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Research Notes: Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)Annu Rev Med. 2007 Sep 24. Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17. FEBS Lett. 2007 Jun 27. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease due to ECGF1 gene mutations causing thymidine phosphorylase (TP) deficiency. Analysis of post-mortem samples of five MNGIE patients and two controls, revealed TP activity in all control tissues, but not in MNGIE samples. Converse to TP activity, thymidine and deoxyuridine were absent in control samples, but present in all tissues of MNGIE patients. Concentrations of both nucleosides in the tissues were generally higher than those observed in plasma of MNGIE patients. Our observations indicate that in the absence of TP activity, tissues accumulate nucleosides, which are excreted into plasma. Clin Neurol Neurosurg. 2007 Jun 1. 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. Eur J Neurol. 2007 May. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the thymidine phosphorylase gene (ECGF1). We present the first detailed report of a Brazilian MNGIE patient, harboring a novel ECGF1 homozygous mutation (C4202A, leading to a premature stop codon, S471X). Multiple deletions and the T5814C change were found in mitochondrial DNA. Together with gastrointestinal symptoms, endocrine involvement and memory dysfunction, not reported in MNGIE to date, were the most preeminent features. Arch Neurol. 2007 Mar. OBJECTIVE: To study the effect of continuous ambulatory peritoneal dialysis on nucleoside levels and clinical course in a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Patient. We studied a patient with genetically verified MNGIE, who prior to treatment had lost weight progressively, developed amenorrhea, vomited multiple times daily, and had abdominal pain. Intervention. The patient was treated with peritoneal dialysis for 3 years, and the effect on symptoms and plasma concentrations of thymidine and deoxyuridine were monitored. RESULTS: Dialysis stopped vomiting and reduced abdominal pain, and the patient gained 5 kg in weight and started to menstruate again. Symptoms returned if dialysis was paused. Dialysis did not affect plasma nucleoside levels. CONCLUSIONS: This study shows an unambiguous clinical benefit of peritoneal dialysis on gastrointestinal symptoms in MNGIE. Dialysis did not affect nucleoside levels, indicating elevated thymidine and deoxyuridine levels are not solely responsible for the pathogenesis of MNGIE. J Neurol. 2007 Feb. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder in which a nuclear mutation of the thymidine phosphorylase (TP) gene causes mitochondrial genomic dysfunction. Patients suffer from gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoparesis, myopathy and polyneuropathy. Magnetic resonance imaging (MRI) shows leukoencephalopathy. We describe clinical, genetic and neuroradiological features of three brothers affected with MNGIE. Clinical examination, laboratory analyses, MRI and magnetic resonance spectroscopy (MRS) of the brain, and genetic analysis have been performed in all six members of the family with the three patients with MNGIE. Two of them are monozygous twins. They all suffered from gastrointestinal dysmotility, cachexia, ophthalmoplegia, muscular atrophies, and polyneuropathy. Urinary thymidine was elevated in the patients related to the severity of clinical disease, and urinary thymidine (normally not detectable) was also found in a heterozygous carrier. Brain MRI showed leukoencephalopathy in all patients; however, their cognitive functioning was normal. Brain MRS demonstrated reduced N-acetylaspartate and choline in severely affected areas. MRI of heterozygous carriers was normal. A new mutation (T92N) in the TP gene was identified. Urinary thymidine is for the first time reported to be detectable in a heterozygous carrier. MRS findings indicate loss of neurons, axons, and glial cells in patients with MNGIE, but not in heterozygous carriers. Indian J Pediatr. 2006 Dec. Mitochondrial neurogastrointestinal encephalomyopathy is a rare disorder affecting the pediatric age group with a heterogeneous multisystem involvement. We happen to manage a young child with symptoms of constipation since infancy along with cachexia, seizures and peripheral neuropathy. The child later went into encephalopathy preterminally. This clinical syndrome fitted very well with mitochondrial neurogastrointestinal encephalomyopathy. The child had elevated lactate levels and electron microscopy of the rectal biopsy was suggestive of a mitochondrial disorder To the best of our knowledge there is no case report of this syndrome from India and since this presents with diagnostic difficulties so is being reported. Clin Neurophysiol. 2006 Nov. OBJECTIVE: To assess the usefulness of brain auditory evoked potentials (BAEPs) in the study of asymptomatic white matter alterations in brain MRI observed in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients. METHODS: The authors studied the neurophysiological characteristics of the BAEPs in four genetically confirmed MNGIE patients who presented varying degrees of leukoencephalopathy in brain MRI. RESULTS: Prolonged I-III and I-V interpeak latencies were the most common abnormalities found, with a correlation between the extent of brain MRI lesions and BAEPs. CONCLUSIONS: The findings suggest a delayed central conduction time along the brainstem. BAEPs may be useful in the neurophysiological evaluation of central white matter lesions in MNGIE. Similar neurophysiological findings have been reported in other myelin disorders in the central nervous system. SIGNIFICANCE: The BAEPs abnormalities identified should be interpreted as an indirect sign of CNS involvement in MNGIE patients and provide comprehensive and integrated information concerning brainstem dysfunction. Further studies are necessary in order to identify whether there is a correlation between BAEPs and the clinical progression of the disease. Neurology. 2006 Oct 24. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by thymidine phosphorylase (TP) deficiency, which leads to toxic accumulations of thymidine (dThd) and deoxyuridine (dUrd). In this work, we report that infusion of platelets from healthy donors to patients with MNGIE restored transiently circulating TP and reduced plasma dThd and dUrd levels, suggesting that treatments to achieve permanent restoration of circulating TP such as allogeneic stem cell transplantation or gene transfer might be therapeutic. Neurology. 2006 Oct 24. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven. Paediatr Anaesth. 2006 Oct. Patients diagnosed with abdominal pain related to mitochondrial neurogastrointestinal encephalopathy (MNGIE) may benefit from splanchnic nerve blockade. MNGIE, varying in age of onset and rate of progression, is caused by loss of function mutation in thymidine phosphorylase gene. Gastrointestinal dysmotility, pseudo-obstruction and demyelinating sensorimotor peripheral neuropathy (stocking-glove sensory loss, absent tendon reflexes, distal limb weakness, and wasting) are the most prominent manifestations. Patients usually die in early adulthood (mean 37.6 years; range 26-58 years). We report a case of an 18-year-old patient with MNGIE. Our patient's abdominal pain was relieved after splanchnic nerve blockade. J Biol Chem. 2006 Aug 11. Mitochondrial (mt) neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease associated with depletion, deletions, and point mutations of mtDNA. Patients lack a functional thymidine phosphorylase and their plasma contains high concentrations of thymidine and deoxyuridine; elevation of the corresponding triphosphates probably impairs normal mtDNA replication and repair. To study metabolic events leading to MNGIE we used as model systems skin and lung fibroblasts cultured in the presence of thymidine and/or deoxyuridine at concentrations close to those in the plasma of the patients, a more than 100-fold excess relative to controls. The two deoxynucleosides increased the mt and cytosolic dTTP pools of skin fibroblasts almost 2-fold in cycling cells and 8-fold in quiescent cells. During up to a two-month incubation of quiescent fibroblasts with thymidine (but not with deoxyuridine), mtDNA decreased to approximately 50% without showing deletions or point mutations. When we removed thymidine, but maintained the quiescent state, mtDNA recovered rapidly. With thymidine in the medium, the dTTP pool of quiescent cells turned over rapidly at a rate depending on the concentration of thymidine, due to increased degradation and resynthesis of dTMP in a substrate (=futile) cycle between thymidine kinase and 5'-deoxyribonucleotidase. The cycle limited the expansion of the dTTP pool at the expense of ATP hydrolysis. We propose that the substrate cycle represents a regulatory mechanism to protect cells from harmful increases of dTTP. Thus MNGIE patients may increase their consumption of ATP to counteract an unlimited expansion of the dTTP pool caused by circulating thymidine. "Presumably, these site-specific mtDNA mutations accumulate over many years in MNGIE because most patients begin to manifest symptoms in their late teenage years..." J Mass Spectrom. 