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D A Applegarth

Publications and source records attributed to D A Applegarth.

At least 55 records · Page 3Linked to original sources
PubMed1990

The high incidence of valproate hepatotoxicity in infants may relate to familial metabolic defects.

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 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.

Chemical and Drug Induced Liver Injury↗
PubMed1989

Use of placental enzyme analysis in assessment of the newborn at risk for non-ketotic hyperglycinaemia (NKH).

The incidence of non-ketotic hyperglycinaemia (NKH), McKusick 23830, in the population of British Columbia, Canada was found to be the same as that reported for Finland. We present the plasma glycine levels in ten non-ketotic hyperglycinaemia patients and outline difficulties in interpreting plasma glycine levels in their newborn siblings. We propose the use of a placental glycine cleavage enzyme (EC 2.1.1.10) assay to rule out a diagnosis of non-ketotic hyperglycinaemia in at-risk infants during the first few days of life.

Amino Acid Metabolism, Inborn Errors↗
PubMed1989

Laboratory detection of metabolic disease.

This article describes the clinical signs, abnormal chemistry, histopathology, and biochemical tests that assist in the diagnosis of many inherited metabolic diseases. Small molecule diseases (for example, amino acid disorders, organic acidurias, and galactosemia) may present with acute illness and lead to unexplained death. Diagnosis of the specific enzyme defect may permit treatment by dietary changes or vitamin supplementation. Large molecule diseases are degenerative disorders due to storage of glycogen, glycoproteins, or mucopolysaccharides. Table 7 presents a compendium of laboratory investigations one should consider using when abnormalities are found in multiple organ systems. The investigation of a child with a mucopolysaccharidosis is used as an example of the use of this table. Investigating pediatricians should realize that many laboratory tests involved in the diagnosis of metabolic disease required special collection and handling by the laboratory.

Amino Acid Metabolism, Inborn Errors↗
PubMed1988

Interstitial 7q deletion [46,XX,del(7)(pter----q21.1::q22----qter)] and the location of genes for beta-glucuronidase and cystic fibrosis.

We report on a patient with a de novo chromosome abnormality del(7)(q21.1q22). The cells of this patient were used to determine the assignment of the gene for the enzyme beta-glucuronidase and the DNA probes around the cystic fibrosis gene--pJ3.11 and metH. Both the beta-glucuronidase gene and the DNA probes pJ3.11 and metH were found in 2 copies in our patient, indicating that neither locus lies in the deleted segment.

Chromosome Deletion↗
PubMed1988

Juvenile galactosialidosis in a white male: a new variant.

We describe a 19-year-old white male with juvenile galactosialidosis. He presented with hip arthralgia and was found to have facial "coarseness," corneal clouding, mitral and aortic insufficiency, and hepatosplenomegaly. Ultrastructural studies of skin biopsy and peripheral blood lymphocytes showed membrane-bound inclusions containing sparse fibrillogranular material. Biochemical analysis showed elevated urinary sialyloligosaccharides and no free sialic acid. Fibroblast enzyme analysis showed low activities of both alpha-neuraminidase and beta-galactosidase. To date, most patients with juvenile galactosialidosis have been Japanese. However, unlike those patients, our patient did not have macular cherry-red spots, neurologic abnormalities, or mental retardation. We speculate that this young man represents a new subtype of juvenile galactosialidosis with a potentially different molecular defect from that of the Japanese variant.

Adult↗
PubMed1988

Carrier detection in Sanfilippo A syndrome.

Leucocytes or fibroblasts from 10 obligate heterozygotes for Sanfilippo A syndrome gave decreased heparan N-sulphatase levels, using a modification of the method of Hall et al. (1978), which did not overlap normal control values. Five family members gave decreased values and are presumed heterozygotes.

Fibroblasts↗
PubMed1987

Morphological and histochemical changes in intestinal mucosa in the reserpine-treated rat model of cystic fibrosis.

