DiagnosisClinical DiagnosisThe diagnosis of MNGIE (mitochondrial neurogastrointestinal encephalopathy) disease is based on the presence of the following clinical findings [Hirano et al 1994, Nishino et al 1999, Nishino et al 2000]: Severe gastrointestinal (GI) dysmotility Cachexia Ptosis External ophthalmoplegia Sensorimotor neuropathy (usually mixed axonal and demyelinating) Asymptomatic leukoencephalopathy manifest as diffusely abnormal brain white matter (increased FLAIR or T₂-weighted signal) on brain MRI. Relative sparing of the corpus callosum is reported in some individuals [Vissing et al 2002, Hirano et al 2004]. (In the absence of leukoencephalopathy, MNGIE disease is very unlikely.) Family history consistent with autosomal recessive inheritanceNote: Although magnetic resonance spectroscopy (MRS) can show increases in lactate within the white matter, it is not a sensitive diagnostic test. TestingDirect evidence of MNGIE disease is provided by one of the following:Increase in plasma thymidine concentration greater than 3 µmol/L and increase in plasma deoxyuridine concentration greater than 5 µmol/L (sufficient to make the diagnosis of MNGIE disease [Marti et al 2004]) Thymidine phosphorylase enzyme (E.C.2.4.2.4) activity in leukocytes less than 10% of the control mean [Nishino et al 1999]
Note: Although unaffected, heterozygotes display about 30%-35% residual thymidine phosphorylase activity. Indirect evidence of MNGIE disease is provided by evidence of mitochondrial dysfunction manifest by any of the following:Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome c oxidase (complex IV).
Note: Normal muscle histopathology can be observed [Szigeti et al 2004]. Acquired mitochondrial DNA (mtDNA) mutations in any tissue. Mitochondrial DNA deletions/duplications are detected by Southern blot analysis and long-range PCR. Mitochondrial DNA depletion is detected by quantitation of mtDNA relative to nuclear DNA. Other metabolic abnormalities causing increased urine concentrations of deoxyuridine and thymidine. These compounds are not detectable in controls and heterozygous TYMP mutation carriers [Fairbanks et al 2002, Spinazzola et al 2002, Marti et al 2003a, Marti et al 2003b, Nishigaki et al 2003]. Post-mortem increase in nucleosides in all tissues [Valentino et al 2007].Molecular Genetic TestingGene. TYMP (previously known as ECGF1), the gene encoding thymidine phosphorylase, is the only gene known to be associated with MNGIE disease. Clinical testingSequence analysis Mutations are detected in genomic DNA by sequencing the TYMP exons and flanking regions in 100% of individuals with enzymatically proven MNGIE disease [Nishino et al 1999, Nishino et al 2000]. Affected individuals are either homozygotes or compound heterozygotes for the identified mutations. Splice-site mutations are identified by sequence analysis of genomic DNA. The pathogenicity of splice-site mutations is confirmed by identification of altered splicing in reverse transcriptase (RT) PCR assays. Table 1. Summary of Molecular Genetic Testing Used in Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) Disease View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityTYMPSequence analysisMissense mutations, microdeletions, insertions, splice-site mutations100% 2 Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutation detection frequency in those individuals with enzymatically proven MNGIE diseaseInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm the diagnosis in a probandDetection of elevated plasma concentrations of thymidine and deoxyuridine is sufficient to make the diagnosis of MNGIE disease. Measurement of thymidine phosphorylase enzyme activity in buffy coat samples confirms the diagnosis. Sequencing TYMP, the gene encoding thymidine phosphorylase, can identify pathogenic mutations for assessment of carrier status. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in TYMP.}

Natural HistoryGestation and delivery are normal. The earliest reported age of onset is five months; onset is usually between the first and fifth decades. In about 60% of individuals, symptoms begin before age 20 years [Nishino et al 2000, Teitelbaum et al 2002]. Prior to the onset of symptoms, many individuals with MNGIE disease are healthy, but usually have a long history of subtle fatigability. The order in which manifestations appear is unpredictable; however, in one review, the first symptoms were gastrointestinal in about 67%, ptosis/ophthalmoplegia in about 21%, hearing loss in about 12%, and neuropathic pain (most commonly in the legs) in about 9% [Teitelbaum et al 2002]. Late-onset variants of the disease occur in individuals harboring