2006 May. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. The disease is due to a thymidine phosphorylase defect. This enzyme catalyses the phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. For this reason, increased levels of thymidine in plasma and urine are found in MNGIE patients. Haemodialysis can reduce circulating plasma thymidine levels and can be beneficial in some MNGIE patients. We developed a fast analytical method based on HPLC-ESI-MS/MS capable of identifying pyrimidine nucleotides (thymine, cytosine, uracil) and nucleosides (thymidine, citidine, uridine) in plasma and urine after direct dilution of the samples without pre-treatment. In the patient studied, we observed a significant reduction of plasmatic and urinary thymidine levels during and after dialysis. However, we noted a progressive reduction of the initial thymidine level after some dialytic trials. This method will be useful not only for thymidine level follow-up during dialysis in MNGIE patients but also for the improvement of the diagnosis or diagnostic suspect in other pyrimidine defects such as dihydropyrimidine dehydrogenase deficiency, dihydropyrimidinase deficiency and ureidopropionase deficiency. Gastroenterology. 2006 Mar. BACKGROUND & AIMS: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease clinically defined by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, white-matter changes in brain magnetic resonance imaging, and mitochondrial abnormalities. Loss-of-function mutations in thymidine phosphorylase gene induce pathologic accumulations of thymidine and deoxyuridine that in turn cause mitochondrial DNA (mtDNA) defects (depletion, multiple deletions, and point mutations). Our study is aimed to define the molecular basis of gastrointestinal dysmotility in a case of MNGIE. METHODS: By using laser capture microdissection techniques, we correlated histologic features with mtDNA abnormalities in different tissue components of the gastrointestinal wall in a MNGIE patient and ten controls. RESULTS: The patient's small intestine showed marked atrophy and mitochondrial proliferation of the external layer of muscularis propria. Genetic analysis revealed selective depletion of mtDNA in the small intestine compared with esophagus, stomach, and colon, and microdissection analysis revealed that mtDNA depletion was confined to the external layer of muscularis propria. Multiple deletions were detected in the upper esophagus and skeletal muscle. Site-specific somatic point mutations were detected only at low abundance both in the muscle and nervous tissue of the gastrointestinal tract. Analysis of the gastrointestinal tract from 10 controls revealed a non-homogeneous distribution of mtDNA content; the small intestine had the lowest levels of mtDNA. CONCLUSION: Atrophy, mitochondrial proliferation, and mtDNA depletion in the external layer of muscularis propria of small intestine indicate that visceral myopathy is responsible for gastrointestinal dysmotility in this MNGIE patient. Intern Med. 2006. OBJECTIVE: The authors identified a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), who completely fulfilled the clinical criteria with low thymidine phosphorylase (TP) activity. However, the same homozygotic S471L TP gene mutation was also found in her unaffected mother, but with normal TP activity. To elucidate the pathogenesis of MNGIE, we performed the analysis below. METHODS: We analyzed the TP gene mutation in the proband and 145 unrelated individuals by direct sequence and restriction fragment length polymorphism (RFLP). TP activity was determined by the spectrophotometric method for each TP S471L genotype. RESULTS: Among 145 normal persons, the S471L homozygote mutants were identified in 2.76% and their enzyme activity was normal. CONCLUSION: TP gene mutation is not a primary cause of MNGIE, but with a mitochondrial deletion mutation, a single nucleotide polymorphism (SNP) of the TP gene may be crucial in the pathogenesis of MNGIE. Cas Lek Cesk. 2006. BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a disorder with autosomal recessive inheritance caused by mutations in the gene encoding thymidine phosphorylase (TP). TP deficiency results in imbalance of mitochondrial pool of nucleotides leading secondary to multiple deletions and depletion of mitochondrial DNA (mtDNA) and impairment of oxidative phosphorylation system. The disease is clinically characterized by gastrointestinal dysmotility with symptoms of pseudo-obstruction, severe failure to thrive, ptosis, leukoencephalopathy, peripheral neuropathy and myopathy. We present results of the clinical, histochemical, biochemical and molecular analyses of the first Czech patient with MNGIE syndrome. METHODS AND RESULTS: Man, 33-years old with twenty-year history of failure to thrive (height 168 cm, weight 34 kg) and progressive gastrointestinal dysmotility, external ophthalmoplegia, leucoencephalopathy and peripheral neuropathy was recommended to metabolic center. Histochemical analyses in muscle biopsy showed the presence of "ragged red fibers" with focal decrease of cytochrome c oxidase activity, but spectrophotometric analyses in isolated muscle mitochondria revealed normal activities of all respiratory chain complexes. Metabolic investigation revealed markedly increased plasma level of thymidine (6.6 micromol/l, controls <0.05 micromol/l) and deoxyuridine (15 micromol/l, controls <0.05 micromol/l). The activity of TP in isolated lymphocytes was low (0.02 micromol/hour/mg protein, reference range 0.78 +/- 0.18). Molecular analyses in muscle biopsy revealed multiple mtDNA deletions and homozygous mutation 1419G>A (Gly145Arg) was found in gene for TP. Both parents are heterozygotes. CONCLUSIONS: MNGIE has to be considered in patients presenting with a combination of gastrointestinal and neurological symptoms. Plasma level of thymidine may serve as the best method for laboratory screening of MNGIE, but molecular analyses are necessary for genetic counselling and prenatal diagnosis in affected families. Turk J Gastroenterol. 2005 Dec. Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive multisystem disorder characterized clinically by severe gastrointestinal dysmotility; cachexia; ptosis, opthalmoparesis or both; peripheral neuropathy; leukoencephalopathy and mitochondrial abnormalities in muscle. Gastrointestinal dysmotility causes intestinal pseudo-obstruction and small intestinal diverticula. In this case report, we present a previously diagnosed 32-year-old female mitochondrial neurogastrointestinal encephalomyopathy syndrome patient who was hospitalized and operated due to ileal diverticulitis perforation and died due to postoperative respiratory complications, and we discuss the characteristic manifestations of the disease. Ann Neurol. 2005 Oct. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the gene encoding thymidine phosphorylase (TP). All MNGIE patients have had severe loss of TP function and prominent plasma accumulations of the TP substrates thymidine (dThd) and deoxyuridine (dUrd). Here, we report for the first time to our knowledge three MNGIE patients with later onset, milder phenotype, and less severe TP dysfunction, compared with typical MNGIE patients. This report demonstrates a direct relationship between the biochemical defects and clinical phenotypes in MNGIE and supports the notion that reduction of dThd and dUrd accumulation or TP replacement could be useful therapy for MNGIE. Turk J Gastroenterol. 2005 Sep. Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive disease characterized by progressive ophthalmoplegia, peripheral neuropathy, mitochondrial abnormalities and gastrointestinal involvement. We describe a 19-year-old male having chronic intestinal pseudoobstruction associated with ophthalmoplegia and proximal muscle weakness. The clinical and radiologic features suggested the diagnosis of mitochondrial neurogastrointestinal encephalomyopathy. Mitochondrial genetic defects should be considered in the differential diagnosis of unexplained chronic gastrointestinal symptoms accompanied by neurological findings, especially in families where there is more than one individual with the same kind of symptoms. Gastroenterol Clin Biol. 2005 Aug-Sep. We report 3 new cases of Mitochondrial-Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE) (or Pseudo-Obstruction-Leukoencephalopathy-Intestinal-Pseudoobstruction Syndrome [POLIP]), a rare disease that associates chronic intestinal pseudo-obstruction (CIPO) and neurological symptoms. A review of the 72 reported cases together with these 3 cases revealed that this condition was associated with (a) a specific cluster of neurological symptoms including leukoencephalopathy (96%), polyneuropathy (96%), ophthalmoplegia (91%) and hearing loss (55%); (b) a CIPO syndrome with the presence of small bowel diverticulae (53%); and (c) mitochondrial cytopathy in 36 of the 37 tested patients (2 of our 3 cases), and thymidine phosphorylase gene mutations in all the 37 tested patients (2 of our cases). The etiology of POLIP/MNGIE syndrome appears therefore to be due to a mitochondrial cytopathy secondary to thymidine phosphorylase gene mutation(s). In 3 cases, including 2 of our 3 patients, mitochondrial abnormalities were evidenced at the ultrastructural level in digestive smooth muscle demonstrating that the pathogenesis of gastrointestinal involvement was directly related to mitochondrial alterations in digestive smooth muscle cells. Gene. 2005 Jul 18. Depletion and multiple deletions of mitochondrial DNA (mtDNA) have been associated with a number of autosomal disorders classified as defects of nuclear-mitochondrial intergenomic signaling. The mendelian forms of progressive external ophthalmoplegia (PEO) are clinically and genetically heterogeneous disorders characterized by the accumulation of multiple deletions of mtDNA in postmitotic patient's tissues. Most of the autosomal dominant PEO (adPEO) families carry heterozygous mutations in either one of three genes: ANT1, Twinkle, and POLG1. Mutations in POLG1 can also cause autosomal recessive PEO (arPEO) and apparently sporadic cases. In addition, recessive POLG1 mutations are responsible for sensory-atactic neuropathy, dysarthria and ophthalmoplegia (SANDO), juvenile spino-cerebellar ataxia-epilepsy syndrome (SCAE) and Alpers-Huttenlocher hepatopathic poliodystrophy. Mutations in thymidine phosphorylase gene (TP) are linked to mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder in which PEO is associated with gastrointestinal dysmotility and leukodystrophy. Finally, mitochondrial DNA depletion syndromes (MDS), defined by tissue-reduction in mtDNA copy number, have been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxyguanosine kinase (DGUOK). J Biol Chem. 2005 Jul 1. Mitochondrial (mt) DNA depletion syndromes can arise from genetic deficiencies for enzymes of dNTP metabolism, operating either inside or outside mitochondria. MNGIE is caused by the deficiency of cytosolic thymidine phosphorylase that degrades thymidine and deoxyuridine. The extracellular fluid of the patients contains 10-20 microM deoxynucleosides leading to changes in dTTP that may disturb mtDNA replication. In earlier work, we suggested that mt dTTP originates from two distinct pathways: (i) the reduction of ribonucleotides in the cytosol (in cycling cells) and (ii) intra-mt salvage of thymidine (in quiescent cells). In MNGIE and most other mtDNA depletion syndromes, quiescent cells are affected. Here, we demonstrate in quiescent fibroblasts (i) the existence of small mt dNTP pools, each usually 3-4% of the corresponding cytosolic pool; (ii) the rapid metabolic equilibrium between mt and cytosolic pools; and (iii) the intra-mt synthesis and rapid turnover of dTTP in the absence of DNA replication. Between 0.1 and 10 microM extracellular thymidine, intracellular thymidine rapidly approaches the extracellular concentration. We mimic the conditions of MNGIE by maintaining quiescent fibroblasts in 10-40 microM thymidine and/or deoxyuridine. Despite a large increase in intracellular thymidine concentration, cytosolic and mt dTTP increase at most 4-fold, maintaining their concentration for 41 days. Other dNTPs are marginally affected. Deoxyuridine does not increase the normal dNTP pools but gives rise to a small dUTP and a large dUMP pool, both turning over rapidly. We discuss these results in relation to MNGIE. J Neurol. 2005 Jun. We report on four patients with severe polyneuropathy associated with intestinal pseudoobstruction (MNGIE). Three patients presented characteristic supranuclear ophthalmoplegia, and hyperdense signals on T2 weighted cerebral MRI and dystrophic mitochondria in Schwann cells and in endothelial cells in nerve biopsy specimens. Two of these patients had a Charcot-Marie-Tooth (CMT) presentation. All three were heterozygous for a recessively transmitted double substitution in the TP gene: Glu286Lys/Glu289Ala, Asp156Gly/Leu177Pro and Glu289Ala/Gly387Asp. The fourth patient, who was the only patient of this series with an affected sib, had no oculomotor manifestations, nor T2 hyperdense signals on brain MRI, and no TP gene mutation and or morphological abnormalities of mitochondria on electron microscopic examination. He was the only patient of this series with an affected sib. The three patients with the full MNGIE syndrome died before the age of 30 years. Detailed results of nerve pathology show that severe axonal degeneration is associated with segmental abnormalities of the myelin sheath in this syndrome which appears genetically heterogeneous. Our findings suggest that only ophthalmoplegia and hyperdense signals on cerebral MRI are directly related to the mitochondriopathy. Mol Genet Metab. 2005 Apr. The mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal and neurological symptoms. It is a rare autosomal recessive mitochondrial disorder with multiple mitochondrial DNA deletions and/or depletion. It is caused by thymidine phosphorylase (TP) gene mutations resulting in a complete abolition of TP activity. We tested 31 unrelated patients presenting either with a complete MNGIE syndrome (8 patients), a severe intestinal pseudo-obstruction (10 patients), and multiple deletions and/or depletion of mitochondrial DNA (13 patients). All the tested patients presenting with a complete MNGIE had increased thymidine levels in plasma and urine, and no TP activity. The group with pseudo-obstruction syndrome had normal or partial reduction of TP activity. We found pathogenic mutations on TP gene only in the MNGIE syndrome group: all the MNGIE patients were compound heterozygous or homozygous for mutations in the TP gene. Eight of these mutations are yet unreported, confirming the lack of genotype/phenotype correlation in this syndrome. Enzymatic activity and thymidine level are thus rapid diagnosis tests to detect MNGIE affected patients prior to genetic testing for patients with gastrointestinal symptoms. J Clin Neurosci. 2005 Feb. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal-recessive disease associated with multiple deletions of mitochondrial DNA in skeletal muscle. MNGIE is a multisystem syndrome affecting muscle, peripheral, and central nervous systems and the gastrointestinal tract. A 25-year-old man is presented with 3 years history of right sided trigeminal neuralgia. He has been diagnosed as MNGIE based on clinical, neurophysiological and pathological findings. He had also received medical therapy and two radiofrequency thermocoagulations for the treatment of trigeminal neuralgia. Gamma Knife radiosurgery was performed and resulted in partial relief. To our knowledge, this is the first case in the literature of MNGIE with trigeminal neuralgia. An analogy is suggested between multiple sclerosis and MNGIE as a cause for trigeminal neuralgia in this patient. J Neurol Sci. 2005 Jan 15. A 29-year-old Spanish man presented with chronic intestinal pseudo-obstruction, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy. This combination of clinical features is characteristic of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Genetic analysis revealed a novel 18-base pair (bp) duplication (5044-5061 dup) in exon 8 of the thymidine phosphorylase (TP) gene. The mutation is predicted to produce a 6 amino acid insertion in the alpha-beta-domain of the protein. This 18-bp insertion in the thymidine phosphorylase gene is the first duplication mutation identified in MNGIE. Ann Neurol. 2004 Dec. Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive multisystemic disorder caused by thymidine phosphorylase deficiency. Whereas the pathomechanism of the secondary mitochondrial dysfunction has been extensively studied, that of the leukoencephalopathy has not been elucidated. We hypothesized that the white matter hyperintensities on T2-weighted magnetic resonance images reflect disturbance of blood-brain barrier function. Albumin immunohistochemistry disclosed quantitative (p < 0.01) and qualitative differences between the mitochondrial neurogastrointestinal encephalomyopathy and control brains, indicating that loss of thymidine phosphorylase function impairs the integrity of the blood-brain barrier. Pediatr Neurol. 