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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a unique autosomal recessive disorder with mitochondrial DNA alterations. The disease is characterized clinically by ptosis, progressive external ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Muscle biopsies typically reveal mitochondrial abnormalities including ragged-red fibers and focal cytochrome c oxidase deficiency. Analysis of mitochondrial DNA in skeletal muscle shows partial depletion, multiple deletions, or both. To identify the cause of MNGIE, we mapped the disease locus to chromosome 22q13.32-qter. Within this region, we identified the gene encoding thymidine phosphorylase as the MNGIE gene. We have identified homozygous or compound-heterozygous thymidine phosphorylase gene mutations in 35 MNGIE patients (21 families) from diverse ethnic groups, including: Ashkenazi Jewish, Western European, Jamaican, Hispanic, and Japanese. We confirmed pathogenicity of the mutations by a spectrophotometric assay of thymidine phosphorylase activity with peripheral leukocytes of 15 MNGIE patients. Thymidine phosphorylase enzymatic activity was severely reduced, thus enabling us to conclude that the loss-of-function mutations in thymidine phosphorylase gene cause MNGIE. Thymidine phosphorylase catabolizes thymidine to thymine. In agreement with this notion, we noted that plasma thymidine level is increased more than 20-fold in MNGIE patients compared to controls. Therefore, we have hypothesized that increased thymidine causes mitochondrial nucleotide pool imbalance which, in turn, leads to motochondrial DNA alterations, via a mitochondria-specific thymidine salvage pathway. The identification of the MNGIE gene has allowed us to classify MNGIE as a disease of nucleoside dysmetabolism. We may be entering a new era of research on mitochondrial nucleoside metabolism.
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PMID:MNGIE: from nuclear DNA to mitochondrial DNA. 1116 60

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive, multisystem disorder, which is clinically defined by ptosis, ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by mutations in the nuclear gene, endothelial cell growth factor 1 (ECGF1), encoding thymidine phosphorylase (TP). ECGF1 mutations cause severe loss of TP activity, abnormal accumulations of thymidine and deoxyuridine in plasma, and alterations of mitochondrial DNA. Here, we report the first Thai patient with MNGIE confirmed genetically by the identification of a homozygous novel ECGF1 gene mutation, c.100insC, which causes a frameshift and premature truncation of TP protein.
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PMID:A novel ECGF1 mutation in a Thai patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). 1754 74

Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, peripheral neuropathy, ptosis, ophthalmoplegia, and leukoencephalopathy with early onset and severe prognosis. Mutations in the TYMP/ECGF1 gene cause a loss of thymidine phosphorylase catalytic activity, disrupting the homeostasis of intramitochondrial nucleotide pool. We report a woman with a very late onset of MNGIE, lacking peripheral neuropathy. Thymidine phosphorylase activity was markedly reduced in cultured fibroblasts, but only mildly reduced in buffy coat, where the defect is usually detected, and plasma thymidine was mildly increased compared to typical MNGIE patients. TYMP/ECGF1 analysis detected two heterozygous mutations, including a novel missense mutation. These findings indicate that a partial loss of thymidine phosphorylase activity may induce a late-onset and incomplete MNGIE phenotype.
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PMID:Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity. 1985 46

Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat (<10% of normal activity), we reviewed their medical records and laboratory studies. We identified 102 patients (50 females) with mitochondrial neurogastrointestinal encephalomyopathy and an average age of 32.4 years (range 11-59 years). We found 20 novel TYMP mutations. The average age-at-onset was 17.9 years (range 5 months to 35 years); however, the majority of patients reported the first symptoms before the age of 12 years. The patient distribution suggests a relatively high prevalence in Europeans, while the mutation distribution suggests founder effects for a few mutations, such as c.866A>G in Europe and c.518T>G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype-phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan-Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation.
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PMID:Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. 2193 6

The aim of the study was to determine the prevalence of MNGIE-like phenotype in patients with recessive POLG1 mutations. Mutations in the POLG1 gene, which encodes for the catalytic subunit of the mitochondrial DNA polymerase gamma essential for mitochondrial DNA replication, cause a wide spectrum of mitochondrial disorders. Common phenotypes associated with POLG1 mutations include Alpers syndrome, ataxia-neuropathy syndrome, and progressive external ophthalmoplegia (PEO). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, PEO and/or ptosis, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by TYMP mutations. Rare cases of MNGIE-like phenotype have been linked to RRM2B mutations. Recently, POLG1 mutations were identified in a family with clinical features of MNGIE but no leukoencephalopathy. The coding regions and exon-intron boundaries of POLG1 were sequence analyzed in patients suspected of POLG1 related disorders. Clinical features of 92 unrelated patients with two pathogenic POLG1 alleles were carefully reviewed. Three patients, accounting for 3.3% of all patients with two pathogenic POLG1 mutations, were found to have clinical features consistent with MNGIE but no leukoencephalopathy. Patient 1 carries p.W748S and p.R953C; patient 2 is homozygous for p.W748S, and patient 3 is homozygous for p.A467T. In addition, patient 2 has a similarly affected sibling with the same POLG1 genotype. POLG1 mutations may cause MNGIE-like syndrome, but the lack of leukoencephalopathy and the normal plasma thymidine favor POLG1 mutations as responsible molecular defect.
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PMID:Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations. 2199 18

