Intractable Ulcerative Colitis of Infancy in a Child with Mitochondrial Respiratory Chain Disorder

Inflammatory bowel diseases are rare in young infants. Most cases of colitis are associated with necrotizing enterocolitis, bacterial infection, or intolerance to dietary proteins. Some cases are associated with immune disorders, Behçet disease, or vascular ischemic causes (systemic vasculitis, hemolytic uremic syndrome) (1). There is one report of five infants with intractable ulcerative enterocolitis of infancy (2). We report a 2-month-old child with a presentation suggesting this last diagnosis. However, elevated lactic acidosis and subsequent onset of a cardiomyopathy led to the discovery of a defect of mitochondrial respiratory chain complex I. PATIENT AND METHODS The female patient of Moroccan origin was born to consanguineous parents. Her sister, born in 1999, died of complex congenital heart disease. The other members of the family are healthy. Born at term, she was dysmature (weight, 2,860 g, <3%ile; height, 47 cm, P3; head circumference: 34 cm, P3). Physical examination showed diffuse hypotonia, absence of deep tendon reflexes and mild hepatomegaly. She had a geographic tongue without ulceration. Because of failure to thrive her formula was changed several times (including a trial of semi-elemental formula) without benefit. During the first 2 months of life, she experienced two episodes of sepsis related first to an acute lobar pneumonia and second to a perianal abscess associated with a fistula. At 3.5 months of age, she presented with bloody diarrhea and high fever. Laboratory investigations included C-reactive protein of 5.7 mg/dL (normal, <0.3 mg/dL), hemoglobin 8.1 g/dL (normal, 12–17 g/dL), red blood cell count 3.35 106/mm3 (normal, 4–6 106/mm3), mean corpuscular volume 78.8 μm3 (normal, 85–95 μm3), hematocrit 27% (normal, 38%–54%), serum iron 39 μg/dL (normal, 50–175 μg/dL), iron-binding capacity 191 μg/dL (normal, 200–360 μg/dL), ferritin 128, μg/L (normal, 10–270 μg/L), total serum proteins 4.3 g/dL (normal 6.1–7.9 g/dL), albumin 2.9 g/dL (normal, 3.5–5.2 g/dL), (-carotene 3 μg/dL (normal, 100–200 μg/dL), and total cholesterol 72 mg/dL. Stool culture was negative. An upper gastrointestinal endoscopy with jejunal biopsies showed subtotal villous atrophy. Colonoscopy revealed destruction of the surface mucosa, patchy ulcers, diffuse infiltration with polymorphonuclear leukocytes, and crypt abscesses. There were no extraintestinal manifestations indicative of inflammatory bowel disease. Genetic testing confirmed the presence of HLA B51+, as observed in Behçet syndrome. The diagnosis of intractable ulcerative enterocolitis of infancy (2) was suspected and 5-ASA treatment was given (50 mg/kg/day). Recurring episodes of colitis led to the initiation of corticosteroid treatment (2 mg/kg/day prednisone). Repeated laboratory evaluations continued to suggest chronic inflammation. Blood lactate was elevated at4.12 mmol/L (normal <1.5 mmol/L). At 6.5 months of age, the patient again became septic apnea and hypotension requiring her transfer to the Pediatric Intensive Care Unit. Laboratory investigations showed a persisting inflammatory syndrome and high lactate levels (19 mmol/L). Blood cultures were positive for Staphylococcus epidermidis. An echocardiograph showed hypertrophic cardiomyopathy that was initially attributed to the therapy with corticosteroids. At 8 months, she once again developed fever, vomiting, diarrhea and septicemia. We noticed an enlarged liver and signs of cardiac failure. Cerebral magnetic resonance imaging, electroencephalography, and electromyography with nerve conduction studies were normal, as was the fundiscopic examination of the eye. Echocardiography revealed severe hypertrophic cardiomyopathy with cardiac failure (ejection fraction: 29%). Her course was then characterized by disappearance of digestive symptoms and progressive worsening of cardiomyopathy (Fig. 1). From this time onward, elevated lactic acid levels were seen consistently with levels as high as 21 mmol/L (normal, <1.5 mmol/L) (Fig. 2).FIG. 1.: Clinical evolution. The evolution was characterized by disappearance of digestive symptoms with progressive worsening of the cardiomyopathy.FIG. 2.: Fluctuations of the lactic acid levels. Metabolic investigations demonstrated fluctuations of lactate levels, peaking at very high levels during sepsis.A muscle biopsy showed massive ragged red fibers, and biochemical analysis revealed a complex I deficiency in the muscle (Table 1) (investigation by Professor R. Van Coster, University Gent, Belgium (8)). The analysis of muscular mitochondrial DNA (investigation by Dr. L. De Meirleir, Vrije Universiteit Brussels, Belgium (9)) excluded the