2004 Nov. This report describes a child having the syndrome of overlapping phenotypic features of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Mitochondrial DNA analysis revealed a point mutation at position A3243G, whereas activity of thymidine phosphorylase and its corresponding gene analysis were normal. The most striking feature of this case was paralysis of one segment of the terminal ileum observed on laparotomy. The electron microscopic findings of the resected ileum and colon by limited right hemicolectomy disclosed accumulation of numerous enlarged mitochondria with ill-defined cristae which were similar to mitochondria reported in three previous MELAS cases and one MNGIE case with intestinal dysmotility. We emphasize that the MELAS and MNGIE phenotypes overlapped in this case and that the mechanism of acute ileus in MELAS was associated with functional paralysis of the intestine. Graefes Arch Clin Exp Ophthalmol. 2004 Oct. PURPOSE: To describe the ocular features of a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) due to a homozygous G1443A mutation in the thymidine-phosphorylase gene. METHODS: A case report with extensive ophthalmological investigation over a 9-year period, until death at age 38 years. Measures used included standard ophthalmological examination, visual field examination and optical coherence tomography (OCT). RESULTS: Ptosis and external ophthalmoplegia progressively worsened during the follow-up, as did the neurological and general status. Corneal and optic disc alterations were also observed at the last visit. Glaucomatous changes of the optic disc were confirmed by the visual field examination and OCT. CONCLUSION: In addition to previously described alterations such as ptosis and external ophthalmoplegia, MNGIE may be associated with glaucomatous-like optic neuropathy. Nucleosides Nucleotides Nucleic Acids. 2004 Oct. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). The disease is characterized clinically by impaired eye movements, gastrointestinal dysmotility, cachexia, peripheral neuropathy, myopathy, and leukoencephalopathy. Molecular genetic studies of MNGIE patients' tissues have revealed multiple deletions, depletion, and site-specific point mutations of mitochondrial DNA. TP is a cytosolic enzyme required for nucleoside homeostasis. In MNGIE, TP activity is severely reduced and consequently levels of thymidine and deoxyuridine in plasma are dramatically elevated. We have hypothesized that the increased levels of intracellular thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in turn, lead to the mtDNA abnormalities. MNGIE was the first molecularly characterized genetic disorder caused by abnormal mitochondrial nucleoside/nucleotide metabolism. Future studies are likely to reveal further insight into this expanding group of diseases. Mitochondrion. 2004 Sep. The clinical presentation of mitochondrial disease can involve a number of organ systems which are seemingly unrelated. Gastrointestinal manifestations are often an early presentation of mitochondrial disorders. Dysphagia, feeding difficulties, gastroesophageal reflux, dysmotility with delayed gastric emptying, intestinal pseudo-obstruction, diarrhea and pancreatic exocrine insufficiency are amongst the major complications. Neuromuscular dysfunction affecting peristalsis is a common pathophysiologic mechanism causing many of these symptoms and treatment is primarily supportive. AJR Am J Roentgenol. 2004 Jun. OBJECTIVE: The purpose of this study was to retrospectively review MR images of the brain in five patients diagnosed with mitochondrial neurogastrointestinal encephalomyopathy. CONCLUSION: Our research supports previously reported findings of confluent abnormal cerebral white matter in patients with mitochondrial neurogastrointestinal encephalomyopathy. In contrast to prior studies, our cohort of five patients showed that involvement of the corpus callosum as well as the capsular white matter, basal ganglia, thalami, midbrain, pons, and cerebellar white matter is not rare and does not preclude the diagnosis of mitochondrial neurogastrointestinal encephalomyopathy. Muscle Nerve. 2004 Mar. We report five patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) who had demyelinating peripheral neuropathy. The MNGIE neuropathy had clinical and electrodiagnostic features typical of acquired, rather than inherited, etiologies. In fact, three patients were actually treated for chronic inflammatory demyelinating polyneuropathy (CIDP). We discuss findings that may help distinguish patients with MNGIE from those with CIDP. J Med Genet. 2004 Feb. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive multisystem disorder caused by thymidine phosphorylase (TP) deficiency, resulting in severe gastrointestinal dysmotility and skeletal muscle abnormalities. A patient is reported with a classical MNGIE clinical presentation but without skeletal muscle involvement at morphological, enzymatic, or mitochondrial DNA level, though gastrointestinal myopathy was present. MNGIE was diagnosed by markedly raised plasma thymidine and reduced thymidine phosphorylase activity. Molecular genetic analysis showed a homozygous novel splice site mutation in TP. On immunohistochemical studies there was marked TP expression in the CNS, in contrast to what has been observed in rodents. It is important to examine the most significantly affected tissue and to measure TP activity and plasma thymidine in order to arrive at an accurate diagnosis in this condition. Hum Mol Genet. 2004 Jan 1. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive multisystem disorder associated with depletion, multiple deletions and site-specific point mutations of mitochondrial DNA (mtDNA). MNGIE is caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP; endothelial cell growth factor 1). Deficiency of TP leads to dramatically elevated levels of circulating thymidine and deoxyuridine. The alterations of pyrimidine nucleoside metabolism are hypothesized to cause imbalances of mitochondrial nucleotide pools that, in turn, may cause somatic alterations of mtDNA. We have now identified five major forms of mtDNA deletions in the skeletal muscle of MNGIE patients. While direct repeats and imperfectly homologous sequences appear to mediate the formation of mtDNA deletions, the nicotinamide adenine dinucleotide dehydrogenase 5 gene is a hot-spot for these rearrangements. A novel aspect of the mtDNA deletions in MNGIE is the presence of microdeletions at the imperfectly homologous breakpoints. Clin Chem. 2004 Jan. BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the gene encoding thymidine phosphorylase (TP). The clinical manifestations of MNGIE are recognizable and homogeneous, but in the early stages, the disease is often misdiagnosed. This study assesses the reliability of biochemical assays to diagnose MNGIE. METHODS: We studied 180 patients with clinical features suggestive of MNGIE, 14 asymptomatic TP mutation carriers, and 20 controls. TP enzyme activity in the buffy coat was determined by a fixed-time method, and the plasma nucleosides thymidine (dThd) and deoxyuridine (dUrd) were assessed by a gradient-elution reversed phase HPLC method. TP was sequenced through standard procedures in patients who met the clinical criteria for MNGIE. RESULTS: Twenty-five of the 180 patients fulfilled the clinical criteria for MNGIE and had homozygous or compound heterozygous TP mutations. All had drastically decreased TP activity [mean (SD), 10 (15) nmol thymine formed. h(-1). (mg protein)(-1) vs 634 (217) nmol thymine formed. h(-1). (mg protein)(-1) for the controls]. Relative to the control mean, TP activities were reduced to 35% in mutation carriers and 65% in MNGIE-like patients. All 25 MNGIE patients had detectable plasma dThd [8.6 (3.4) micromol/L] and dUrd [14.2 (4.4) micromol/L]. Controls, carriers, and MNGIE-like patients showed no detectable plasma dThd and dUrd. CONCLUSIONS: We propose a diagnostic algorithm based on the determination of plasma dThd and dUrd, TP activity in buffy coat, or both to make a definitive diagnosis of MNGIE. Increased concentrations of dThd (>3 micromol/L) and dUrd (>5 micromol/L) in plasma or a decrease in buffy coat TP activity to </=8% relative to controls is sufficient to diagnose MNGIE. Neurologist. 2004 Jan. BACKGROUND: Mitochondrial encephalomyopathies are clinically and genetically heterogeneous because mitochondria are the products of 2 genomes: mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Among the mendelian-inherited mitochondrial diseases are defects of intergenomic communication, disorders due to nDNA mutations that cause depletion and multiple deletions of mtDNA. REVIEW SUMMARY: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder of intergenomic communication and is defined clinically by 1) severe gastrointestinal dysmotility; 2) cachexia; 3) ptosis, ophthalmoparesis, or both; 4) peripheral neuropathy; and 5) leukoencephalopathy. Skeletal muscle biopsies of patients have revealed abnormalities of mtDNA and mitochondrial respiratory chain enzymes. