A 15-year-old female with carbamyl phosphate synthetase deficiency, cystic fibrosis, and cystic fibrosis-related diabetes underwent orthotopic cadaveric liver transplantation. Metabolic control was maintained during the procedure with nutritional support and the use of intravenous sodium phenylacetate and benzoate. Her postoperative course was complicated by seizures and a transient decline in her pulmonary function tests, which returned to preoperative levels within one year of the transplant. Now, four years post-transplant, her quality of life has dramatically improved. There are only four Canadian centres with paediatric liver transplantation programs. However, expert medical care for adults with inborn error of metabolism is even more limited, suggesting that access to adult medical care is one of the many factors to be considered when liver transplantation is contemplated for patients with metabolically unstable conditions.

Pseudomonas aeruginosa is the most common respiratory pathogen in patients with cystic fibrosis (CF), but the predominant mechanism by which it is acquired is controversial. To determine the frequency of patient-to-patient spread, we evaluated P. aeruginosa isolates from 174 patients treated at the CF clinics in Vancouver, BC, Canada, since 1981. Multiple isolates were obtained from each patient and genetically typed by random amplified polymorphic DNA and pulsed field gel electrophoresis analyses. A total of 157 genetic types of P. aeruginosa was identified, 123 of which were unique to individual patients. A total of 34 types was shared by more than one patient; epidemiologic evidence linked these individuals only in the cases of 10 sibships and 1 pair of unrelated patients. We conclude that there is an extremely low risk in Vancouver for patients with CF to acquire P. aeruginosa from other patients. It appears that prolonged close contact, such as occurs between siblings, is necessary for patient-to-patient spread. The major source of acquisition of P. aeruginosa in CF appears to be from the environment. Considering these observations, we do not recommend segregation of patients with CF on the basis of their colonization status with P. aeruginosa.

Infection with Burkholderia cepacia complex in patients with cystic fibrosis (CF) results in highly variable clinical outcomes. The purpose of this study was to determine if there are genomovar-specific disparities in transmission and disease severity. B. cepacia complex was recovered from 62 patients with CF on > or =1 occasions (genomovar III, 46 patients; genomovar II [B. multivorans], 19 patients; genomovar IV [B. stabilis], 1 patient; genomovar V [B. vietnamiensis], 1 patient; and an unclassified B. cepacia complex strain, 1 patient). Patient-to-patient spread was observed with B. cepacia genomovar III, but not with B. multivorans. Genomovar III strains replaced B. multivorans in 6 patients. Genomovar III strains were also associated with a poor clinical course and high mortality. Infection control practices should be designed with knowledge about B. cepacia complex genomovar status; patients infected with transmissible genomovar III strains should not be cohorted with patients infected with B. multivorans and other B. cepacia genomovars.

Photoonycholysis in association with a generalized phototoxic reaction or as an isolated event is a well-recognized complication of the tetracycline group of antibiotics. We describe a 14-year-old white girl with cystic fibrosis who developed photoonycholysis of all 20 nails while receiving treatment with doxycycline. Pediatricians who prescribe tetracyclines should be aware of this potential complication.

Variable clinical course has been reported with the acquisition of Burkholderia cepacia in patients who have cystic fibrosis (CF). We hypothesized that the perceived worsening with B. cepacia may reflect the underlying severity of pulmonary disease at the time of acquisition. To test this hypothesis, we matched CF patients colonized with B. cepacia with CF patients not colonized with the organism. Two-year pre- and postacquisition data and long-term data were compared. Patients were matched for gender, age (+/- 1 yr), height (+/- 5 cm), weight (+/- 8 kg), percent predicted forced expiratory volume in one second (% pred FEV(1)) (+/- 10%), and pancreatic sufficiency status. Differences in rates of change pre- and postacquisition for FEV(1), FVC, weight, and frequency of intravenous courses were compared within pairs with the Wilcoxon signed rank test. Two-year and long-term survival was compared within pairs with the McNemar test. No significant differences were observed in mean annual rates of change in weight (0.33 and -0.28 kg/yr), % pred FEV(1) (-0.36 and -1.74%/yr), and percent predicted forced vital capacity (% pred FVC) (-3.80 and -2.32%/yr) between B. cepacia and control pairs in 2-yr and long-term postacquisition interval, respectively. Similar rates of change were noted for pre- to postacquisition intervals within pairs for weight (0.17 kg/yr), % pred FEV(1) (-0.16%/yr), % pred FVC (5.02 %/yr). There was a significantly higher rate of intravenous antibiotic courses in B. cepacia cases in the 2-yr and long-term postacquisition interval. Higher mortality was observed in the B. cepacia cases in the long term (p < 0.05). We conclude that colonization with B. cepacia does not necessarily adversely affect pulmonary status, but is associated with reduced long term survival. Whereas previous associations may be attributed to a propensity to colonize those who had more advanced disease, specific strain types of B. cepacia may have enhanced pathogenicity.

