Lawrence T. K. Wong

Infection with Burkholderia cepacia Complex Genomovars in Patients with Cystic Fibrosis: Virulent Transmissible Strains of Genomovar III Can Replace Burkholderia multivorans

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.

An Unusual Presentation of Doxycycline-Induced Photosensitivity

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.

Biochemical and Histologic Pathology in an Infant with Cross-Reacting Material (Negative) Pyruvate Carboxylase Deficiency

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.

Observed range of assay values for plasma and cerebrospinal fluid amino acid levels in infants and children aged 3 months to 10 years

From data collected at the Childrens Hospital, Vancouver, during a two year period, 1976 - 1977, we have determined a range of values for children aged 3 months to 6 years for 24 plasma amino acids and for children aged 3 months to 10 years for 18 cerebrospinal fluid amino acids. A total of 26 plasma and 21 cerebrospinal fluid samples were accepted for our reference population. Six of the children in the plasma group were also in the cerebrospinal fluid group, making a total of 39 children in the study.

Review of Metabolic Screening Program of Children's Hospital, Vancouver, British Columbia. 1971--1977.

1. Between 1971 to 1977, 74,521 urines, collected on filter paper and mailed in, were screened by the Metabolic Screening Program of the Childrens Hospital. These represented 45.9% of live births in B.C. hospitals were the program has been available. The mean age of the infants was 4.4 weeks. Urines were examined by chromatography with ethyl acetate-pyridine-water for sugars. 1423 (2.13%) had an abnormal pattern necessitating a repeat urine card. A persistent abnormality was noted in 167 (0.22%) and from these a liquid urine sample was obtained for two dimensional amino acid chromatography and/or a repeat sugar chromatography. 2. In 47 (0.06%) of these a definite metabolic abnormality was confirmed. These included cases of Iminoglycinuria (8), Hartnup trait (4), Nonketotic hyperglycinemia (2), Histidinemia (1), Cystathioninuria (5), Argininosuccinic aciduria (1), Maple Syrup Urine Disease (1), Diabetes Mellitus (1), Renal glycosuria (1) and Persistent galactosuria (3). 201 infants had a slight increase of cystine and/or lysine, and 19 of these were documented to be heterozygous for cystinuria.

A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency

OBJECTIVE Multiple carboxylase deficiency (MCD, MIM:253270) is a common organic aciduria and caused by deficiency of either biotinidase or holocarboxylase synthetase (HLCS; EC 6.3.4.10). Patients commonly present during early infancy with acute metabolic derangements and severe metabolic acidosis. Recently, a late onset form of HLCS deficiency was also described. The different phenotypes (early and late presenting) may be related to a spectrum of mutations in HLCS gene. Applications of mutation analysis in HLCS had been limited previously by the requirement of cDNA from living tissue for study. We described here a genomic approach for molecular diagnosis of HLCS deficiency which we have used to detect mutations in Chinese patients who had the late-onset form of HLCS deficiency. In addition, a fibroblast cell line with MCD from Coriell Cell repositories was also studied. DESIGN AND METHODS Three Chinese patients with late onset HLCS deficiency were studied. The genomic sequence of HLCS was retrieved and newly designed primers were used to cover all coding sequences of the gene. PCR products were analyzed by direct sequencing. Population allelic frequencies of mutations detected were determined by genotyping of control samples by restriction fragment length polymorphism. RESULTS We found a recurrent mutation, R508W, in the three unrelated Chinese patients. Two were homozygous for this mutation. The other patient was a compound heterozygote of R508W and a novel mutation, D634N. The results suggest that R508W may be an important and relatively prevalent disease-causing mutation in Chinese MCD patients. A fibroblast cell-line from an African patient revealed an additional novel mutation, R565X and a known mutation, V550M. CONCLUSION R508W is a recurrent mutation in Chinese MCD patients which is associated with the late onset phenotype. This new genomic approach for mutation analysis of HLCS gene provides new opportunities in studies of MCD.

Anti-plasmin (α2-macroglobulin) activity of plasma from cystic fibrosis patients

Abstract We have studied the plasmin-α 2 -macroglobulin interaction using plasma from cystic fibrosis patients. In this system α 2 -macroglobulin from cystic fibrosis plasma does not differ from controls in its ability to bind with and inhibit plasmin.

Abnormal anion exchange mechanism operates in the sweat glands of cystic fibrosis patients.

It has recently been suggested that an abnormal anion exchange mechanism operates in the sweat glands of cystic fibrosis (CF) patients (1, 2). According to this suggestion, a defect in the CF sweat gland results in abnormally low permeability of the sweat duct to chloride ion. The normal exchange of chloride for bicarbonate cannot then occur, so that in CF sweat there is an abnormally low level of bicarbonate as well as an abnormally high level of chloride. There is now well established evidence that pancreatic bicarbonate secretion is abnormal in all CF patients (3, 4, 5, 6) and, therefore, it seemed sensible to look at chloride levels in these secretions. We examined duodenal aspirates obtained during pancreatic function testing previously described (5 ) , and obtained the data shown in Table 1. Bicarbonate values were obtained on the samples at the time of collection. Chloride values were obtained on samples stored at -70°C. Chloride output from CF patients is lower than that of controls so at first glance Quintons hypothesis of defective chloridebicarbonate exchange would not appear to be true for secretinpancreozymin stimulated pancreatic secretions. Interestingly, however, the ratio of chloride output to bicarbonate output is much higher for CF patients than controls (P < 0.001). This is true for all the CF patients regardless of their trypsin output although the patient with highest trypsin output has the lowest chloride/bicarbonate ratio. It may be, therefore, that both the pancreas and sweat gland in CF exhibit abnormalities in ion exchange involving chloride and bicarbonate. The hypothesis of Johansen et al. (8) and Hadorn et al. (7), suggesting a generalized disturbance of water and electrolyte movement in exocrine tissue warrants re-examination to take into account this added information. We urge other investigators to collect more data on total electrolyte output of pancreatic secretions to see if our findings can be substantiated and explained. REFERENCES AND NOTES

574 HEREDITARY FRUCTOSE INTOLERANCE: FATE OF PLASMA POTASSIUM DURING FRUCTOSE LOAD

A one year old North American Indian boy who presented with episodes of vomiting, lethargy and periodic hypoglycaemia was shown to have hereditary fructose intolerance. A liver biopsy showed typical histological changes and fructose-l-phosphate aldolase activity was greatly diminished.Although blood fructose increased only slightly during an oral fructose tolerance test, he developed severe hypoglycaemia which did not respond to glucagon. Insulin levels remained low. Plasma lactic acid, uric acid, magnesium, methionine, valine, leucine, isoleucine and aspartate aminotransferase rose during the test while potassium and phosphate fell markedly. Continuous EEG monitoring showed no significant changes, but an ECG showed a slight cardiac arrhythmia when potassium was at its lowest level. Urinary excretion of uric acid and magnesium increased during the fructose load, but there was no rise in the excretion of potassium, phosphate, or bicarbonate.Patients with hereditary fructose intolerance may exhibit a Fanconi syndrome and this has been blamed for the falling plasma potassium during a fructose load. The hypokalemic response to acute fructose loading in this patient has been demonstrated not to be due to renal losses. We speculate that potassium probably entered the intracellular space when fructose was administered.