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So far, just under 100 sporadic and familial cases have been reported.

The first clinical manifestations generally appear between the ages of 10 and 40 (most often before 20 years of age). The symptoms are progressive and the clinical picture is dominated by severe gastrointestinal disorders (cramping, vomiting, diarrhea, intestinal pseudo-obstruction, dysphagia and gastroparesis) due to abnormal bowel motility. Gastrointestinal disorders gradually progress to chronic pseudo-obstruction leading to cachexia. Neurological involvement includes chronic progressive ophthalmoplegia with or without ptosis, and sensorimotor peripheral neuropathy. Cerebral imaging often reveals subclinical leukodystrophy. Deafness, pigmentary retinopathy, and cerebellar involvement are less frequent findings and are not defining features of the syndrome. Patients are usually thin with short stature. Morphological studies of the muscles reveal the presence of a low proportion of muscle fibers with mitochondrial proliferation (ragged-red fibers) or cytochrome c oxidase deficiency.

MNGIE syndrome is inherited in an autosomal recessive manner and is caused by mutations in the TYMP gene (22q13.32-qter), encoding a protein involved in thymidine phosphorylation. These mutations lead to total abolition of enzyme activity, thymidine and deoxyuridine accumulation in body fluids and tissues, and imbalanced mitochondrial DNA replication and repair leading to multiple deletions and sometimes partial depletion.

Diagnosis is based on measurement of thymidine phosphorylase activity in leukocytes (absence of activity in symptomatic individuals and reduced activity in asymptomatic heterozygous individuals), and on genetic analysis.

Differential diagnoses include similar disorders with phenotypes that overlap between MNGIE and MELAS, MERRF or progressive external ophthalmoplegia (PEO), for example patients with prominent gastrointestinal symptoms and genetic alterations either in the mitochondrial DNA (such as the MT-TL1 or MT-TK genes with the m.3243A>G ``MELAS'' mutation or the m.8313G>A ``MERRF'' mutation) or in the nuclear POLG gene encoding DNA polymerase gamma (responsible for mitochondrial DNA replication and implicated in PEO).

Management is mainly symptomatic, involving treatment of the chronic intestinal pseudo-obstruction. Thymidine and deoxyguanosine clearance appears to be an efficient approach. However, hemodialysis is not an effective treatment due to the rapid re-accumulation of compounds between sessions. Bone marrow transplantation has been performed on a few patients with promising results (stabilization of the disease course).

The prognosis is unfavorable due to the severity of the digestive involvement with infections and the need for permanent parenteral nutrition.

Last update: November 2009 - Expert reviewer(s): Dr Anne LOMBES