scholarly journals Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE-MTDPS1)

2018 ◽  
Vol 7 (11) ◽  
pp. 389 ◽  
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.

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

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Catarina Falcão de Campos ◽  
Miguel Oliveira Santos ◽  
Rafael Roque ◽  
Isabel Conceição ◽  
Mamede de Carvalho
Keyword(s):  
Thymidine Phosphorylase ◽  
Novel Mutation ◽  
Positive Family History ◽  
Autosomal Recessive Disorder ◽  
Abdominal Distension ◽  
Pathogenic Mutation ◽  
Mitochondrial Neurogastrointestinal Encephalomyopathy ◽  
Motor Disability ◽  
Sensorimotor Polyneuropathy ◽  
Gastrointestinal Dysmotility

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.

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

2019 ◽  
Vol 8 (4) ◽  
pp. 457 ◽  
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.

scholarly journals Anesthetic Management of a Child with Mitochondrial Neurogastrointestinal Encephalopathy

2015 ◽  
Vol 2015 ◽  
pp. 1-3 ◽  
Author(s):  
Vianey Q. Casarez ◽  
Acsa M. Zavala ◽  
Pascal Owusu-Agyemang ◽  
Katherine Hagan
Keyword(s):  
Case Report ◽  
Anesthetic Management ◽  
Volatile Anesthetic ◽  
Autosomal Recessive Disorder ◽  
Hearing Impairments ◽  
Hematopoietic Stem ◽  
Gastrointestinal Dysmotility ◽  
Anesthetic Agents ◽  
Medication Selection ◽  
Repeated Use

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder associated with deficiency of thymidine phosphorylase (TP). Associated manifestations include visual and hearing impairments, peripheral neuropathies, leukoencephalopathy, and malnutrition from concomitant gastrointestinal dysmotility and pseudoobstruction. Given the altered metabolic state in these patients, specific consideration of medication selection is advised. This case report will describe the anesthetic management used in a 10-year-old girl with MNGIE. She had multiple anesthetics while undergoing allogeneic hematopoietic stem cell transplantation. This case report will discuss the successful repeated use of the same anesthetic in this pediatric patient, with the avoidance of volatile anesthetic agents, propofol, and muscle relaxant.

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

2019 ◽  
Vol 8 (8) ◽  
pp. 1096 ◽  
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.

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

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.

scholarly journals Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome

2021 ◽  
Author(s):  
Stephanie C. Harrison ◽  
Christo Tsilifis ◽  
Mary A. Slatter ◽  
Zohreh Nademi ◽  
Austen Worth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Early Report ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Hyper Ige Syndrome

AbstractAutosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

scholarly journals IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells

2021 ◽  
Vol 9 (6) ◽  
pp. e002856
Author(s):  
Ksenia Magidey-Klein ◽  
Tim J Cooper ◽  
Ksenya Kveler ◽  
Rachelly Normand ◽  
Tongwu Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Data Analysis ◽  
Conditioned Medium ◽  
Mononuclear Cells ◽  
Fluorescent Protein ◽  
Metastatic Potential ◽  
Loss Of Function ◽  
Tumor Spread ◽  
Hematopoietic Stem ◽  
Proteomic Screen

BackgroundMetastasis is the major cause of death in patients with cancer. Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the bone marrow (BM) compartment and their differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) have not been explored.MethodsWe used a unique model system consisting of tumor cell clones with low metastatic potential or high metastatic potential (met-low and met-high, respectively) to investigate the fate of HSPC differentiation using murine melanoma and breast carcinoma. Single-cell RNA sequencing (scRNA-seq) analysis was performed on HSPC obtained from the BM of met-low and met-high tumors. A proteomic screen of tumor-conditioned medium integrated with the scRNA-seq data analysis was performed to analyze the potential cross talk between cancer cells and HSPCs. Adoptive transfer of tumor-educated HSPC subsets obtained from green fluorescent protein (GFP)+ tagged mice was then carried out to identify the contribution of committed HSPCs to tumor spread. Peripheral mononuclear cells obtained from patients with breast and lung cancer were analyzed for HSPC subsets.ResultsMice bearing met-high tumors exhibited a significant increase in the percentage of HSPCs in the BM in comparison with tumor-free mice or mice bearing met-low tumors. ScRNA-seq analysis of these HSPCs revealed that met-high tumors enriched the monocyte-dendritic progenitors (MDPs) but not granulocyte-monocyte progenitors (GMPs). A proteomic screen of tumor- conditioned medium integrated with the scRNA-seq data analysis revealed that the interleukin 6 (IL-6)–IL-6 receptor axis is highly active in HSPC-derived MDP cells. Consequently, loss of function and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Importantly, IL-6-educated MDPs induce metastasis within mice bearing met-low tumors—through further differentiation into immunosuppressive macrophages and not dendritic cells. Consistently, MDP but not GMP levels in peripheral blood of breast and lung cancer patients are correlated with tumor aggressiveness.ConclusionsOur study reveals a new role for tumor-derived IL-6 in hijacking the HSPC differentiation program toward prometastatic MDPs that functionally differentiate into immunosuppressive monocytes to support the metastatic switch.

scholarly journals Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Samina Yasin ◽  
Outi Makitie ◽  
Sadaf Naz
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Loss Of Function ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Skeletal Malformations ◽  
Tarsal Bones ◽  
The Family ◽  
Heterozygous Carriers

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

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