neuroimaging findings of three boys with MNGIE from a Pakistani family with a novel homozygous mutation, c.798_801dupCGCG p. (Ala268Argfs*?), in exon 7 of TYMP.

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Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE-MTDPS1)

Journal of Clinical Medicine ◽

10.3390/jcm7110389 ◽

2018 ◽

Vol 7 (11) ◽

pp. 389 ◽

Cited By ~ 3

Author(s):

Massimiliano Filosto ◽

Stefano Cotti Piccinelli ◽

Filomena Caria ◽

Serena Gallo Cassarino ◽

Enrico Baldelli ◽

...

Keyword(s):

Early Diagnosis ◽

Thymidine Phosphorylase ◽

Early Adulthood ◽

Autosomal Recessive Disorder ◽

Diagnostic Procedures ◽

Loss Of Function ◽

Hematopoietic Stem ◽

Mitochondrial Neurogastrointestinal Encephalomyopathy ◽

Gastrointestinal Dysmotility ◽

Near Future

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE-MTDPS1) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause a loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues, and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy, and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Other two MNGIE-type phenotypes have been described so far, which are linked to mutations in POLG and RRM2B genes. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped thymidine phosphorylase therapy) and newer, promising therapies are expected in the near future. Since successful treatment is strictly related to early diagnosis, it is essential that clinicians be warned about the clinical features and diagnostic procedures useful to suspect diagnosis of MNGIE-MTDPS1. The aim of this review is to promote the knowledge of the disease as well as the involved mechanisms and the diagnostic processes in order to reach an early diagnosis.

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Safety and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase in Mitochondrial Neurogastrointestinal Encephalomyopathy

Journal of Clinical Medicine ◽

10.3390/jcm8040457 ◽

2019 ◽

Vol 8 (4) ◽

pp. 457 ◽

Cited By ~ 11

Author(s):

Michelle Levene ◽

Murray Bain ◽

Nicholas Moran ◽

Niranjanan Nirmalananthan ◽

Joanna Poulton ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Thymidine Phosphorylase ◽

Dose Range ◽

Autosomal Recessive Disorder ◽

Plasma Metabolites ◽

Serious Adverse Events ◽

Clinical Safety ◽

Mitochondrial Neurogastrointestinal Encephalomyopathy ◽

Enzyme Replacement

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP; dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients; these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.

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Erythrocyte Encapsulated Thymidine Phosphorylase for the Treatment of Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy: Study Protocol for a Multi-Centre, Multiple Dose, Open Label Trial

Journal of Clinical Medicine ◽

10.3390/jcm8081096 ◽

2019 ◽

Vol 8 (8) ◽

pp. 1096 ◽

Cited By ~ 15

Author(s):

Bax ◽

Levene ◽

Bain ◽

Fairbanks ◽

Filosto ◽

...

Keyword(s):

Multiple Dose ◽

Thymidine Phosphorylase ◽

Autosomal Recessive Disorder ◽

Open Label ◽

Post Dose ◽

Mitochondrial Neurogastrointestinal Encephalomyopathy ◽

Clinical Assessments ◽

Enzyme Replacement ◽

Normal Metabolism ◽

Open Label Trial

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.

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Mitochondrial Neurogastrointestinal Encephalopathy Disease: A Rare Disease Diagnosed in Siblings with Double Vision

Case Reports in Ophthalmology ◽

10.1159/000514098 ◽

2021 ◽

pp. 174-181

Author(s):

Armin Farahvash ◽

Charles D. Kassardjian ◽

Jonathan A. Micieli

Keyword(s):

Thymidine Phosphorylase ◽

Autosomal Recessive ◽

Pathogenic Mutation ◽

Clinical Syndrome ◽

Progressive External Ophthalmoplegia ◽

Chronic Progressive External Ophthalmoplegia ◽

Gastrointestinal Dysmotility ◽

History Of ◽

Autosomal Recessive Condition ◽

Future Therapy

Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE) is a rare autosomal recessive condition characterized by gastrointestinal dysmotility, external ophthalmoplegia, leukoencephalopathy, and sensorimotor neuropathy. A 31-year-old man was referred for a 1-year history of horizontal diplopia related to a large exotropia from chronic progressive external ophthalmoplegia. MRI revealed a diffuse leukoencephalopathy and his 3-year history of chronic intermittent diarrhea, cachexia, and diffuse sensory more than motor peripheral neuropathy led to a unifying clinical diagnosis of MNGIE. This was later confirmed with genetic testing, which revealed a homozygous pathogenic mutation in the thymidine phosphorylase (TYMP) gene. His younger brother had an identical clinical syndrome and was similarly diagnosed. MNGIE diagnosis is important to establish to avoid unnecessary invasive testing for gastrointestinal, ophthalmological, and neurological symptoms and to ensure patients receive appropriate nutritional and genetic counselling. Gene therapy offers a potential future therapy for patients with this condition.

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