March 08, 2012
Years published: 1992, 2000, 2007, 2008, 2012
NORD gratefully acknowledges Michio Hirano, MD, Professor of Neurology, Columbia University Medical Center, for assistance in the preparation of this report.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem disorder characterized by progressive degeneration of the muscles of the gastrointestinal tract causing gastrointestinal dysmotility, weakness of extra-ocular muscles causing drooping of the eyelids (ptosis) and restricted eye movements (ophthalmoparesis), degeneration of peripheral nerves causing altered sensation and weakness the distal arms and legs, and general wasting (cachexia). The specific symptoms associated with MNGIE vary from case to case and may include vomiting, nausea, diarrhea, abdominal pain, and numbness or sensations of pins and needles in the hands and feet. . Additional findings may occur in some cases. MNGIE is caused by changes (mutations) in the TYMP gene encoding thymidine phosphorylase (TP) and is inherited as an autosomal recessive trait.
MNGIE patients also show changes (e.g. depletions, deletions, or point mutations) in the genetic material (DNA) of the mitochondria. Mitochondria, found by the hundreds within virtually every cell of the body, generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body.
The symptoms and severity of MNGIE vary from case to case. Onset of symptoms is usually before 20 years of age, but may range from 5-60 years of age. MNGIE is characterized by a variety of gastrointestinal and neurological findings.
The most prominent symptom of MNGIE is progressive dysfunction of the muscles of the gastrointestinal tract (gastrointestinal dysmotility). Any portion of the gastrointestinal tract from the back of the throat (oropharynx) to the large intestine may be affected. The most common form of gastrointestinal dysmotility associated with MNGIE is small intestine hypomotility, in which the muscles of the intestinal walls fail to contract normally and generate the wave-like (peristaltic) motions required to push food through the digestive tract. Failure to push food through the intestines although no physical blockage is present is known as intestinal pseudoobstruction. When the muscles of the wall of the stomach are involved the condition is known as gastroparesis.
Individuals with MNGIE may develop a variety of gastrointestinal symptoms. The specific symptoms will vary from case to case, but may include vomiting, nausea, diarrhea, abdominal pain, a feeling of early fullness (premature satiety), stomach rumblings (borborygmi), and difficulty swallowing (dysphagia). Some affected individuals may also develop small sac-like protrusions (diverticula) of inner intestinal layer through the outer muscular wall of the small intestine.
The gastrointestinal symptoms associated with MNGIE may result in a variety of complications including bacterial overgrowth in the intestines and, less frequently, failure of the intestines to absorb nutrients during digestion (malabsorption). Consequently, affected individuals may develop weight loss, and the loss of tissue and muscle mass (cachexia). Most individuals with MNGIE are extremely thin and some individuals may have short statute.
The most common neurological symptoms associated with MNGIE are drooping of the upper eyelid (ptosis) because of weakness of muscles of the eyelid, weakness of additional muscles around the eye gradually restricting the movements of the eyes (ophthalmoplegia), hearing loss, and peripheral neuropathy, a condition in which there is damage or malfunction of the peripheral nervous system (i.e., the nerves outside the central nervous system). The symptoms of peripheral neuropathy vary greatly, but may include weakness of the muscles of the distal arms or legs or abnormal sensations such as tingling (paresthesias), burning or numbness. The legs are affected more often and earlier than the arms.
Individuals with MNGIE often exhibit destruction of the myelin sheath that covers nerve fibers in the brain (leukoencephalopathy). This clinical finding is usually not associated with symptoms (asymptomatic).
MNGIE is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
MNGIE is caused by mutations of the TYMP gene encoding thymidine phosphorylase (TP); the gene is located near the end (telomere) of the long arm (q) of chromosome 22 (22q13.32-qter). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 22q13.32-qter” refers to bands 13 to the end portion (ter) of the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The TYMP gene contains instructions (encodes) for the production of thymidine phosphorylase, an enzyme necessary for the breakdown and conversion of certain chemical compounds (nucleosides) in the body. Mutations of the TP gene cause very low activity of thymidine phosphorylase in the cells and tissues of the body. Deficiency of TP enzyme results in abnormally elevated levels of nucleosides, deoxyuridine and thymidine, in the body. Researchers believe that elevated levels of thymidine damage or impair mitochondrial DNA replication, repair, or both. Individuals with MNGIE have mitochondrial DNA defects (e.g., depletions, deletions, duplications). Mitochondrial DNA continually repairs and replicates throughout life so affected individuals are believed to accumulate additional abnormalities of mitochondrial DNA as they age.
MNGIE is an extremely rare disorder that affects males and females in equal numbers. The prevalence is unknown and as of 2011 fewer than 200 cases have been reported in the medical literature. Researchers believe that the disorder often goes unrecognized or misdiagnosed, making it difficult to determine its true frequency in the general population.
