Frequency of Mitochondrial Defects in Patients With Chronic Intestinal Pseudo-Obstruction
Received 17 December 2008; accepted 23 March 2009. published online 03 April 2009.
Background & Aims
Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder caused by intestinal dysmotility and characterized by chronic symptoms suggesting bowel obstruction in the absence of fixed, occluding lesions. CIPO has been associated with primary defects of the mitochondrial oxidative phosphorylation pathway, although the frequency of mitochondrial disorders in patients with CIPO is unknown. This study evaluates mitochondrial function in patients with CIPO.
Methods
A retrospective study was performed of data collected from 80 CIPO patients at a tertiary centre over a 25-year period. Mitochondrial disorders were detected by analysis of serum lactate and thymidine phosphorylase activities, brain magnetic resonance images, and muscle biopsies. Genes encoding thymidine phosphorylase, mitochondrial DNA tRNAleu(UUR) or tRNAlys, and DNA polymerase-γ were analyzed for mutations.
Results
Mitochondrial defects were identified in 15 patients (10 women; median age at diagnosis 32 years), representing 19% of the study cohort. All 15 patients had extra-digestive symptoms, 5 had mutations in the thymidine phosphorylase gene, 2 had mutations in tRNAleu(UUR), and 5 had mutations in the DNA polymerase-γ gene. No genetic defect was detected in 3 of the patients with mitochondrial disorders. Patients with mitochondrial CIPO differed from patients without mitochondrial defects in their very severe nutritional status (frequent and long-term requirement for parenteral nutrition) and poor prognosis (frequent digestive and neurologic complications that led to a high incidence of premature death).
Conclusion
Mitochondrial disorders seem to be an important cause of CIPO. Patients with CIPO, especially severe cases with associated neurologic symptoms, should be tested for mitochondrial defects.
§INSERM, U975, Hôpital de La Salpêtrière, Paris, France
∥AP-HP, Hôpital de La Salpêtrière, Centre de référence des maladies neuromusculaires, Paris, France
¶AP-HP, Hôpital Bicêtre, Service de Biochimie, Le Kremlin-Bicêtre, France
#AP-HP, Hôpital Beaujon, Service d'anatomie pathologique, Clichy, France
⁎⁎AP-HP, Hôpital de La Salpêtrière, Service de Biochimie Métabolique, Paris, France
‡‡Université Pierre et Marie Curie-Paris 6 UPMC-Paris 6, Paris, France
Reprint requests Address requests for reprints to: Anne Lombès, MD, PhD, INSERM 975, Hôpital Pitié-Salpêtrière,75651 Paris Cedex 13, France; fax: +331 40 16 57 00
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Conflicts of interest The authors disclose no conflicts.
Funding Aurélien Amiot was the recipient of a fellowship from Sanofi-Aventis. The work was supported by grant from the Association Française contre les myopathies (AFM).
ABSTRACT
Frequency of Mitochondrial Defects in Patients With Chronic Intestinal Pseudo-Obstruction