Clinical Guidance

Late-onset disease occurs in individuals harboring TYMP pathogenic variants that produce less severe thymidine phosphorylase dysfunction, such as the c.622GA variant (p.Val208Met), identified in two of four patients .

Source: GeneReviews — "Mitochondrial Neurogastrointestinal Encephalopathy Disease"

Diagnostic Criteria

Suggestive Findings

MNGIE (mitochondrial neurogastrointestinal encephalopathy) disease is suggested by the presence of the following clinical findings, neuroimaging, and family history :

• Clinical findings

• Severe gastrointestinal (GI) dysmotility

• Cachexia

• Ptosis

• External ophthalmoplegia

• Sensorimotor neuropathy (usually mixed axonal and demyelinating)

• Neuroimaging. Asymptomatic leukoencephalopathy manifest as diffusely abnormal brain white matter (increased FLAIR or T2-weighted signal) on brain MRI. Relative sparing of the corpus callosum is reported in some individuals . (In the absence of leukoencephalopathy, MNGIE disease is very unlikely.)

Note: Although magnetic resonance spectroscopy (MRS) can show increases in lactate within the white matter, it is not a sensitive diagnostic test.

Source: GeneReviews — "Mitochondrial Neurogastrointestinal Encephalopathy Disease"

Differential Diagnosis

MNGIE (mitochondrial neurogastrointestinal encephalopathy) disease has been confused with anorexia nervosa and other classes of GI diseases such as intestinal pseudo-obstruction (e.g., ACTG2-related disorders), inflammatory bowel disease, celiac disease, and irritable bowel disease. Acute abdominal pain in individuals with MNGIE disease has been misdiagnosed as superior mesenteric artery syndrome. Because of the rapid appearance of neuropathic symptoms over several months in some individuals, chronic inflammatory demyelinating polyneuropathy (CIDP) has been misdiagnosed . Oxidative phosphorylation (OXPHOS) diseases.

Source: GeneReviews — "Mitochondrial Neurogastrointestinal Encephalopathy Disease"

Management Guidelines

Evaluations at Initial Diagnosis

To establish the extent of disease and needs in a proband with MNGIE (mitochondrial neurogastrointestinal encephalopathy) disease, the following are recommended:

• EMG/NCV

• Brain MRI

• EKG

• Ophthalmologic evaluation

• Audiologic evaluation

• Assessment of hepatic function, renal function, plasma concentrations of amino acids, and serum concentration of lactate and pyruvate

• GI evaluation, which depends on the symptoms and may include abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, and antroduodenal manometry. Radiologic studies may show hypoperistalsis, gastroparesis, dilated duodenum, and diverticulosis. Small bowel manometry shows reduced amplitude of contractions.

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Cooperation among multiple specialties including neurology, clinical genetics, nutrition, gastroenterology, pain management, psychiatry, and physical/occupational therapy helps with timely detection and treatment of the various aspects of multiorgan dysfunction. Once symptoms appear, treatment is primarily supportive. Management of GI dysfunction can include the following:

Source: GeneReviews — "Mitochondrial Neurogastrointestinal Encephalopathy Disease"

Clinical Guidance

Avoid drugs that interfere with mitochondrial function; these include valproate, phenytoin, chloramphenicol, tetracycline, and certain antipsychotic medications . Medications primarily metabolized in the liver should be used with caution .

Source: GeneReviews — "Mitochondrial Neurogastrointestinal Encephalopathy Disease"

Therapies Under Investigation

Normalization of intracellular thymidine concentrations could reduce the rate of the mtDNA damage, which progressively increases in an individual over time. Possible future treatments include decreasing plasma thymidine concentration by reducing renal reabsorption of thymidine (i.e., blocking the Na+/thymidine transporter), by dialysis, and by enzyme replacement therapy (ERT). Approaches to ERT include allogeneic stem cell transplantation (AHSCT) , carrier erythrocyte entrapped thymidine phosphorylase , and platelet transfusion.

Source: GeneReviews — "Mitochondrial Neurogastrointestinal Encephalopathy Disease"

Surveillance Guidelines

Breath test to screen for bacterial overgrowth is recommended. Surveillance should be individualized based on symptoms and organs affected.

Source: GeneReviews — "Mitochondrial Neurogastrointestinal Encephalopathy Disease"