The course of a 12-year-old girl with cystic fibrosis (CF) and with recurrent hemoptysis since age 8 years is described. Conservative measures failed to control her bleeding. Hemoptysis was only partially controlled by repeated bronchial arterial embolizations. However, the addition of tranexamic acid (TXA) resulted in complete cessation of bleeding. Attempts to withdraw TXA therapy resulted in recurrence of hemoptysis; this patient has, therefore, been continuously maintained on this therapy for the past 4 years. No side effects of long-term TXA treatment have been noted.

One hundred and six specimens from 90 patients with cystic fibrosis were evaluated for the presence of Burkholderia cepacia using a current routine diagnostic protocol as well as a research protocol involving polymyxin B-MacConkey agar without crystal violet, PC agar, OFPVL agar, and a selective brain-heart infusion broth. Ten specimens from eight patients (8.9%) were positive by any method. The selective enrichment broth was the only medium that yielded B cepacia from all 10 positive samples, although the routine protocol was successful for eight of these. Transient carriage was identified in one patient. Epidemiological studies may be better served by the use of selective enrichment rather than selective solid media alone. Carrier status for B cepacia requires more strict definition if positive carrier status is to be accepted as having medical importance.

The effective dose and schedule of enzyme replacement therapy for Gaucher's disease have not been definitely established. We report a case of mixed chimeric state in an allogeneic BMT patient and followed her clinical and laboratory progress. The result shows that a low but sustained glucocerebrosidase level may provide symptomatic relief for this lysosomal disorder.

Respiratory and fecal specimens from 111 patients with cystic fibrosis (CF) were cultured on 394 occasions to determine which site Pseudomonas aeruginosa colonizes first. By an enrichment and selection culture technique, P. aeruginosa was recovered from fecal cultures in 21 (42%) of 50 respiratory tract-positive patients but from only 3 (6.3%) of 48 respiratory tract-negative patients and from 1 (2.2%) of 45 control subjects. In 4 (22%) of the 18 patients who became culture-positive during the study, P. aeruginosa was recovered from a fecal specimen before respiratory colonization. Only 1 of these 4 became persistently colonized with P. aeruginosa in the respiratory tract; however, the serotype of the respiratory isolate was different from that of the fecal isolate. P. aeruginosa is recovered rarely from the feces of patients with CF who are culture-negative in the respiratory tract. In patients with CF, primary colonization with P. aeruginosa probably occurs in the respiratory tract.

Barrett's esophagus (BE) is a premalignant condition, and a recognized complication of severe gastroesophageal (GE) reflux. Children with cystic fibrosis (CF) have a marked predilection to develop GE reflux, but Barrett's esophagus is one complication of GE reflux not previously described in CF. We describe in detail two adolescents with CF who were found to have Barrett's esophagus, and mention three other cases. The presence of Barrett's esophagus in CF patients may be missed because GE reflux is often relatively silent in CF, because patients may consider mild upper gastrointestinal (GI) symptoms as "part of CF," and because of the nature of Barrett's epithelium itself. Upper gastrointestinal (GI) endoscopy with documentation of landmarks and multiple targeted biopsies should be performed in children with CF with even mild symptoms of GE reflux or an abnormal 24 h intra-esophageal pH study. Any biopsies containing columnar epithelium should be stained with Alcian blue at pH 2.5 to look for goblet cell metaplasia, i.e., Barrett's esophagus. Children with CF may be a high-risk group for development of Barrett's esophagus and its complications, especially given the increased survival in CF.