mutations that produce less severe thymidine phosphorylase dysfunction [Marti et al 2005].Gastrointestinal dysmotility and cachexia. Progressive GI dysmotility, caused by the combined effects of neuromuscular dysfunction and autonomic dysfunction, occurs in virtually all individuals with MNGIE disease at some point during the course of the illness. Symptoms usually progress slowly over several decades and can affect any part of the GI tract. Gastric and small bowel hypomotility are the most common. Symptoms include early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain, episodic abdominal distention, and diarrhea. Weight loss and cachexia coincide with the onset of GI symptoms. The average weight loss is about 15 kg [Nishino et al 2000]. Affected individuals generally have a thin body habitus and reduced muscle mass. Despite severe GI dysfunction, serum concentrations of micronutrients, vitamins E and B₁₂, and folate are typically normal.Rectal biopsy can show eosinophilic cytoplasmic inclusions, representing abnormal mitochondria, in the submucosal ganglion cells [Perez-Atayde et al 1998]. Duodenal pathology can demonstrate focal muscle atrophy or absence with increased nerve numbers, serosal granulomas, and focal loss of Auerbach's plexus with fibrosis [Teitelbaum et al 2002]. Mitochondrial DNA depletion, mitochondrial proliferation, and smooth cell atrophy are observed in the external layer of the muscularis propria in the stomach and in the small intestine [Giordano et al 2006, Giordano et al 2008]. Of note, controls demonstrated the lowest amounts of mtDNA at the same sites. Loss of the pacemaker cells that stimulate gut contraction (interstitial cells of Cajal) is also noted in the small bowel [Zimmer et al 2009].Eye findings. Ptosis and ophthalmoplegia (weakness of the extraocular muscles) or ophthalmoparesis (lack of function of the extraocular muscles) are common findings. Because of the absence of symptoms like diplopia, individuals with MNGIE disease are not usually aware of the eye movement defect. Instead, the abnormalities are usually first noted by a health care provider. Sensorimotor neuropathy. All individuals with MNGIE disease have peripheral neuropathy. The neuropathy is demyelinating in all cases and about half also have axonal neuropathy. In some, the first symptoms are paresthesias and weakness. Paresthesias occur in a stocking-glove distribution and may be described as tingling, numbness, or even pain. The weakness is usually symmetric and distal. Proximal weakness is less common. Lower extremities are more prominently affected than upper extremities. Unilateral or bilateral foot drop, as well as clawed hands, may occur. The severity of the neuropathic symptoms often fluctuates during the early stages of the disease. The segmental demyelination is hypothesized to be caused by the uneven distribution of mtDNA abnormalities (depletion, point mutations, deletions, duplication) along the nerve. Areas with the highest concentration of these mutations may be predisposed to demyelination. Electrodiagnostic features can include decreased motor and sensory nerve conduction velocities, prolonged F-wave latency, and partial conduction block. Myopathic changes are common.Histologically, demyelination and remyelination (onion bulb formation) are observed. Loss of large myelinated fibers is common.Leukoencephalopathy. The leukoencephalopathy is usually asymptomatic. Spasticity is not present. Although intellectual disability is described in some individuals, dementia can be a rare late feature of the disease [Finsterer 2009].Other. Other highly variable manifestations: Active hepatic cirrhosis with increased liver enzymes and macrovesicular steatosis Anemia Early-onset sensorineural hearing loss involving either the cochlea or eighth cranial nerve. Short stature Autonomic nervous system dysfunction (usually orthostatic hypotension) Bladder dysfunction Ventricular hypertrophy and bundle branch block in the absence of cardiac symptoms Significantly increased CSF protein (typically 60 - >100 mg/dL; normal: 15 - 45 mg/dL) Lactic acidemia (increased serum concentration of lactate without a change in the pH) and hyperalaninemia. Lactic acidosis (increased serum lactate concentration associated with a decrease in blood pH) is unusual, but is more likely to occur in the presence of renal or hepatic impairment. Diverticula, which may become infected (diverticulitis) or perforate, causing peritonitis, which may be fatal.Prognosis. MNGIE disease is a progressive, degenerative disease with a poor prognosis. In the study of Nishino et al [2000], the mean age of death was 37.6 years (range 26-58 years).

