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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Mitochondrial Neurogastrointestinal Encephalopathy Disease

Synonyms: MNGIE Syndrome, Mitochondrial Neurogastrointestinal Encephalopathy Syndrome, Myoneurogastrointestinal Encephalopathy Syndrome, Thymidine Phosphorylase Deficiency
, MD
Medical Neurogenetics, LLC
Georgia State University
Atlanta, Georgia

Initial Posting: ; Last Update: May 11, 2010.

Summary

Disease characteristics. Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is characterized by progressive gastrointestinal dysmotility and cachexia manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea; ptosis/ophthalmoplegia or ophthalmoparesis; hearing loss; and demyelinating peripheral neuropathy manifesting as paresthesias (tingling, numbness, and pain) and symmetric and distal weakness more prominently affecting the lower extremities. The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades; in about 60% of individuals, symptoms begin before age 20 years.

Diagnosis/testing. The clinical diagnosis of MNGIE disease is based on the presence of severe gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoplegia, sensorimotor neuropathy, asymptomatic leukoencephalopathy as observed on brain MRI, and family history consistent with autosomal recessive inheritance. Direct evidence of MNGIE disease is provided by increase in plasma thymidine concentration greater than 3 µmol/L and increase in plasma deoxyuridine concentration greater than 5 µmol/L. Thymidine phosphorylase enzyme activity in leukocytes is less than 10% of the control mean. Molecular genetic testing of TYMP, the gene encoding thymidine phosphorylase, detects mutations in approximately 100% of affected individuals.

Management. Treatment of manifestations: Management is supportive and includes attention to swallowing difficulties and airway protection; dromperidone for nausea and vomiting; celiac plexus block with bupivicaine to reduce pain; bolus feedings, gastrostomy, and parenteral feeding for nutritional support; antibiotics for intestinal bacterial overgrowth; morphine, amitriptyline, gabapentin, and phenytoin for neuropathic symptoms; specialized schooling arrangements; and physical and occupational therapy.

Prevention of secondary complications: Attention to swallowing abnormalities and diverticulosis, respectively, may help prevent aspiration pneumonia and ruptured diverticula.

Agents/circumstances to avoid: Drugs that interfere with mitochondrial function should be avoided; medications that are primarily metabolized in the liver should be used with caution.

Genetic counseling. MNGIE disease is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele; heterozygotes are asymptomatic. Unless an individual with MNGIE disease has offspring with either an affected individual or a carrier, his/her offspring will be obligate heterozygotes for a disease-causing mutation in TYMP. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once the disease-causing TYMP mutations in the family are known.

Diagnosis

Clinical Diagnosis

The 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 inheritance

Note: Although magnetic resonance spectroscopy (MRS) can show increases in lactate within the white matter, it is not a sensitive diagnostic test.

Testing

Direct 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 Testing

Gene. TYMP (previously known as ECGF1), the gene encoding thymidine phosphorylase, is the only gene known to be associated with MNGIE disease.

Clinical testing

  • Sequence 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

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
TYMPSequence analysisMissense mutations, microdeletions, insertions, splice-site mutations100% 2

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Mutation detection frequency in those individuals with enzymatically proven MNGIE disease

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

  • Detection 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.

Clinical Description

Natural History

Gestation 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 Correlations

Late-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].

Nomenclature

MNGIE disease was first described as congenital oculo-skeletal myopathy with abnormal muscle and liver mitochondria. Other acronyms for MNGIE disease include polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction (POLIP); oculogastrointestinal muscular dystrophy (OGIMD); and mitochondrial myopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obstruction (MEPOP).

Prevalence

MNGIE disease is rare. The prevalence is unknown. Fewer than 70 individuals with features consistent with MNGIE disease have been reported since it was first described.

No ethnic predilection for MNGIE disease has been observed; it occurs in individuals of mixed European, Puerto Rican, Ashkenazi Jewish, Iranian Jewish, German American, Asian, Spanish, and African American heritage.

Parental consanguinity is common, representing nearly half the families in some reports [Nishino et al 1999, Nishino et al 2000].

Differential Diagnosis

MNGIE 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

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).

Management

Evaluations 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 Manifestations

Cooperation 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 Complications

Establishing 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 Avoid

Avoid 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 Risk

Testing 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 Investigation

Normalization 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MNGIE disease is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Unless an individual with MNGIE disease has offspring with either an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a disease-causing mutation in TYMP.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier detection for at-risk family members is possible if the TYMP mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and clarification of carrier status is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation)..

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TYMP22q13​.33Thymidine phosphorylaseTYMP homepage - Mendelian genesTYMP

Data 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)

131222THYMIDINE PHOSPHORYLASE: TYMP
603041MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE); MTDPS1

Molecular Genetic Pathogenesis

MNGIE 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.

References

Literature Cited

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Chapter Notes

Acknowledgments

Foundation of Molecular Medicine; Department of Defense
Grants GW808138 and AR080046

Revision History

  • 11 May 2010 (me) Comprehensive update posted live
  • 22 April 2005 (me) Review posted to live Web site
  • 16 September 2004 (jms) Original submission
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