A girl aged eight months, who presented with developmental delay and dislocated optic lenses, was diagnosed as having combined sulfite oxidase and xanthine dehydrogenase deficiencies consistent with molybdenum cofactor deficiency. The diagnosis was confirmed by demonstrating the absence in urine of urothione, a molybdenum cofactor metabolite. Prenatal diagnosis excluded the disease in the mother's second pregnancy. A summary of an in vitro study of molybdenum cofactor synthesis in the patient is given.

ABSTRACT:The incidence of fatal hepatic failure associated with valproic acid (VPA) therapy is highest in children under the age of three years, particularly in those with developmental delay. The pathogenesis of VPA hepatotoxicity is unclear but may relate to the accumulation of a toxic metabolite of VPA which impairs fatty-acid oxidation. We describe two unrelated infants with developmental delay who developed hepatic failure while receiving VPA. Siblings of both children subsequently developed hepatic steatosis and intractable seizures without being exposed to VPA. This suggests that that the two children who developed liver failure when receiving VPA may have had a familial metabolic disorder. Familial metabolic disorders may account partly for the higher incidence of fatal hepatotoxicity described in infants receiving VPA.

Although it is well established that components of wheat gluten and structurally-related cereal proteins produce intestinal damage in Coeliac disease (CD), the primary defect which confers upon the host susceptibility to these dietary substances remains a mystery. To date, three main hypotheses have been framed to explain this susceptibility, but none has yet been proven. Diagrammatic representation of these aetiologic hypotheses facilitates their analysis and illustrates the potential importance of a relatively ignored possibility, i.e., that there may be a defect in the intraluminal phase of the in vivo processing of dietary gluten. We suggest that future work should be directed towards investigating the potential role of abnormalities of this phase in the aetiology of CD.

A deficiency of hepatic guanosine triphosphate cyclohydrolase I is reported in a 4-month-old infant in whom positive results on a Guthrie phenylketonuria test in the neonatal period were found. Because of the significantly elevated serum phenylalanine levels a diagnosis of classical phenylketonuria was made, and dietary therapy was started. Urinary pteridine screening for cofactor variants, however, revealed extremely low levels of both neopterin and biopterin. This suggested the possibility of guanosine triphosphate cyclohydrolase I deficiency and led to additional confirmatory assays. Repeat urine, serum, and CSF pteridine profiles, combined with tetrahydrobiopterin-loading studies and the assay of guanosine triphosphate cyclohydrolase I activity in a liver biopsy, confirmed the defect. It is significant to note that the diagnosis was made before the onset of major clinical symptoms. This case illustrates the need for routine cofactor variant screening of all infants in whom hyperphenylalaninemia is diagnosed in the neonatal period.

ABSTRACT: An infant with the acute neonatal form of pyruvate carboxylase deficiency (cross-reacting material negative) presented with severe intractable lactic acidosis within 4 h after birth. He also had hyperammonemia, hypercitrullinemia, and hyperlysinemia. Plasma glutamine was not elevated. He had a rapidly deteriorating clinical course with severe liver dysfunction, repeated septicemia and seizures; he was comatose and was on a ventilator throughout; death occurred at 8 wk of age. Skin fibroblast study confirmed the enzyme deficiency. Detailed biochemical parameters and histopathology of the brain and liver are presented. The evidence from this infant suggests that disturbances of intracellular oxaloacetate levels as a result of the primary enzyme defect might also contribute to deficiency in ATP generation which may explain the various other biochemical changes and liver pathology.

An infant with argininosuccinic aciduria was detected through the routine newborn screening program for inborn metabolic diseases and has been followed for over 7 years. Treatment consisting of restricted protein intake and arginine base supplementation was initiated at the age of 8 months and was continued intermittently. She maintained normal psychomotor development to the age of 3 years and currently at the age of 7.3 years, she has measured intelligence in the borderline range. She has had mild symptoms of cerebellar ataxia. Her physical growth has been below normal. Biochemical abnormalities are described. Special metabolic investigations and the effects of treatment are discussed.