Genotype-Phenotype CorrelationsLate-onset variants of the disease occur in individuals harboring mutations that produce less severe thymidine phosphorylase dysfunction [Marti et al 2005].No relationship exists between the enzymatic activity of thymidine phosphorylase and the clinical severity of MNGIE disease.TYMP mutation type does not correlate with the severity of the enzyme defect or clinical expression of the disease [Spinazzola et al 2002].

Differential DiagnosisMNGIE disease has been confused with anorexia nervosa and other classes of GI diseases such as intestinal pseudo-obstruction, inflammatory bowel disease, celiac disease, and irritable bowel disease. Acute abdominal pain in individuals with MNGIE disease has been misdiagnosed as superior mesenteric artery syndrome.Because of the rapid appearance of neuropathic symptoms over several months in some individuals, chronic inflammatory demyelinating polyneuropathy (CIDP) has been misdiagnosed [Bedlack et al 2004]. Oxidative phosphorylation (OXPHOS) diseases. Because of the cumulative effects on cells of mtDNA depletion and increasing levels of mtDNA deletions and point mutations in MNGIE disease, affected individuals present with clinical and metabolic features of oxidative phosphorylation diseases, which are characterized by GI dysmotility, polyneuropathy, and leukoencephalopathy (see Mitochondrial Disorders Overview). However, when the diagnostic criteria for MNGIE disease are strictly applied, thymidine phosphorylase activity and molecular genetic testing of TYMP are found to be normal in these other disorders [Vissing et al 2002, Hirano et al 2004]. Disorders caused by imbalance in the mitochondrial nucleotide pools or by quantitative or qualitative defects in mtDNA Autosomal dominant progressive external ophthalmoplegia, caused by: Mutations in ANT1, the gene encoding the heart/skeletal muscle isoform of adenine nucleotide translocator [Kaukonen et al 2000]; Mutations in the gene encoding Twinkle, which is responsible for mtDNA integrity [Spelbrink et al 2001]; and Mutations in the gene encoding DNA polymerase gamma, which is responsible for mtDNA replication [Van Goethem et al 2001]. Amish lethal microcephaly, caused by mutations in the mitochondrial deoxynucleotide carrier [Rosenberg et al 2002] Kearns-Sayre syndrome/chronic progressive external ophthalmoplegia, caused by sporadic mtDNA deletions/duplications A larger array of mtDNA point mutation diseases (for review see Shoffner 2001, Mitochondrial Disorders Overview) Mitochondrial myopathy with mtDNA depletion caused by mutations in TK2, the gene encoding thymidine kinase [Saada et al 2001] (See TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form.) Mitochondrial hepatopathy and encephalopathy with mtDNA depletion caused by mutations in DGUOK, the gene encoding deoxyguanosine kinase [Mandel et al 2001]. (See DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form.)Leukodystrophy. Various leukodystrophies are distinguished from MNGIE disease by clinical features. These include metachromatic leukodystrophy, X-linked adrenoleukodystrophy, childhood ataxia with central nervous system hypomyelination/vanishing white matter disease, connexin 46.6 (GJA12) mutations, PLP1-related disorders, Krabbe disease, Alexander disease, Canavan disease, congenital muscular dystrophy with merosin deficiency (see Congenital Muscular Dystrophy Overview), and Salla disease. Although mutations in GJB1, the gene encoding connexin 32, can be associated with transient white matter defects [Hanemann et al 2003], most individuals present with X-linked Charcot-Marie-Tooth disease (CMTX).