MNGIE was first described in the medical literature in 1976 as congenital oculoskeletal myopathy with abnormal muscle and liver mitochondria. Since then, it has been reported under a variety of different names including mitochondrial encephalomyopathy with sensorimotor polyneuropathy, ophthalmoplegia and pseudo-obstruction (MEPOP); myoneurogastrointestinal encephalopathy syndrome; oculogastrointestinal muscular dystrophy; and polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction (POLIP).
A diagnosis of MNGIE is suspected based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic findings, and a variety of specialized tests such as blood tests or magnetic resonance imaging (MRI). Blood tests may reveal elevated lactic acid. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In individuals with MNGIE, it is used to demonstrate asymptomatic leukoencephalopathy.
A diagnosis of MNGIE may be confirmed biochemically by demonstrating low TP enzyme activity in the buffy coat containing white blood cells (leukocytes) and platelets or by detecting elevated plasma levels of the nucleosides thymidine and deoxyuridine. Alternatively, the diagnosis can be confirmed through molecular genetic testing, in which examination of deoxyribonucleic acid (DNA) reveals specific genetic mutations associated with MNGIE.
The treatment of MNGIE is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, internists, gastroenterologists, neurologists, surgeons, cardiologists, dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists), eye specialists and others may need to systematically and comprehensively plan an affected patient's treatment.
Specific treatments may include drug therapies for nausea and vomiting and for symptoms secondary to nerve dysfunction (neuropathy) such as pain. Pain affecting certain organs of the gastrointestinal tract (abdominal viscera) may be treated by a procedure known as celiac plexus neurolysis. During this procedure, nerve impulses are temporarily disrupted thereby lessening pain.
Affected individuals may need to be evaluated for swallowing difficulties to prevent aspiration.
Nutritional supplementation may become necessary and may be provided through parenteral feedings or a gastrostomy tube. Parenteral feeding is being fed through any pathway that does not involve the gastrointestinal tract or lungs, i.e., feeding through a tube directly into the veins (intravenous). Gastrostomy refers to creating a surgical opening in the stomach through which a tube is inserted to provide direct nutritional support.
Individuals with MNGIE should avoid drugs that interfere or hamper mitochondrial function. Such drugs include valproate, phenytoin, chloramphenicol, linezolid, aminoglycosides, and tetracycline.
Some affected individuals may benefit from occupational and physical therapy. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Researchers are studying a variety of therapeutic options aimed at lowering the levels of nucleosides in the cells and tissues of individuals with MNGIE. Such therapies include dialysis and allogenic stem cell (bone marrow) transplantation. These therapies are in the early stages of investigation and carry notable drawbacks and risks. Another therapeutic option under investigation is reducing the absorption of thymidine by the kidneys, which allows for more thymidine to be excreted through the urine. Further investigation is warranted to determine the long-term safety and efficacy of these potential therapies for individuals with MNGIE.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Halter J, Schüpbach WM, Casali C, et al. Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach. Bone Marrow Transplant. 2011;46:330-337.
Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain. 2011;134:326-332.
Lara MC, Weiss B, Illa I, et al. Infusion of platelets transiently reduces nucleoside overload in MNGIE. Neurology. 2006;67:1461-3.
Hirano M, Marti R, Casali C, et al. Allogenic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology. 2006;67:1458-60.
Marti R, Verschuuren JJ, Buchman A, et al. Late-onset MNGIE due to partial loss of thymidine phosphorylase deficiency. Ann Neurol. 2005;58:649-52.
Szigeti K, Wong LJC, Perng CL, et al. MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation. J Med Genet. 2004;41:125-9.
Spinazzola A, Marti R, Nishino I, et al. Altered thymidine metabolism due to defects of thymidine phosphorylase. J Biol Chem. 2002;6:4128-33.
Teitelbaum JE, Berde CB, Nurko S, et al. Diagnosis and management of MNGIE syndrome in children: case report and review of the literature. J Pediatr Gastroenterol Nutr. 2002;35:377-83.
Spinazzola A, Marti R, Nishino I, et al. Altered thymidine metabolism due to defects of thymidine phosphorylase. J Biol Chem. 2001;277:4128-33.
Nishino I, Spinazzola A, Papadimitriou A, et al. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol. 2000;47:792-800.
Hirano M, Garcia-de-Yebenes J, Jones AC, et al. Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter. Am J Hum. 1998;63:526-33.
Bardosi A, Creutzfeldt W, DiMauro S, et al. Myo-,neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase. Acta Neuropathol. 1987.74:248-58.
Ionasescu V. Oculogastrointestinal muscular dystrophy. Am J Med Genet. 1983;15:103-12.
Anuras S, Mitros FA, Nowak TV. A familial visceral myopathy with external ophthalmoplegia and autosomal recessive transmission. Gastroenterology. 1983;84:346-53.
Shoffner JM. (Updated May 11, 2010). Mitochondrial Neurogastrointestinal Encephalopathy Disease. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 6, 2012.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mitochondrial DNA Depletion Syndrome 1 (MNGIE Type); MTDPS1. Entry No: 603041. Last Edited February 17, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 6, 2012.
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