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. In MNGIE patients, TP enzyme activity is reduced drastically, and plasma thymidine and deoxyuridine are elevated dramatically. We have hypothesized that alterations of nucleoside metabolism cause an imbalanced mitochondrial nucleotide pool that leads to depletion and deletions of mtDNA. CONCLUSIONS: MNGIE is a recognizable clinical syndrome caused by mutations in TP. The diagnosis can be confirmed by measuring TP activity in buffy coat or plasma levels of thymidine and deoxyuridine. Reduction of circulating thymidine and deoxyuridine in MNGIE patients may be therapeutic. Gastroenterol Clin North Am. 2003 Sep. Although non-specific gastrointestinal and hepatic symptoms are commonly found in most mitochondrial disorders, they are among the cardinal manifestations of several primary mitochondrial diseases, such as: mitochondrial neurogastrointestinal encephalomyopathy; mitochondrial DNA depletion syndrome; Alpers syndrome; and Pearson syndrome. Management of these heterogeneous disorders includes the empiric supplementation with various "mitochondrial cocktails," supportive therapies, and avoidance of drugs and conditions known to have a detrimental effect on the respiratory chain. There is a great need for improved methods of treatment and controlled clinical trials of existing therapies. Liver transplantation is successful in acquired cases; however neuromuscular involvement in primary mitochondrial disorders should be a contraindication for liver transplantation. Eur J Hum Genet. 2003 Jul. Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associated with multiple mitochondrial DNA deletions and can be caused by missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is another autosomal recessive disorder associated with PEO and multiple deletions of mitochondrial DNA in skeletal muscle. In several patients this disorder is caused by loss of function mutations in the gene encoding thymidine phosphorylase (TP). We report a recessive family with features of MNGIE but no leukoencephalopathy in which two patients carry three missense mutations in POLG, of which two are novel mutations (N846S and P587L). The third mutation was previously reported as a recessive POLG mutation (T251I). This finding indicates the need for POLG sequencing in patients with features of MNGIE without TP mutations. Clin Chem Lab Med. 2003 Jul. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). TP deficiency alters the metabolism of the nucleosides thymidine and deoxyuridine, which, in turn, produces abnormalities of mitochondrial DNA (mtDNA) including depletion, deletions, and point mutations. MNGIE is the best characterized of the expanding number of mitochondrial disorders caused by alterations in the metabolism of nucleosides/nucleotides. Because mitochondria contain their own machinery for nucleoside and nucleotide metabolism and have physically separate nucleotide pools, it is not surprising that disorders of these pathways cause human diseases. Other diseases in this group include mtDNA depletion syndromes caused by mutations on the nuclear genes encoding the mitochondrial thymidine kinase and deoxyguanosine kinase; autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA due to mutations in the genes encoding the muscle-isoform of mitochondrial ADP/ATP translocator; and mitochondrial DNA depletion due to toxicities of nucleoside analogues. Mutations in the deoxynucleotide carrier, a transporter of deoxynucleoside diphosphates, have been identified as a cause of congenital microcephaly. However, alterations of mtDNA have not yet been established in this disorder. Future studies are likely to reveal additional diseases and provide further insight into this new subject. J Clin Invest. 2003 Jun. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). This deficiency of TP leads to increased circulating levels of thymidine (deoxythymidine, dThd) and deoxyuridine (dUrd) and has been associated with multiple deletions and depletion of mitochondrial DNA (mtDNA). Here we describe 36 point mutations in mtDNA of tissues and cultured cells from MNGIE patients. Thirty-one mtDNA point mutations (86%) were T-to-C transitions, and of these, 25 were preceded by 5'-AA sequences. In addition, we identified a single base-pair mtDNA deletion and a TT-to-AA mutation. Next-nucleotide effects and dislocation mutagenesis may contribute to the formation of these mutations. These results provide the first demonstration that alterations of nucleoside metabolism can induce multiple sequence-specific point mutations in humans. We hypothesize that, in patients with TP deficiency, increased levels of dThd and dUrd cause mitochondrial nucleotide pool imbalances, which, in turn, lead to mtDNA abnormalities including site-specific point mutations. Biochem Biophys Res Commun. 2003 Mar 28. Mutations in the nuclear gene encoding thymidine phosphorylase (TP) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disease with mitochondrial dysfunction and mitochondrial DNA abnormalities. We have demonstrated alterations of thymidine (dThd) metabolism in MNGIE patients. Here, we report the accumulation of another substrate of TP, deoxyuridine (dUrd), whose circulating levels ranged from 5.5 to 24.4 microM (average 14.2) in MNGIE and were undetectable (<0.05 microM) in both TP mutation carriers and controls. The dramatic accumulation of dUrd may contribute to nucleotide pool imbalances and, together with the increased levels of dThd, is likely to contribute to the pathogenesis of MNGIE. Am J Otolaryngol. 2003 Mar-Apr. No abstract available. Eur J Hum Genet. 2003 Jan. Mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) is a rare autosomal recessive neurologic disorder characterised by multiple mitochondrial DNA deletions. In this study, five Turkish MNGIE patients are investigated for mtDNA deletions and TP gene mutations. The probands presented all the clinical criteria of the typical MNGIE phenotype; the muscle biopsy specimens also confirmed the diagnosis with ragged red fibres and cytochrome C oxidase (COX) negative fibres. The mitochondrial DNA analysis revealed no deletions in the probands' skeletal muscle samples. We have identified four novel mutations in the TP gene while one of the patients also harboured a nucleotide change, which was previously reported as a mutation. Mitochondrion. 2002 Nov. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease with mitochondrial DNA (mtDNA) alterations and is caused by mutations in the nuclear gene encoding thymidine phosphorylase (TP). The cardinal clinical manifestations are ptosis, ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. Skeletal muscle shows mitochondrial abnormalities, including ragged-red fibers and cytochrome c oxidase deficiency, together with mtDNA depletion, multiple deletions or both. In MNGIE patients, TP mutations cause a loss-of-function of the cytosolic enzyme, TP. As a direct consequence of the TP defect, thymidine metabolism is altered. High blood levels of this nucleoside are likely to lead to mtDNA defects even in cells that do not express TP, such as skeletal muscle. We hypothesize that high concentrations of thymidine affect dNTP (deoxyribonucleoside triphosphate) metabolism in mitochondria more than in cytosol or nuclei, because mitochondrial dNTPs depend mainly on the thymidine salvage pathway, whereas nuclear dNTPs depend mostly on de novo pathway. The imbalance in the mitochondrial dNTP homeostasis affects mtDNA replication, leading to mitochondrial dysfunction. Neurology. 2002 Sep 24. Two sisters developed gastrointestinal malabsorption with pain and unsteady gait due to polyneuropathy at age 15. Both had ophthalmoplegia, neurogenic EMG, and COX-negative muscle fibers. One patient had low muscle complex I-IV activity, multiple mtDNA deletions, and depletion, but no thymidine phosphorylase (TP) or dNT-2 gene mutations. TP activity and brain MRI were normal. The condition resembles mitochondrial neurogastrointestinal encephalomyopathy, except for the absence of leukoencephalopathy, and is likely caused by a nuclear DNA mutation that disrupts intergenomic signaling. J Pediatr Gastroenterol Nutr. 2002 Sep. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare disorder that presents in childhood; however, marked delay in diagnosis is common. We report a case and review the literature describing the typical features that should alert pediatricians to the diagnosis. We also describe a novel management strategy for providing symptomatic relief. Neurology. 