General description

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder characterized by severe gastrointestinal dysfunction, neurological abnormalities, and distinctive brain imaging findings.

MNGIE is caused by mutations in the thymidine phosphorylase gene (TYMP, formerly known as ECGF1), which result in a loss of function of the thymidine phosphorylase (TP) enzyme. This enzyme normally catalyzes the phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate, playing a crucial role in pyrimidine metabolism. In MNGIE patients, TP enzyme activity is markedly reduced or absent, leading to dramatically elevated plasma and tissue levels of thymidine and deoxyuridine.

The excessive accumulation of these nucleosides creates an imbalance in the mitochondrial nucleotide pool, which subsequently impairs mitochondrial DNA maintenance and integrity. This nucleoside imbalance ultimately results in mitochondrial DNA damage, manifesting as depletion and multiple deletions of mitochondrial DNA. The disruption of intergenomic communication and mitochondrial function leads to the multi-system manifestations characteristic of MNGIE.

MNGIE presents with a clinically recognizable syndrome characterized by several cardinal features, though the order of appearance is unpredictable. The onset typically occurs between the first and fifth decades of life, with approximately 60% of cases manifesting before age 20. Despite relatively homogeneous clinical features, the disease exhibits variability in age of onset and rate of progression.

The most prominent manifestation is severe gastrointestinal dysmotility, which includes recurrent nausea, vomiting, diarrhea, borborygmi, early satiety, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and intestinal pseudo-obstruction. These digestive symptoms often lead to progressive cachexia, a defining feature of the disease.

Neurological manifestations include ptosis and ophthalmoplegia or ophthalmoparesis, which are present in virtually all patients. A demyelinating peripheral neuropathy is also characteristic, manifesting as paresthesias (tingling, numbness, and pain) and symmetric distal weakness that more prominently affects the lower extremities. Electrophysiological studies typically reveal sensorimotor neuropathy, and some patients show EMG findings suggesting a myogenic process.

Although less common, some patients may develop central nervous system involvement including cognitive impairment, dementia, seizures, headaches, or psychiatric symptoms. However, many patients with extensive white matter abnormalities on MRI remain cognitively unaffected, suggesting that these abnormalities may not always reflect extensive structural damage.

References

1. Christodoulou, Maria Veatriki, Nikoletta Anagnostou, and Anastasia K. Zikou. "Brain magnetic resonance imaging findings in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): A case-based review." Radiology Case Reports 20.3 (2025): 1298-1305.
2. Scarpelli, Mauro, et al. "The role of brain MRI in mitochondrial neurogastrointestinal encephalomyopathy." The neuroradiology journal 26.5 (2013): 520-530.