The present investigation was undertaken to determine whether or not there are histochemical and morphological changes in the intestine of the chronically reserpine-treated rat, an animal model of cystic fibrosis. Male Sprague-Dawley rats were given seven daily intraperitoneal injections of reserpine at dosages of 0.5 (n = 6) or 1.0 mg/kg body weight (n = 6). Control groups consisted of parfed solvent-injected (n = 6), solvent-injected (n = 4), and saline-injected animals (n = 4). Light microscopic histochemical procedures and morphological assessments were performed on sections of "Swiss rolls" of small and large intestine. Chronic reserpine treatment caused an increase in the sulfation of goblet cell mucin in the small intestine without accompanying morphological change; these findings resemble those reported in cystic fibrosis. No qualitative differences in mucin were found in the large intestine but there was an increased number of goblet cells in the surface epithelium and retention of mucus within these cells. Similar although less marked changes were noted in the parfed controls suggesting that those observed in the treated groups may be due, in part, to the reserpine-induced anorexia. The resemblance between the changes in the small intestine of the reserpine-treated rat and those observed in CF patients supports the contention that the chronically reserpine-treated rat is suitable as a model of cystic fibrosis.

Animals↗
PubMed1987

Morquio disease presenting as hydrops fetalis and enzyme analysis of chorionic villus tissue in a subsequent pregnancy.

We describe the prenatal diagnosis of a fetus at risk for mucopolysaccharidosis (MPS) Type IVA (Morquio syndrome) using enzyme analysis of chorionic villus tissue. The family had two previous affected children, one with progressive nonimmune hydrops fetalis presenting at 16 weeks gestation and one mildly affected 5 year old. The parents had decreased levels of N-acetyl galactosamine-6-sulphate sulphatase in cultured skin fibroblasts indicating that carrier detection is possible for Morquio A syndrome.

Adult↗
PubMed1987

Guanosine triphosphate cyclohydrolase I deficiency: early diagnosis by routine urine pteridine screening.

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.

Aminohydrolases↗
PubMed1986

Fluorometric determination of nanogram quantities of protein in small samples: application to calcium-transport adenosine triphosphatase.

A fluorometric micro protein assay based on fluorescamine-labelling of homogeneous proteins in solution has been developed which is capable of accurately quantitating as little as 25 ng protein at a concentration of 1.25 micrograms/ml. This micro assay uses a flow-through HPLC fluorescence detector. Typical micro assays measuring bovine serum albumin standards (0-25 mg/l) yielded linear regression coefficients of r = 0.999. Assays of purified Ca2+-ATPase solutions determined by the micro fluorescamine procedure correlated well with measurements made using the deoxycholate-TCA-precipitation modification of the Lowry assay: 1.0 microgram ATPase by Lowry method = 1.1 microgram protein by fluorescamine microassay (when both procedures were standardized with bovine serum albumin) (r = 0.995). The assay proposed offers a 100-fold increase in sensitivity, compared to the Lowry procedure.

Calcium-Transporting ATPases↗
PubMed1986

Free and total serum valproate concentrations: their relationship to seizure control, liver enzymes and plasma ammonia in children.

The relationships between total and free serum valproate (VPA) concentrations and seizure control, serum liver enzyme activity and plasma ammonia concentration were studied in 61 epileptic children. Enzyme-immunoassay (EMIT)R methods gave higher values of total VPA concentration than gas-liquid chromatography (GLC) methods. In over 80% of children with complete seizure control the ranges of total VPA concentration were 140-420 mumol/L with GLC methods and 210-560 mumol/L with EMIT methods. The range of free VPA concentrations in 78% of children with complete seizure control was 8.8-26.4 mumol/L. Increased liver enzyme activity was observed in 6 of the 61 children and raised plasma ammonia concentration in 11 of 50 children. Plasma ammonia concentration was related to total serum VPA but was not related to free serum VPA. Increased serum liver enzyme activity was related to VPA dose per kg but not to free or total serum VPA concentration. Thus free VPA concentrations do not appear to be more useful than total VPA concentrations in predicting seizure control and do not correlate with liver enzyme activity or plasma ammonia concentration.

Adolescent↗
PubMed1986

Biochemical and histologic pathology in an infant with cross-reacting material (negative) pyruvate carboxylase deficiency.

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.

Acidosis↗
PubMed1985

Screening of newborn infants for galactosemia in British Columbia.

With simple microbiologic and fluorescent tests, we detected two cases of classic galactosemia, confirmed by specific enzyme assays, in the first 25 000 newborn infants in British Columbia screened for this disorder. The results were equivocally abnormal for another 31 infants, and a second blood sample was requested from each, either for repeat screening or for enzyme assays. The two infants with galactosemia were in hospital with an undiagnosed acute illness and had only a trace of non-glucose reducing substances in the urine when the screening tests were done. Screening for galactosemia fits well with our established programs of screening for phenylketonuria and hypothyroidism and costs less than $1 per infant tested.

British Columbia↗