2002 Aug 13. Clinical, biochemical, and genetic features of a Spanish family with mitochondrial neurogastrointestinal encephalomyopathy are reported. The proband presented with severe gastrointestinal dysmotility and the affected sister had extraocular muscle weakness. In both affected individuals, biochemical defects of thymidine phosphorylase and a pathogenic G-to-A transition mutation at nucleotide 435 in the thymidine phosphorylase gene were identified. The first thymidine phosphorylase mutation identified in Spain showed phenotypic variability at onset. Mol Cell Biol. 2002 Jul. Thymidine phosphorylase (TP) regulates intracellular and plasma thymidine levels. TP deficiency is hypothesized to (i) increase levels of thymidine in plasma, (ii) lead to mitochondrial DNA alterations, and (iii) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In order to elucidate the physiological roles of TP, we generated mice deficient in the TP gene. Although TP activity in the liver was inhibited in these mice, it was fully maintained in the small intestine. Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. We therefore generated TP-UP double-knockout (TP(-/-) UP(-/-)) mice. TP activities were inhibited in TP(-/-) UP(-/-) mice, and the level of thymidine in the plasma of TP(-/-) UP(-/-) mice was higher than for TP(-/-) mice. Unexpectedly, we could not observe alterations of mitochondrial DNA or pathological changes in the muscles of the TP(-/-) UP(-/-) mice, even when these mice were fed thymidine for 7 months. However, we did find hyperintense lesions on magnetic resonance T(2) maps in the brain and axonal edema by electron microscopic study of the brain in TP(-/-) UP(-/-) mice. These findings suggested that the inhibition of TP activity caused the elevation of pyrimidine levels in plasma and consequent axonal swelling in the brains of mice. Since lesions in the brain do not appear to be due to mitochondrial alterations and pathological changes in the muscle were not found, this model will provide further insights into the causes of MNGIE. J Clin Gastroenterol. 2002 Apr. Mitochondrial neurogastrointestinal encephalomyopathy is a rare, multisystem disorder characterized by gastrointestinal dysmotility, ptosis, neurologic findings (e.g., peripheral neuropathy), leukoencephalopathy, and thin body habitus. Gastrointestinal motility studies and skeletal muscle biopsy are recommended diagnostic tools. We report two patients that highlight the diagnostic characteristics of this rare entity. Dtsch Med Wochenschr. 2002 Mar 22. HISTORY AND CLINICAL FINDINGS: A 24-year-old female patient suffered for 4 months from recurrent abdominal pain, vomiting and diarrhea. Signs of an acute abdomen were the initial reason for admitting the patient to our hospital. The slim, pale patient had a complete bloated abdomen. Neurological status was normal. INVESTIGATIONS, TREATMENT AND COURSE: Radiographic examination showed a paralytic ileus with a megacolon. The recurrent abdominal symptoms were due to a covered perforation of the stomach. This was shrunken, scarred and had to be resected. Further intestinal pseudoobstructions were accompanied by substantial exsudations in the lungs, intestines and abdomen. At this time mutism like behavior patterns and an ophthalmoplegia appeared. Leukoencephalopathy in brain MRI scans and increased liquor-lactate suggested mitochondrial myopathy. DIAGNOSIS: The diagnosis of a mitochondrial myopathy was confirmed by increased liquor-lactate level, muscle biopsy with ragged-red fibers as well as abnormal mitochondrias and molecular-genetic investigations (mtDNA point mutation A3243G). Associations to MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and MNGIE (mitochondrial neuro-gastrointestinal encephalomyopathy) syndrome are discussed. CONCLUSIONS: Unclear recurrent gastrointestinal symptoms even in the absence of neurological changes may reflect a mitochondrial disease. This applies especially to young patients with recurrent anorexia, vomiting and pseudoobstruction. In case of additional symptoms like ophthalmopathy, deafness, diabetes mellitus or signs of a MELAS syndrome the search for a mitochondrial system disorder is mandatory. J Biol Chem. 2002 Feb 8. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive human disease due to mutations in the thymidine phosphorylase (TP) gene. TP enzyme catalyzes the reversible phosphorolysis of thymidine to thymine and 2-deoxy-D-ribose 1-phosphate. We present evidence that thymidine metabolism is altered in MNGIE. TP activities in buffy coats were reduced drastically in all 27 MNGIE patients compared with 19 controls. All MNGIE patients had much higher plasma levels of thymidine than normal individuals and asymptomatic TP mutation carriers. In two patients, the renal clearance of thymidine was approximately 20% that of creatinine, and because hemodialysis demonstrated that thymidine is ultrafiltratable, most of the filtered thymidine is likely to be reabsorbed by the kidney. In vitro, fibroblasts from controls catabolized thymidine in medium; by contrast, MNGIE fibroblasts released thymidine. In MNGIE, severe impairment of TP enzyme activity leads to increased plasma thymidine. In patients who are suspected of having MNGIE, determination of TP activity in buffy coats and thymidine levels in plasma are diagnostic. We hypothesize that excess thymidine alters mitochondrial nucleoside and nucleotide pools leading to impaired mitochondrial DNA replication, repair, or both. Therapies to reduce thymidine levels may be beneficial to MNGIE patients. Rev Neurol. 2001 Aug 16-31. INTRODUCTION: Jejunal and ileal diverticula are acquired lesions that are often associated with intestinal motility disturbances like those occurring in myopathies and neuropathies with visceral affection. Mitochondrial neurogastrointestinal encephalomyopathy is characterized by gastrointestinal dysmotility, cachexia, ptosis with external ophthalmoparesis, neuropathy, leukoencephalopathy and laboratory evidence of mitochondrial alteration. CLINICAL CASE: A female patient that since 9 months age presented digestive symptoms: diarrhea, nauseous, vomits, slow digestions and abdominal pain. She had myopia. At the age of 20, in a seven months period, she precised urgent abdominal surgical intervention in three occasions for acute diffuse peritonitis related to jejunal and ileal diverticula. She presented cachexia, mild palpebral ptosis, external ophthalmoparesis, hypertrophic major auricular nerves, scoliosis, pes cavus, distal weakness and hypoesthesia in extremities, bilateral neurosensorial hypoacusia and lactic acidosis. The electroneurographic study was compatible with severe chronic demyelinating sensitive motor polyneuropathy. In the cerebral MR leukoencephalopathy was detected. In muscular tissue it was seen alteration in all fibers type I with numerous lipid vacuoles and an increase of mitochondrial number in the form of thick grains and subsarcolemmal mitochondrial bags. There was no ragged red fibers nor ultrastructural mitochondrial alterations. There was chain respiratory complex III deficiency. CONCLUSIONS: In patients with intestinal dysmotility manifestations and jejunal and ileal diverticula neuropathies and myopathies with visceral affection must be suspected, among them MNGIE syndrome. Neuromuscul Disord. 2001 Jan. 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. Gut. 2001 Jan. BACKGROUND: Mitochondrial DNA (mtDNA) defects are an important cause of disease. Although gastrointestinal symptoms are common in these patients, their pathogenesis remains uncertain. AIM: To investigate the role of the mtDNA defect in the production of gastrointestinal dysfunction. PATIENT: A 20 year old woman who presented at 15 years of age with recurrent vomiting and pseudo-obstruction, who did not respond to conservative management and ultimately had subtotal gastrectomy and Roux-en-y reconstruction. She subsequently presented with status epilepticus and was found to have a mitochondrial respiratory chain disorder due to a pathogenic mtDNA point mutation (A3243G). METHODS: Resected bowel was studied using light and electron microscopy and mtDNA analysed from both mucosal and muscular layers using polymerase chain reaction generated RFLP analysis. RESULTS: Histological and electron microscopic studies revealed no morphological abnormalities in the resected stomach, and molecular genetic analysis failed to identify the genetic defect in either the mucosal or muscle layers. CONCLUSION: This study suggests that in some individuals with gastrointestinal symptoms associated with established mitochondrial DNA disease, the primary pathology of the mitochondrial enteropathy lies outside the gastrointestinal tract. Brain Pathol. 