ManagementEvaluations at Initial Diagnosis To establish the extent of disease in a proband, the following are recommended: EMG/NCV EKG Ophthalmologic evaluation Audiologic evaluation Developmental assessment Assessment of hepatic function, renal function, plasma concentrations of amino acids, and serum concentration of lactate and pyruvate GI evaluation, which depends on the symptoms and may include abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, and antroduodenal manometry. Radiologic studies may show hypoperistalsis, gastroparesis, dilated duodenum, and diverticulosis. Small bowel manometry shows reduced amplitude of contractions. Treatment of ManifestationsCooperation among multiple specialties including neurology, medical genetics, nutrition, gastroenterology, pain management, psychiatry, and physical/occupational therapy helps with timely detection and treatment of the various aspects of multi-organ dysfunction. Once symptoms appear, treatment is supportive. Management of GI dysfunction can include:Early attention to swallowing difficulties and airway protection, especially in the most severely affected individuals Trial of dromperidone for nausea and vomiting Celiac plexus block with bupivicaine. This has been successful in reducing pain by interrupting visceral afferent pain sensation and increasing GI motility by inhibiting sympathetic efferent activity to the upper abdominal viscera and much of the small bowel [Teitelbaum et al 2002]. Splanchnic nerve block has been used successfully to reduce abdominal pain [Celebi et al 2006].Nutritional support including, when necessary, bolus feedings, gastrostomy tube placement, and total parenteral nutrition Antibiotic therapy for intestinal bacterial overgrowth, a complication of dysmotility Complex medication regimens that include morphine, amitriptyline, gabapentin, and phenytoin for relief of neuropathic symptoms, which are difficult to treat Specialized schooling arrangements, typically necessary for children and young adults Physical therapy and occupational therapy to help preserve mobility. Activity as tolerated should be encouraged. Prevention of Secondary ComplicationsEstablishing the correct diagnosis of MNGIE disease may help avoid unnecessary exploratory abdominal surgeries, risks associated with anesthesia, and inappropriate therapies. The approximately 20% of individuals with MNGIE disease who have hepatopathy may be at increased risk for worsening hepatic dysfunction caused by medications metabolized by the liver and as a result of total parenteral nutrition. Therefore, medications that are primarily metabolized in the liver should be used with caution. Attention to swallowing abnormalities associated with oropharyngeal muscle dysfunction may help decrease the risk for aspiration pneumonia. Early attention to diverticulosis can help prevent complications such as ruptured diverticula and fatal peritonitis. Surveillance Surveillance should be individualized based on symptoms and organs affected.Agents/Circumstances to AvoidAvoid drugs that interfere with mitochondrial function including valproate, phenytoin, chloramphenicol, tetracycline, and certain antipsychotic medications. For a detailed table of drugs that interfere with mitochondrial function see Shoffner [2008].Evaluation of Relatives at RiskTesting of asymptomatic and at-risk relatives is recommended as it allows for assessment of new symptoms in the context of MNGIE disease rather than risking incorrect assignment of symptoms to other diseases and unnecessary procedures. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationNormalization of intracellular thymidine concentrations could reduce the rate of the mtDNA damage which progressively increases in an individual over time. Possible future treatments include decreasing plasma thymidine concentration by reducing renal reabsorption of thymidine (i.e., blocking the Na+/thymidine transporter), by dialysis, and by enzyme replacement therapy (ERT). Approaches to ERT include allogeneic stem cell transplantation [Hirano et al 2006, Rahman & Hargreaves 2007], carrier erythrocyte entrapped thymidine phosphorylase [Moran et al 2008], and platelet transfusion. Allogeneic stem-cell transplantation produced a nearly full biochemical correction of the dexoythymidine and deoxyridine imbalances in blood of one individual [Hirano et al 2006]. Polymeric enzyme-loaded nanoparticles are being explored for use in MNGIE disease but have not been used in humans [De Vocht et al 2009]. Platelet transfusion produced only transient reductions in blood nucleosides [Lara et al 2006]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.Other Supplements like coenzyme Q₁₀, vitamin K, vitamin C, riboflavin, niacin, and other compounds have no proven efficacy and do not change the natural history of the disease [Shoffner, personal observation]. Although plasma concentration of thymidine can be reduced by hemodialysis, the plasma concentration becomes elevated again in about three hours [Spinazzola et al 2002]. Improvement of symptoms like vomiting and abdominal pain were reported with peritoneal dialysis [Yavuz et al 2007]. No change in blood nucleoside levels was observed.