usual deletions and mutations (MELAS A3243G, MERRF A8344G, NARP T8893C/G), as well as tRNA mutations. The final diagnosis was severe complex I deficiency (NADH-CoQ oxidoreductase). Denaturing gradient gel electrophoresis analysis on muscular mitochondrial DNA of the ND1, ND2, ND3, ND4, ND4L, ND5 and ND6 genes of complexI in our patient did not reveal a mitochondrial DNA mutation. A liver biopsy was also performed, but no mitochondrial defect was found. At 10 months of age, the patient died of cardiac failure. Postmortem intestinal and cardiac biopsies were proposed to the family but were refused for religious reasons.TABLE 1: Mitochondrial respiratory chain enzyme activities, units shown as nmol/min/mg proteinDISCUSSION Our patient was similar at presentation to five patients reported earlier with intractable ulcerative colitis of infancy (2). They all had lesions of the mouth and colon; four had jejunal disease, and four had a perineal disease. None improved with immunosuppressive treatment, and all required total colectomy. Consanguinity of parents was reported in four of the five (2). In addition to this original report, we found in our patient high lactate levels that led us to consider the diagnosis of a mitochondrial respiratory chain deficiency. The presence of ragged red fibers, strongly indicative of a mitochondrial disorder, supported the diagnosis. This was confirmed histologically and biochemically on muscle biopsy. Mitochondrial enzyme activities were not measured in the intestinal tissue because the parents refused postmortem examination. In view of the severe complex I deficiency in skeletal muscle, however, we feel it is reasonable to attribute the intestinal and cardiac manifestations to this defect. However, we cannot exclude a fortuitous association. One particular feature of her clinical course was the improvement of digestive symptoms as cardiomyopathy became more prominent. The same feature was previously observed by Cormier and al. (3) in two other patients with intestinal mitochondrial respiratory chain disorder (MRCD) complex III deficiency. The children from this report had similar villous atrophy but no ulcerative colitis. The disease may fluctuate in severity during life, with acute episodes followed by recovery (Fig. 1). These fluctuations previously were observed in patients with liver-based MRCD and may be caused by the segregative replication phenomenon, by which during a replicative process, daughter cells may inherit a different proportion of normal or abnormal mitochondria than contained in the maternal heteroplasmic cell, thus changing their phenotype according to the normal or abnormal mitochondria received. If daughter cells inherit only normal or only abnormal mitochondria, they become homoplasmic, and if these cells are the main population of proliferating cells, their phenotype will become dominant in the patient. The segregative replication phenomenon may also explain why the disease does not involve all organs, depending on the segregation during fetal development. Phenotype is determined by the relative proportion of normal and mutated genomes (4,5). The mutation could also be in the nuclear genome, interfering with normal expression or translation of the mitochondrial genome explaining in our case the autosomal recessive pattern of presentation suggested by parental consanguinity (6). Thus, MRCD may have an autosomal recessive, dominant, or X-linked pattern of transmission. In our patient, no mutation or deletion of mitochondrial DNA could be demonstrated, but it does not exclude point mutations of mitochondrial DNA. It is now recognized that the liver and gastrointestinal tract are major target organs in inherited defects of mitochondrial function. Previous reports of children with intestinal MRCD have underlined the particularly poor prognosis associated with this presentation (5). Liver involvement is well known in MRCD and can be associated with intestinal disease (5,6). Our initial diagnosis was an incomplete form of Behçet disease, in view of the presenting symptoms, the consanguinity of the parents, their Mediterranean origin, and the detection of HLA B51. However, the HLA B51 is found in 15% in the normal population, and Behçet disease most often appears later in life and rarely before 6 to 8 years. We conclude that MRCD is a potential etiology for intractable ulcerative enterocolitis of infancy and that these patients should have mitochondrial biochemistry and genetic analysis performed when a bowel biopsy is performed. Acknowledgments: The authors thank Professor Rudy Van Coster, from Gent Universiteit, and Dr. Linda De Meirleir, from Vrije Universiteit Brussels, for performing mitochondrial respiratory chain investigations.