Mitochondrial Neurogastrointestinal Encephalopathy Disease

[MNGIE Syndrome, Myoneurogastrointestinal Encephalopathy Syndrome, Thymidine Phosphorylase Deficiency, Mitochondrial Neurogastrointestinal Encephalopathy Syndrome]

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].

  
  Note: 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 reliable 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 are sufficient to make the diagnosis of MNGIE disease [Marti et al 2004].

• Thymidine phosphorylase enzyme (E.C.2.4.2.4) activity in leukocytes is less than 10% of the control mean [Nishino et al 1999].

  
  Note: Although unaffected, heterozygotes display about 30% to 35% residual thymidine phosphorylase activity.

For laboratories offering biochemical testing, see .

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. mtDNA deletions/duplications are detected by Southern blot analysis and long-range PCR. mtDNA 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 ECGF1 mutation carriers [Fairbanks et al 2002; Spinazzola et al 2002; Marti, Nishigaki, Hirano 2003; Marti, Nishigaki, Vila et al 2003; Nishigaki et al 2003].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. ECGF1, the gene encoding thymidine phosphorylase, is the only gene known to be associated with MNGIE disease.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing

• Carrier testing

Molecular genetic testing: Clinical method

• Sequence analysis

  • Mutations are detected in genomic DNA by sequencing the ECGF1 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 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Mitochondrial Neurogastrointestinal Encephalopathy Disease

Test Method	Mutations Detected	Mutation Detection Rate	Test Availability
Sequence analysis	ECGF1 missense, microdeletions, insertions, splice-site mutations	100% 1	Clinical

1. Mutation detection rate refers to 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 for 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 ECGF1, the gene encoding thymidine phoshorylase, can identify pathogenic mutations for assessment of carrier status.

Genetically Related Disorders

No other phenotypes are known to be associated with mutations in the ECGF1 gene.

Natural History

Gestation and delivery are normal. Although 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].

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, post-prandial 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.

Histopathology. 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].

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. Retinitis pigmentosa can also be present.

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 symmetrical 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 mental retardation is described in some individuals, dementia can be a rare late feature of the disease.

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 mg/dL to over 100 mg/dL (normal: 15-45 mg/dL)

• Lactic acidemia (increased serum lactate without a change in the pH) and hyperalaninemia. Lactic acidosis (increased serum lactate 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

No relationship exists between the enzymatic activity of thymidine phosphorylase and the clinical severity of MNGIE disease.

ECGF1 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 [Okamura et al 1976]. Other acronyms for MNGIE disease include polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction (POLIP) [Simon et al 1990]; oculogastrointestinal muscular dystrophy (OGIMD) [Ionasescu 1983]; and mitochondrial myopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obstruction (MEPOP) [Rowland 1992].

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 [Okamura et al 1976]. 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].

Evaluations at Initial Diagnosis

• EMG/NCV

• EKG

• Ophthalmologic evaluation

• Audiologic evaluation

• Developmental assessment

• Assessment of hepatic function, renal function, plasma 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].

• 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 Primary Manifestations

• No specific therapy for MNGIE disease is currently available.

• 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 [Bresolin et al 1990; Matthews et al 1993; 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].

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.

Agents/Circumstances to Avoid

• Drugs that interfere with mitochondrial function such as valproate, phenytoin, chloramphenicol, tetracycline, and certain anti-psychotic medications

Therapies Under Investigation

Possible future treatments include reducing plasma thymidine concentration by reducing renal reabsorption of thymidine (i.e.,blocking the Na+/thymidine transporter). Normalization of intracellular thymidine concentrations could reduce the rate of the mtDNA damage, which progressively increases in an individual over time.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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 child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers.

• 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 the ECGF1 gene.

Other family members of a proband. Sibs of the proband's parents are at 50% risk of being carriers.

Carrier Detection

Carrier detection for at-risk family members is available on a clinical basis once the ECGF1 mutations have been identified in the proband.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk and clarification of carrier status is before pregnancy.

DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of MNGIE disease are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see .

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 ECGF1. 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 [Goulian et al 1980, Bestwick et al 1982]. 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]. mtDNA 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].

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.

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 [Yoshimura et al 1990].

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 [Miyazono et al 1987]. 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.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 22 April 2005 (me) Review posted to live Web site

• 16 September 2004 (jms) Original submission