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Mitochondrial Neurogastrointestinal Encephalopathy Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTYMP22q13​.33Thymidine phosphorylaseTYMP homepage - Mendelian genesTYMPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Mitochondrial Neurogastrointestinal Encephalopathy Disease (View All in OMIM) View in own window 131222THYMIDINE PHOSPHORYLASE: TYMP 603041MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE); MTDPS1Molecular Genetic PathogenesisMNGIE disease results from the mutagenic effect of thymidine phosphorylase deficiency on mitochondrial DNA (mtDNA). Thymidine phosphorylase deficiency results from mutations in the nuclear gene TYMP. The pathologic consequences of thymidine phosphorylase deficiency are thought to be the accumulation of qualitative mtDNA defects (deletions and duplications) and quantitative mtDNA defects (depletion) in various tissues over time. Nuclear DNA damage does not appear to be a factor in the pathogenesis of MNGIE disease.During mtDNA synthesis, polymerase gamma is unable to distinguish between dTTP and dUTP. Normally, incorporation of thymidine over uracil into replicating mtDNA is accomplished by maintaining a high dTTP/dUTP ratio (>10⁵) in the mitochondria. However, in MNGIE disease, imbalances in these mitochondrial deoxynucleoside 5'-triphosphate (dNTP) pools caused by increases in deoxythymidine and deoxyuridine result in increased uracil incorporation into the mtDNA, producing mtDNA instability [Nishigaki et al 2003]. This preferential damage to mtDNA over time appears to be caused by several factors: The mitochondrial dNTP pool is sequestered within the mitochondria. mtDNA is more dependent on thymidine salvage than nuclear DNA, which depends primarily on de novo thymidine synthesis. mtDNA has a limited capability to repair damage as compared to nuclear DNA. Since mtDNA continues to replicate throughout an individual's life, various tissues throughout the body develop abnormalities over time as a result of progressive oxidative phosphorylation (OXPHOS) impairment. Accumulation of mtDNA mutations can be observed in fibroblasts of individuals with MNGIE disease as well in HeLa cells cultured in the presence of increased thymidine [Nishigaki et al 2003, Song et al 2003]. Mitochondrial DNA depletion and mtDNA deletions are present in most individuals with MNGIE disease, but not all [Hirano et al 1994, Debouverie et al 1997, Hamano et al 1997]. Thymidine-deficient mice (TP -/-) appear normal and do not show features of MNGIE disease [Haraguchi et al 2002]. Since mice can use uridine phosphorylase to clear thymidine, deficiency in both thymidine phosphorylase and uridine phosphorylase are required to affect nucleoside metabolism. Mice that are double mutants for these two enzymes produce increased T₂-weighted signal on MRI in the white matter. Muscle is normal and no mtDNA mutations are observed.Normal allelic variants. The gene contains ten exons spanning more than 4.3 kb [Hagiwara et al 1991]. See Table 2 (pdf).Pathologic allelic variants. The nucleotide positions listed in the genomic DNA are according to Hagiwara et al [1991]. No large deletions involving this gene have been described. See Tables 3-6 (pdf).Normal gene product. Thymidine phosphorylase is a homodimer that catalyzes the conversion of thymidine to thymine and 2-deoxy-D-ribose 1-phosphate [Brown & Bicknell 1998]. The forward reaction (thymidine to thymine) is important to nucleoside catabolism. Although the reverse reaction is possible (thymidine to thymidine triphosphate), only the forward reaction appears important physiologically. Thymidine phosphorylase is expressed in the GI system, brain, peripheral nerves, autonomic nerves, spleen, bladder, and lungs and is not expressed in muscle, kidney, gallbladder, aorta, or fat. Thymidine phosphorylase was originally mistakenly identified as a "growth factor" abundant in platelets; therefore, it was named "platelet-derived endothelial cell growth factor" (PD-ECGF or ECGF1). The misconception that thymidine phosphorylase (TP) is a growth factor is based on [³H]-labeled thymidine incorporation assays. Purified "ECGF" was added to cell culture medium 18 hours prior to addition of [³H]-thymidine, which was rapidly incorporated by cultured endothelial cells. This result was misinterpreted as stimulation of mitosis. In reality, the addition of TP degraded thymidine in the culture medium, and subsequently the thymidine-starved endothelial cells rapidly incorporated the [³H]-thymidine. TP may be angiogenic indirectly because ribose liberated from the degradation of thymidine may stimulate cell division and migration [Brown & Bicknell 1998]. In addition to its function in angiogenesis, it also limits glial cell proliferation.Abnormal gene product. See Molecular Genetic Pathogenesis.