Mitochondrial neurogastrointestinal encephalopathy syndrome

Synonyms

MNGIE, MNGIE syndrome, MNGIE disease, POLIP, POLIP syndrome, Mitochondrial neurogastrointestinal encephalopathy disease, Mitochondrial DNA depletion syndrome 1, Myoneurogastrointestinal encephalopathy syndrome, Thymidine phosphorylase deficiency, Oculogastrointestinal muscular dystrophy, OGIMD, MEPOP,

Overview

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is a condition that affects several parts of the body, particularly the digestive system and nervous system. The major features of MNGIE disease can appear anytime from infancy to adulthood, but signs and symptoms most often begin by age 20. The medical problems associated with this disorder worsen over time.

Almost all people with MNGIE disease have a condition known as gastrointestinal dysmotility, in which the muscles and nerves of the digestive system do not move food through the digestive tract efficiently. The resulting digestive problems include feelings of fullness (satiety) after eating only a small amount, trouble swallowing (dysphagia), nausea and vomiting after eating, episodes of abdominal pain, diarrhea, and intestinal blockage. These gastrointestinal problems lead to extreme weight loss and reduced muscle mass (cachexia).

MNGIE disease is also characterized by abnormalities of the nervous system, although these tend to be milder than the gastrointestinal problems. Affected individuals experience tingling, numbness, and weakness in their limbs (peripheral neuropathy), particularly in the hands and feet.

Additional neurological signs and symptoms can include droopy eyelids weakness of the muscles that control eye movement (ophthalmoplegia), and hearing loss. Leukoencephalopathy, which is the deterioration of a type of brain tissue known as white matter, is a hallmark of MNGIE disease. These changes in the brain can be seen with magnetic resonance imaging (MRI), though they usually do not cause symptoms in people with this disorder.

Symptoms

he 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).

Causes

Variants (also called mutations) in the TYMP gene cause most cases of MNGIE disease. The TYMP gene provides instructions for making an enzyme called thymidine phosphorylase. Thymidine is a molecule known as a nucleoside. After a chemical modification, thymidine is used as a building block of DNA.

Thymidine phosphorylase breaks down thymidine into smaller molecules, which helps regulate the level of nucleosides in cells.

TYMP gene variants greatly reduce or eliminate the activity of thymidine phosphorylase.  A shortage of this enzyme allows thymidine to build up to very high levels in the body. Researchers believe that this excess of thymidine damages a particular kind of DNA known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA.

Mitochondria use nucleosides, including thymidine, to build new molecules of mtDNA. A loss of thymidine phosphorylase activity and the resulting buildup of thymidine disrupt the usual maintenance and repair of mtDNA. As a result, variants can accumulate in mtDNA, causing it to become unstable. In people with MNGIE disease, mitochondria may also have less mtDNA than usual (mtDNA depletion). These genetic changes impair the normal function of mitochondria. Although mtDNA abnormalities underlie the digestive and neurological problems characteristic of MNGIE disease, it is unclear how defective mitochondria cause the specific features of the disorder.

Rarely, variants in other genes can cause MNGIE disease. In the remaining cases, the cause of the condition is unknown.

Diagnosis

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.

Treatment

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.