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause 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. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped TP therapy) and newer, promising therapies are expected in the near future. However, successful treatment is strictly related to early diagnosis. We report on an incomplete MNGIE phenotype in a young man harboring the novel heterozygote c.199 C>T (Q67X) mutation in exon 2, and the previously reported c.866 A>C (E289A) mutation in exon 7 in TYMP. The correct diagnosis was achieved many years after the onset of symptoms and unfortunately, the patient died soon after diagnosis because of multiorgan failure due to severe malnutrition and cachexia before any therapeutic option could be tried. To date, early diagnosis is essential to ensure that patients have the opportunity to be treated. MNGIE should be suspected in all patients who present with both gastrointestinal and nervous system involvement, even if the classical complete phenotype is lacking.
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PMID:Poor Outcome in a Mitochondrial Neurogastrointestinal Encephalomyopathy Patient with a Novel TYMP Mutation: The Need for Early Diagnosis. 2334 16

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystemic disorder caused by TYMP gene mutations. Here, we report on the first MNGIE patient diagnosed in Bulgaria who carries a novel homozygous TYMP mutation (p.Leu347Pro). The patient presented with gastrointestinal complaints, cachexia, hearing loss, ptosis, ophthalmoparesis, polyneuropathy, cognitive impairment, and leukoencephalopathy on magnetic resonance imaging (MRI) examination of the brain. The patient's motor capacity declined significantly, leading to wheelchair dependence several months following administration of tuberculostatic treatment, suggesting mitochondrial toxicity of these agents. The advanced stage of the disease and the poor medical condition prevented us from performing allogenic hematopoietic stem cell transplantation (HSCT). Early diagnosis is important not only for genetic counseling but also in view of the timely treatment with allogenic HSCT.
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PMID:Possible toxicity of tuberculostatic agents in a patient with a novel TYMP mutation leading to mitochondrial neurogastrointestinal encephalomyopathy. 2359 May 77

Leukoencephalopathy is a hallmark of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) a devastating disorder characterized by ptosis, ophthalmoparesis, gastrointestinal dysfunction and polyneuropathy. To characterize MNGIE-associated leukoencephalopathy and to correlate it with clinical, biochemical and molecular data, four MNGIE patients with heterogeneous clinical phenotypes (enteropathic arthritis, exercise intolerance, CIDP-like phenotype and typical presentation) were studied by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps were also obtained. In two patients we also investigated the role of brain MRI in monitoring the evolution of leukoencephalopathy by performing follow-up imaging studies at an interval of one and two years. The extension and distribution of leukoencephalopathy were not clearly linked with age, phenotype or disease severity, and did not seem to be related to TYMP mutations, enzyme activity or pyrimidine levels. In the studied patients MRS revealed reduced N-acetyl-aspartate and increased choline signals. Although DWI appeared normal in all patients but one, ADC maps always showed moderate increased diffusivity. Leukoencephalopathy worsened over a two-year period in two patients, regardless of the clinical course, indicating a lack of correlation between clinical phenotype, size and progression of white matter abnormalities during this period. Brain MRI should be considered a very useful tool to diagnose both classical and atypical MNGIE. Serial MRIs in untreated and treated MNGIE patients will help to establish whether the leukoencephalopathy is a reversible condition or not.
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PMID:The role of brain MRI in mitochondrial neurogastrointestinal encephalomyopathy. 2419 12

Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE) is a rare autosomal-recessive syndrome, resulting from mutations in the TYMP gene, located at 22q13. The mutation induces a thymidine phosphorylase (TP) deficit, which leads to a nucleotide pool imbalance and to instability of the mitochondrial DNA. The clinical picture regroups gastrointestinal dysmotility, cachexia, ptosis, ophthalmoplegia, peripheral neuropathy, and asymptomatic leukoencephalopathy. The prognosis is unfavorable. We present the case of a 14-year-old Caucasian female whose symptoms started in early childhood. The diagnosis was suspected after magnetic resonance imaging (MRI), performed given the atypical features of mental anorexia, which revealed white matter abnormalities. She presented chronic vomiting, postprandial abdominal pain, and problems gaining weight accompanied by cachexia. This diagnosis led to establishing proper care, in particular an enteral and parenteral nutrition program. There is no known specific effective treatment, but numerous studies are in progress. In this article, after reviewing the existing studies, we discuss the main diagnostic and therapeutic aspects of the disease. We argue for the necessity of performing a cerebral MRI given the atypical features of a patient with suspected mental anorexia (or when the clinical pattern of a patient with mental anorexia seems atypical), so that MNGIE can be ruled out.
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PMID:[Mitochondrial neurogastrointestinal encephalopathy disease]. 2528 63

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder associated with mitochondrial alterations. MNGIE is characterized by severe gastrointestinal dysmotility, cachexia, ophthalmoplegia, ptosis, peripheral neuropathy, and leukoencephalopathy. The condition is caused by mutation of the TYMP gene. We studied the clinical and biochemical characteristics of a family with MNGIE. The proband was a 48-year-old male presenting with diarrhea and progressive weight loss. He also had ptosis and exhibited eyeball fixation. His blood and cerebrospinal fluid lactate levels were elevated. Magnetic resonance imaging of the brain revealed diffuse leukoencephalopathy. Ragged red fibers and cytochrome c oxidase-deficient fibers were apparent on muscle biopsy. His vision and ptosis deteriorated significantly during follow-up. Our clinical diagnosis of MNGIE was confirmed by TYMP gene analysis. We discovered a homozygous TYMP c.1193-1216 dup-GGGCGCTGCCGCTGGCGCTGGTGC mutation (a duplication). Some of the family members were heterozygous for the mutation but had no clinical features. We predicted the function of this mutation using PredictProtein and found that the secondary structure had changed in the region of the helix and strand, the transmembrane region, and the protein-protein binding sites. The family described herein exhibited biochemically, genetically, and functionally confirmed MNGIE syndrome.
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PMID:A novel thymidine phosphorylase mutation in a Chinese MNGIE patient. 2770 5


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