Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a very rare, progressive and fatal autosomal recessive disease caused by mutations in the thymidine phosphorylase gene. It is characterized by gastrointestinal and neurological symptoms such as altered GI motility, cachexia, ptosis, and peripheral neuropathy. Diagnostic tests include brain MRI showing leukoencephalopathy and nerve conduction studies demonstrating demyelinating neuropathies. Treatment options include temporary measures like dialysis and encapsulated thymidine phosphorylase, as well as permanent treatments like hematopoietic stem cell transplantation and liver transplantation.

1. Ade Wijaya, MD – October 2022
Mitochondrial Neurogastrointestinal
Encephalomyopathy (MNGIE)

2. Introduction
 MNGIE is an autosomal recessive disease
caused by mutations in the thymidine
phosphorylase gene (TYMP)
 Ultra rare condition
 Progressive and fatal
Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

3. Pathophysiology
 TYMP encodes for thymidine phosphorylase (TP),
which catabolizes thymidine (dThd) and
deoxyuridine (dUrd) into their respective bases.
 TYMP mutations markedly reduce/abolish TP
activity leading to accumulation of dThd and dUrd
and mitochondrial DNA (mtDNA) defects.
Pacitti D, Levene M, Garone C, Nirmalananthan N, Bax BE. Mitochondrial Neurogastrointestinal Encephalomyopathy: into the fourth decade, what we have learned so
far. Front Genet. 2018;9:669.

4. Cardinal Manifestation
 Symptoms and signs of otherwise unexplained GI
dysmotility
 Thin constitution/cachexia, even with normal food
behavior and nutritional intake
 Neurological features such as ptosis and
symptoms suggesting peripheral neuropathy
A progressive course of the above
Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

5. Full-blown Clinical Elements
 Symptoms onset: childhood, adolescence/young adulthood
(typical), adulthood (late onset, >40 years)
 GI symptoms/signs: sub-occlusive episodes, nausea, vomiting,
early satiety, borborygmi, severe abdominal pain, abdominal
distension, dysphagia, constipation and diarrhea, acute
peritonitis due to small bowel perforation
 Unexplained weight loss, thinness, cachexia, even with normal
food behavior and nutritional intake
 Radiological GI signs: small bowel diverticulosis, GI dilation (eg,
gastric or intestinal dilation)
 Neurological symptoms/signs: chronic progressive external
ophthalmoplegia (CPEO), ptosis, peripheral neuropathy, hearing
loss
 Neuroradiological signs: leukoencephalopathy without other
neuroradiological abnormalities
 Metabolic alterations: liver steatosis evolving in cirrhosis,
pancreatitis, early onset diabetes mellitus, increased triglyceride
levels, elevated plasma lactate
Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

6. Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

7. Natural History
 Mean age at onset: 17.9 years (5 months to 43 years).
 GI symptoms (57% at onset; 100% at diagnosis);
onset/diagnosis: diarrhea, abdominal pain, borborygmi, vomiting,
pseudo-obstruction (32%−65%), weight loss/cachexia (100%);
evolution: diverticulosis/diverticulitis (67%), hepatopathy (22%).
 Neurological symptoms/signs (43% at onset; 100% at diagnosis);
onset/diagnosis/evolution: ocular signs (ptosis,
ophthalmoparesis) (74%−100%), polyneuropathy (92%−100%),
hearing loss (39%−45%), leucoencephalopathy (±100%);
cognitive impairment (20%).
 Symptoms are cumulative and progressive.
 Mean age at death is reported to range between 35 and 37
years; survival 100% before 19 years and <5% after 50 years.
 Death is mainly due to GI and liver complications (intestinal
perforation, intestinal bleeding, liver failure, aspiration
pneumonia, complications due to small intestinal bacterial
overgrowth [SIBO] or infection related to central venous catheter
for parenteral nutrition) and cachexia.
Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

8. Diagnostic Tests (1)
 Swallowing test, gastric emptying and GI
manometry (when possible): altered GI motility
and transit
 Brain MRI: leukoencephalopathy without any
other neuroradiological abnormalities (almost
universally present)
 Nerve conduction studies: peripheral neuropathy,
predominantly demyelinating

9. Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

10. Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

11. Diagnostic Test (2)
 Muscle biopsy: ragged-red and COX deficient
fibers, deficiencies of respiratory chain enzyme
activities, ultra-structurally abnormal
mitochondria, and mtDNA depletion, multiple
deletions, and somatic point mutations
 Mucosal GI histology of small bowel (to exclude
other conditions), and gut full thickness biopsy
(when possible)
 Metabolic and genetic tests
Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

12. Diagnostic Algorhytm
Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

13. Assestment of Disease Course
Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

14. Treatment
Temporary:
 Hemodialysis (HD)
 Continuous ambulatory peritoneal dialysis
(CAPD)
 Erythrocyte encapsulated thymidine
phosphorylase (EE-TP)
 Platelet infusion
Permanent:
 Hematopoietic stem cell transplantation
 Orthotopic liver transplantation
Hirano, M., Carelli, V., De Giorgio, R., Pironi, L., Accarino, A., Cenacchi, G., ... & Zeviani, M. (2021). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. Journal of inherited metabolic disease, 44(2), 376-387.

15. Summary
 Very rare disease
 autosomal recessive disease caused by
mutations in the thymidine phosphorylase gene
(TYMP)
 Progressive and fatal
 Gastrointestinal and neurological symptoms
 Brain MRI: leukoencephalopathy
 Nerve conduction study: demyelinating
neuropathies
 Treatment: temporary and permanent treatment

16. THANK YOU