2000 Jul. An expanding number of autosomal diseases has been associated with mitochondrial DNA (mtDNA) depletion and multiple deletions. These disorders have been classified as defects of intergenomic communication because mutations of the nuclear DNA are thought to disrupt the normal cross-talk that regulates the integrity and quantity of mtDNA. In 1989, autosomal dominant progressive external ophthalmoplegia with multiple deletions of mitochondrial DNA was the first of these disorders to be identified.Two years later, mtDNA depletion syndrome was initially reported in infants with severe hepatopathy or myopathy. The causes of these diseases are still unclear, but genetic linkage studies have identified three chromosomal loci for AD-PEO. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder associated with both mtDNA depletion and multiple deletions, is now known to be due to loss-of-function mutations in the gene encoding thymidine phosphorylase. Increased plasma thymidine levels in MNGIE patients suggest that imbalanced nucleoside and nucleotide pools in mitochondria may lead to impaired replication of mtDNA. Future research will certainly lead to the identification of additional genetic causes of intergenomic communication defects and will likely provide insight into the normal "dialogue" between the two genomes. Ann Neurol. 2000 Jun. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both; peripheral neuropathy; leukoencephalopathy; and mitochondrial abnormalities. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. We identified 21 probands (35 patients) who fulfilled our clinical criteria for MNGIE. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudo-obstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26-58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. We have identified 16 TP mutations. Homozygous or compound heterozygous mutations were present in all patients tested. Leukocyte TP activity was reduced drastically in all patients tested, 0.009 +/- 0.021 micromol/hr/mg (mean +/- SD; n = 16), compared with controls, 0.67 +/- 0.21 micromol/hr/mg (n = 19). MNGIE is a recognizable clinical syndrome caused by mutations in thymidine phosphorylase. Severe reduction of TP activity in leukocytes is diagnostic. Altered mitochondrial nucleoside and nucleotide pools may impair mtDNA replication, repair, or both. Dig Dis. 2000. Chronic intestinal pseudo-obstruction (CIPO) is a syndrome defined by the presence of chronic intestinal dilation and dysmotility in the absence of mechanical obstruction or gross inflammatory disease. Specific diseases may affect any level of the brain-gut axis. For most patients, the diagnosis relies upon a combination of historical, laboratory, manometric and histological features. Recent advances into the autoimmune nature of etiologies such as Chagas' disease and paraneoplastic dysmotility and into the genetic basis of mitochondrial neurogastrointestinal encephalomyopathy, multiple endocrine neoplasia IIB and Hirschsprung's disease have greatly refined our understanding and diagnosis of these disorders. At present, medical therapy of CIPO remains limited. Current and future developments in pharmacologic agents targeting specific enteric neurotransmitters and motility patterns hold much promise for improving the care of the patients afflicted with this complex and often debilitating syndrome. Science. 1999 Jan 29. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive human disease associated with multiple deletions of skeletal muscle mitochondrial DNA (mtDNA), which have been ascribed to a defect in communication between the nuclear and mitochondrial genomes. Examination of 12 MNGIE probands revealed homozygous or compound-heterozygous mutations in the gene specifying thymidine phosphorylase (TP), located on chromosome 22q13.32-qter. TP activity in leukocytes from MNGIE patients was less than 5 percent of controls, indicating that loss-of-function mutations in TP cause the disease. The pathogenic mechanism may be related to aberrant thymidine metabolism, leading to impaired replication or maintenance of mtDNA, or both. Neurology. 1998 Oct. OBJECTIVE: To describe the unique combination of partial depletion and multiple deletions of mitochondrial DNA (mtDNA) on muscle DNA analysis of three siblings with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). BACKGROUND: MNGIE is a relatively homogeneous autosomal recessive disorder characterized by gastrointestinal dysmobility, ophthalmoparesis, peripheral neuropathy, mitochondrial myopathy, and altered white matter signal at brain imaging. Muscle multiple mtDNA deletions have been found in about half of the described cases. METHODS: We studied three affected siblings (two were monozygotic twins) born to nonconsanguineous parents. Muscle mtDNA was investigated by quantitative Southern and Slot blot techniques and by PCR analysis. Morphologic confirmation in the muscle tissue was achieved by using in situ hybridization with a mtDNA probe complementary to an undeleted region and by DNA immunohistochemistry. RESULTS: All three patients showed ragged red (RRF) and cytochrome c oxidase-negative fibers, as well as partial deficiency of complexes I and IV. Southern and Slot blot analyses showed mtDNA depletion in all patients. Multiple mtDNA deletions were also detected by PCR analysis. In situ hybridization demonstrated an overall signal weaker than controls, with a relatively higher signal in RRF. Antibodies against DNA showed a decreased cytoplasmic network. CONCLUSIONS: The muscle histopathology and respiratory chain enzyme defects may be accounted for by the decreased mtDNA amount and by the presence of mtDNA deleted molecules; however, relative levels of mtDNA seem to correlate with life span in these patients. The combination of partial depletion and multiple deletions of mtDNA might indicate the derangement of a common genetic mechanism controlling mtDNA copy number and integrity. Am J Surg Pathol. 1998 Sep. A 14-year-old girl with the mitochondrial neurogastrointestinal encephalopathy syndrome had an 8-year history of intestinal pseudoobstruction with abdominal pain, persistent vomiting, gastric and duodenal dilatation, and duodenal diverticulosis. The child appeared chronically malnourished and had severe growth failure. Multisystem involvement was evident with the presence of ptosis, external ophthalmoplegia, muscle wasting, peripheral neuropathy, and diffuse white matter disease seen on magnetic resonance imaging. Lactic acidosis and increased cerebrospinal fluid protein were observed. Mitochondrial enzyme analysis of fresh-frozen skeletal muscle revealed a respiratory chain defect. Molecular genetic studies showed multiple mitochondrial DNA deletions. Pathologic findings in the intestine included atrophy of the external layer of the muscularis propria and an increased number of abnormal-appearing mitochondria in ganglion and smooth-muscle cells. Microvesicular steatosis was observed in liver, skeletal, and gastrointestinal smooth muscle, and Schwann cells of peripheral nerve. Brightly eosinophilic inclusions in the cytoplasm of gastrointestinal ganglion cells were visible by light microscopy, which were confirmed to be megamitochondria by ultrastructural studies. This is the first report of abnormal mitochondria observed in intestinal ganglion and smooth-muscle cells in this syndrome. Am J Hum Genet. 1998 Aug. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare, multisystem disorder characterized clinically by ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility, leukoencephalopathy, thin body habitus, and myopathy. Laboratory studies reveal defects of oxidative-phosphorylation and multiple mtDNA deletions frequently in skeletal muscle. We studied four ethnically distinct families affected with this apparently autosomal recessive disorder. Probands from each family were shown, by Southern blot, to have multiple mtDNA deletions in skeletal muscle. We mapped the MNGIE locus to 22q13.32-qter, distal to D22S1161, with a maximum two-point LOD score of 6.80 at locus D22S526. Cosegregation of MNGIE with a single chromosomal region in families with diverse ethnic backgrounds suggests that we have mapped an important locus for this disorder. We found no evidence to implicate three candidate genes in this region, by using direct sequence analysis for DNA helicase II and by assaying enzyme activities for arylsulfatase A and carnitine palmitoyltransferase. Acta Neuropathol (Berl). 