Recalcitrant Vomiting, Disturbed Eye Movements, and Leukoencephalopathy
Article Outline
- Answer to the Clinical Challenges and Images in GI Question: Image 2 (page 1581): Mitochondrial Neurogastrointestinal Encephalomyopathy
- Acknowledgments
- References
- Copyright
Question: A 34-year-old woman was referred for workup of severe cachexia (26 kg, 160 cm; body mass index, 10.2 kg/m2; highest weight, 40 kg), new-onset intractable vomiting and upper abdominal pain. She had initially undergone operative exploration at another hospital owing to high-grade gastric and proximal small bowel dilatation on abdominal CT scan (Figure A). However, mechanical obstruction was excluded at surgery. On admission to our department, physical examination was pertinent for hyperactive bowel sounds and a scaphoid abdomen painful on gentle palpation. Neurological evaluation disclosed discrete bilateral ptosis with horizontal (Figure B) and vertical ophthalmoparesis as well as pallhypaesthesia in the right foot. Liver enzymes were significantly elevated (normal values in parentheses): alanine aminotransferase, 466 U/L and aspartate aminotransferase, 223 U/L (10–35 each); γ-glutamyltransferase, 155 U/L (0–39); AP 206 U/L (35–104). However, β-carotene (12 μg/dL; normal, 40–322) and 25-hydroxyvitamin D levels (9.3 ng/mL; normal, 20–68) were reduced. Notably, serum lactate values were repeatedly increased, fluctuating from 3.2 to a maximum of 9.5 mmol/L (normal, 0.5–2.2). Celiac serology and autoantibodies (antinuclear antibody, antimitochondrial antibody, anti-smooth muscle antibody, antineutrophil cytoplasmic antibody, anti-myenteric antibodies) were negative. Viral hepatitis was excluded.
Abdominal ultrasound displayed hepatomegaly and advanced hepatic steatosis. Whereas ileocolonoscopy was unremarkable, upper endoscopy revealed severe gastric dilatation with almost completely abolished motility, and a small bowel follow-through was significant for a retropulsive small bowel motility pattern largely precluding duodenal contrast media passage. Diffuse hyperintensities in the cerebral white matter were detected on MRI (Figure C, fluid-attenuated inversion recovery sequences). Of interest, 1 of the patient's sisters had a similar history with unexplained cachexia, however, with chronic diarrhea, prompting us to consider a hereditary basis of the clinical picture.
What may be the diagnosis, and how should we proceed?
Look on page 1861 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.
Answer to the Clinical Challenges and Images in GI Question: Image 2 (page 1581): Mitochondrial Neurogastrointestinal Encephalomyopathy
Clinical presentation and apparative findings were consistent with chronic intestinal pseudoobstruction. Disturbed eye motility and chronically elevated serum lactate values raised the possibility of an underlying mitochondrial disorder. Indeed, advanced leukencephalopathy on cerebral imaging further supported the diagnosis of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), which could be confirmed by severely increased plasma nucleoside levels (deoxyuridine, 11.4 μmol/L, thymidine, 3.6 μmol/L; normal <0.05 μmol/L each). Sequencing of the thymidine phosphorylase (TYMP) gene revealed compound heterozygous mutations (c.261G>T; c.340G>A). Upon combined enteral–parenteral nutrition via a jejunal access, the weight stabilized to about 36 kg, although the clinical course over 6 years now was repeatedly complicated by painful exacerbations and catheter-associated infections. Liver disease, namely, nonalcoholic steatohepatitis, was considered most likely owing to mitochondrial dysfunction.
MNGIE is a complex, autosomal-recessive, multisystem disorder with gastrointestinal dysmotility and severe cachexia as clinical hallmarks. Although mostly clinically subtle, extraocular muscle weakness and peripheral neuropathy occur regularly, providing clues for timely diagnosis.1 Clinical suspicion may first be substantiated by neuroimaging, followed by confirmatory biochemical and genetic studies. As for molecular pathogenesis, mutations in the TYMP gene cause cellular and systemic accumulations of pyrimidine nucleosides, which evokes secondary mitochondrial DNA mutations, ultimately resulting in mitochondrial dysfunction.2 Therapeutic options are limited, and clinicians should rely on principles established for chronic intestinal pseudoobstruction, focusing on symptomatic control and adequate nutritional support. MNGIE-specific approaches reducing the circulating nucleoside levels are only beginning to emerge with allogenic stem cell transplantation holding greatest promise.3
Acknowledgments
The authors thank Georg Becker, Stefan Jung, and Eva Röll (Department of Neurology, Saarland University Hospital, Homburg, Germany) for neurological consultations.
References
- Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology. 1994;44:721–727
- . Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999;283:689–692
- Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology. 2006;67:1458–1460
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PII: S0016-5085(09)01141-X
doi:10.1053/j.gastro.2009.06.056
© 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
