Clinical characteristics: Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is characterized by progressive gastrointestinal dysmotility (manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea); cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; 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. The diagnosis of MNGIE disease can be established in a proband by detection of one of the following: (1) biallelic pathogenic variants in TYMP (formerly known as ECGF1); (2) markedly reduced levels of thymidine phosphorylase enzyme activity; or (3) elevated plasma concentrations of thymidine and deoxyuridine.
Management: Treatment of manifestations: Management is primarily supportive and includes attention to swallowing difficulties and airway protection; dromperidone for nausea and vomiting; gastrostomy, and parenteral feeding for nutritional support; antibiotics for intestinal bacterial overgrowth; amitriptyline, nortriptyline, and gabapentin 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 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 individual are obligate heterozygotes and therefore carry one mutated 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 pathogenic variant in TYMP. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once the TYMP pathogenic variants in the family are known.
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