1998 Jul. A 40-year-old woman who developed intestinal dysmobility was found, at rectal biopsy, to have marked microvacuolation of mucosal muscle layer cells, which corresponded to increased accumulation of abnormal mitochondria. Skeletal muscle biopsy specimens showed ragged-red fibers, vessels strongly reactive for succinic dehydrogenase, and focal deficiency of cytochrome c oxidase. Autopsy performed at the age of 50 revealed prominent accumulation of abnormal mitochondria in the intestinal smooth muscle cells with a mottled distribution of focal necrosis, multiple small cerebral infarcts with diffuse neuronal loss, and rarefaction of the perivascular white matter. Mitochondrial DNA analysis showed a point mutation at position 3243. This case, showing features of both mitochondrial neurogastrointestinal encephalomyopathy and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), indicates that routine intestinal biopsy can detect mitochondrial encephalomyopathy with gastrointestinal involvement. The main intestinal changes were extensive accumulation of abnormal mitochondria in the leiomyocytes and scattered focal necrosis. Rev Neurol (Paris). 1997 Oct. Two siblings (one man, one woman), presenting with diarrhea, severe weight loss peripheral neuropathy, ophthalmoparesis, asymptomatic leukoencephalopathy were diagnosed as a new cases of Mitochondrial Neuro Gastro Intestinal Encephalomyopathy syndrome (MNGIE). Hirano (1994) defined four criteria for the diagnostic: peripheral neuropathy, ophthalmoparesis, gastro intestinal dysmotility, muscle biopsy with histologic features of mitochondrial myopathy (ragged-red fibers, muscle fibers with increased succinate deshydrogenase stain or ultra structurally abnormal mitochondria). In a review of the literature, we found 31 cases with MNGIE. With our two cases, we study this group of 33 patients. First symptoms begin about 13.5 years with a median of 10 years and extremes for 1 to 32 years. The first signs are gastro intestinal symptoms (recurrent nausea, vomiting or diarrhea with intestinal dysmotility) in 22 cases, an ophthalmoparesia in 4 cases, intestinal and ocular signs in 1 case, gait ataxia or peripheral neuropathy in 3 cases, hearing loss in 1 case, gait ataxia or peripheral neuropathy in 3 cases, hearing loss in 1 case. During the evolution, besides the cardinal signs, the following features have been observed with a variable frequency: hearing loss, short stature, facial palsy, dysphonia, dysarthria, sweating, orthostatic hypotension, bladder dysfunction, hepatomegalia, The laboratory features are: abnormal Nerve Condition Studies/EMG compatible with a sensory motor neuropathy, lactic acidosis, mitochondrial respiratory chain defect (essentially complex IV deficiency, complex I deficiency or multiple complex defect), MRI leukodystrophy, elevated CSF protein, heart block, ragged-red fibers or increased SDH stain. The prognosis is poor, due to a severe weight loss bordering on cachexia 13 patients died with a mean age of 28.5 years (median 24 years, extreme 3 years to 51 years). The prognosis seems to be worsened by a young age of onset. The 33 patients belong to 19 families with 7 cases of consanguinity. 25 patients had a brother, a sister or a cousin affected. The study of these families is compatible with an autosomic recessive transmission, suggesting a pathology of the nuclear genomi, probably impliying the control of the mitochondrial DNA replication. In fact, in 13 cases, a study of the mt DNA was realized: multiple deletions were founded in 6 cases, multiples mutations in one case, unique mutation in 1 case. In 5 cases ther was no evidence of abnormality. These precise etiology and pathophysiologic significance of the mt DNA deletions, and the heterogeneity of the modifications of the mt DNA remain unknown. However, the possibility of various phenotypes for a same genotype or inversely is known in mitochondriopathies. Rinsho Shinkeigaku. 1997 Oct. We report a 56-year old female with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), presenting with protein-losing gastroenteropathy and serum copper deficiency. There was no neuromuscular disease in her family members. Three years prior to admission, she developed severe gastrointestinal symptoms including diarrhea, nausea, vomiting and ascites, and was diagnosed as having protein-losing gastroenteropathy based on alpha(1)-antitrypsin clearance and other tests. She was referred to our department when neurological symptoms were apparent. Neurological examinations revealed bilateral ptosis, ophthalmoplegia, hearing loss, facial and limb muscle weakness, mild sensory deficit of vibration on her feet and hypoactive deep tendon reflexes. Pigmentary retinopathy, cerebellar ataxia and heart block were not seen. Serum copper level was decreased to 45 micrograms/dl (normal: 83-155). Chronic intestinal pseudo-obstruction was proven by X-ray studies, and diffuse leukoencephalopathy demonstrated on brain MRI. On EMG, motor nerve conduction velocities were prolonged with temporal dispersion. Her muscle biopsy from biceps brachii muscle showed both neuropathic and myopathic changes, scattered ragged-red fibers and focal cytochrome c oxidase deficiency. Southern blot and polymerase chain reaction analysis on mitochondrial DNA showed no deletions nor point mutations. The clinical and pathologic findings of the present patient fulfilled the diagnostic criteria of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) proposed by Hirano et al. There are few reported patients with MNGIE in Japan, but none presented with protein-losing gastroenteropathy and serum copper deficiency. Since the copper is a cofactor of cytochrome c oxidase, decreased serum copper level may aggravate the respiratory chain enzyme metabolism in mitochondria. Therefore, treatment for gastrointestinal tract disturbance and copper administration may be necessary to prevent disease progression. Pediatr Neurol. 1996 Apr. Three children are reported with mitochondrial encephalomyopathy who presented with autonomic dysfunction. Autonomic dysfunction included gastrointestinal dysmotility, apnea, cardiac arrhythmias, decreased lacrimation, supersensitivity to metacholine, altered sweating, and postural hypotension. These patients illustrate that in some mitochondrial encephalomyopathies autonomic features may be prominent and can mimic the clinical features associated with hereditary sensory and autonomic neuropathies. Muscle Nerve. 1994 Jun. This article describes a 37-year-old woman with progressive external ophthalmoplegia, peripheral neuropathy, and chronic intractable diarrhea. Laboratory studies disclosed lactic acidosis, ragged red fibers lacking cytochrome c oxidase, high-normal muscular mitochondrial enzymes, demyelinating neuropathy, leukoencephalopathy and multiple mitochondrial DNA deletions. This is the fourth patient described with this clinical syndrome, which represents a separate entity among multisystemic mitochondrial disorders. The patient described here is the first with this syndrome to have multiple mitochondrial DNA deletions. Neurology. 1994 Apr. We studied the clinical, biochemical, and genetic features of eight patients with the autosomal recessive mitochondrial syndrome mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). MNGIE is clinically characterized by ophthalmoparesis, peripheral neuropathy, leukoencephalopathy, gastrointestinal symptoms (recurrent nausea, vomiting, or diarrhea) with intestinal dysmotility, and histologically abnormal mitochondria in muscle. Brain MRI scans were consistent with leukodystrophy in seven patients examined. Nerve conduction and EMG studies were compatible with a sensorimotor neuropathy; quantitative EMG of two patients suggested a myogenic process. Muscle mitochondrial enzyme analysis revealed a partial defect of cytochrome c oxidase activity in five patients; three had additional respiratory chain enzyme defects. Two patients had isolated complex I defects, and one had normal respiratory chain function. Southern blot analysis revealed multiple deletions of mitochondrial DNA in four of eight patients. Acta Neuropathol (Berl). 1987. A 42-year-old woman had a 10-year history of external ophthalmoplegia, malabsorption resulting in chronic malnutrition, muscle atrophy and polyneuropathy. Computer tomography revealed hypodensity of her cerebral white matter. A metabolic disturbance consisted of lactic acidosis after moderate glucose loads with increased excretion of hydroxybutyric and fumaric acids. Post-mortem studies revealed gastrointestinal scleroderma as the morphological manifestation of her malabsorption syndrome, ocular and skeletal myopathy with ragged red fibers, peripheral neuropathy, vascular abnormalities of meningeal and peripheral nerve vessels. Biochemical examination of the liver and muscle tissues revealed a partial defect of cytochrome-c-oxidase (complex IV of the respiratory chain). This mitochondrial multisystem disorder may represent a separate entity to be classified between the spectrum of myoencephalopathies and oculo-gastrointestinal muscular dystrophy. |