Ronald Holmes

Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation☆☆☆★★★

We studied three pediatric patients with protein-losing enteropathy in conjunction with univentricular hearts and right atrial to pulmonary artery anastomosis (Fontan operation) before and during heparin therapy. Each patient showed dramatic improvements in symptoms, marked elevations in serum albumin levels, and quantitative reversal of enteric protein loss within a few weeks of beginning therapy. These findings suggest that heparin may be an important treatment for this poorly understood condition.

Evaluation of liquid yeast-derived sucrase enzyme replacement in patients with sucrase-isomaltase deficiency

BACKGROUND No enzyme replacement therapy exists for patients with congenital sucrase-isomaltase deficiency (CSID). A by-product of the manufacture of bakers yeast is a liquid preparation containing high sucrase activity. The aim of the present study was to investigate the activity and stability of this preparation and its effect on breath hydrogen excretion and gastrointestinal symptoms after sucrose ingestion in 14 patients with CSID. METHODS The homogeneity of yeast sucrase was studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and its activity was measured. Stability at various temperatures and pH ranges and in the presence of gastric aspirate, pepsin, and bovine serum albumin was assessed. Fourteen patients with CSID underwent double-blind placebo-controlled breath tests with yeast sucrase. They then completed an 8-week dose response study that used different enzyme concentrations while consuming a sucrose-containing diet. RESULTS Liquid yeast sucrase is highly glycosylated, contains no lactase activity, and is stable at 4 degrees C and over a wide range of pH. Pepsin digestion of the enzyme in vitro can be blunted by bovine serum albumin and by increasing the pH. Yeast sucrase reduces breath hydrogen excretion in patients with CSID who are given a sucrose load (P < 0.001) and allows most patients to consume a sucrose-containing diet. CONCLUSIONS Liquid yeast sucrase offers effective enzyme replacement therapy for patients with CSID.

Immunology of inflammatory bowel disease: Summary of the proceedings of the subcommittee on immunosuppressive use in IBD

As outlined, scanty data exist with regard to immunologic therapy in children with IBD despite the fact that the pediatric population affords a unique opportunity for clinical evaluation. Children are less affected by modifying conditions such as smoking, alcohol ingestion, and the long-term use of medications, and because of their specific needs for ponderal and linear growth, children might benefit most from immunological therapy that has been proven to be steroid sparing. Therefore, clinical trials to evaluate the efficacy of 6-MP and/or azathioprine in growing children with Crohns disease would appear to provide a fruitful avenue for collaborative research. Efforts to organize a multicenter evaluation of these agents have been initiated. The studies are crucial in evaluating the efficacy and safety of immunosuppressive therapy in the pediatric population with IBD.

Oral Ether Lipid Therapy in Patients with Peroxisomal Disorders

IDepartment of Pediatrics, William Beaumont Hospital, 3601 West Thirteen Mile Road, Royal Oak, MI 48072, USA; 2Room A717, Montreal Childrens Hospital, McGill University, 2300 Rue Tupper, Montreal, PQH3H, 1P3, Canada; 3Neuroscience Laboratory, University of Michigan, 1103 E. Huron, Ann Arbor, Michigan 48109, USA

Lactic acidosis and mitochondrial dysfunction in two children with peroxisomal disorders

SummaryMitochondrial myopathies and defects in oxidative phosphorylation have been described in some patients with peroxisomal disorders. Although peroxisomes and mitochondria play a role in the β-oxidation of fatty acids, the metabolic interactions between the two are not well defined. Defects in peroxisomal β-oxidation are associated with extracellular accumulation of very long-chain fatty acids and may be accompanied by alterations in the intracellular pool of fatty acyl-CoAs, which are known to alter mitochondrial function. This study was initiated to examine alterations in the intracellular pool of acyl-CoAs and mitochondrial function in two children with generalized disorders of peroxisomal function and clinical lactic/pyruvic acidaemia. Fibroblasts were cultured from skin biopsies obtained from one child with neonatal adrenoleukodystrophy (NALD) and another with rhizomelic chondrodysplasia punctata (RCDP). Fibroblast lactate oxidation was significantly inhibited in NALD by 76% and RCDP by 92% compared to control values of 1.9±0.1 nmol/min per mg protein. Pyruvate dehydrogenase (PDH) (mean±SEM; activity nmol/min per mg protein) was: NALD 0.55±0.02 (p<0.01), RCDP 0.44±0.02 (p<0.01), and controls 0.83±0.02. The acid-insoluble (long-chain and very long-chain) acyl-CoA levels (mean±SEM; pmol/mg protein) were: NALD 129±69 (p<0.01), RCDP 65±15 (p<0.05), and control 45±7. These two patients with generalized peroxisomal disorders exhibited an increase in intracellular acyl-CoA species accompanied by decreased PDH activity and clinical lactic/pyruvic acidaemia.

Relapsing pseudomembranous colitis.

Pseudomembranous colitis secondary to C. difficile and its toxin(s) is a well-recognized disease in children and usually responds to treatment with oral vancomycin. There are well-documented reports of relapse in adults after initial successful treatment with vancomycin. This report documents relapse in a child who developed diarrhea following treatment of pseudomembranous colitis. Stool cultures were negative for C. difficile at the end of the initial course of treatment, but the organism was isolated from the stool when the diarrhea recurred. The symptoms improved following a second course of treatment with vancomycin and have not recurred during 8 months of follow-up monitoring.

PEROXISOMAL ENZYME DEFICIENCY IN THE CONRADI-HUNERMAN FORM OF CHONDRODYSPLASIA PUNCTATA

Heymans et al (New Engl. J. Med. 313: 187, 1985) have reported deficient dihydroxyacetone phosphate acyltransferase (DHAP-AT) in the autosomal recessive, rhizomelic form of chondrodysplasia punctata. We describe a partial deficiency of this peroxisomal enzyme in a female child with a dominant form of chondrodysplasia punctata (Conradi-Hunerman syndrome; chondrodysplasia calcificans congenita). Clinical manifestations in the child (age 7 months) included short stature, dysmorphic face with frontal bossing, shallow nasal bridge, shortened nose, brachycephaly and patchy alopecia; bilateral lenticular cataracts; asymmetric shortening of the left femur with scoliosis and multiple epiphyseal, punctate calcifications; ichthyosis prominent at birth with residual swirls of hyperkeratotic skin. Her mother (age 39) had an adult height of 56 inches with similar clinical findings; she had a normal daughter by a different husband, two normal brothers, and no history of miscarriages or consanguinity. Activity of fibroblast DHAP-AT was 0.16 nmol per min per mg protein in the daughter and 0.46 in the mother compared to 0.50 in controls. Erythrocyte plasmalogens were normal in both patients. Other indices of peroxisomal dysfunction such as very long chain fatty acids, phytanic acid, and peroxisomal morphology were normal except for a qualitatively elevated urinary pipecolic acid in the child. These results add another disorder to the expanding spectrum of peroxisomal disease.

152 ACYL CoA CONTENT IN A PATIENT WIH A PEROXISOMAL DISORDER AND MITOCHONDRIAL DYSFUNCTION

Very long chain fatty acids are increased in peroxisomal disorders. We have measured the Acyl CoA content, total and peroxisomal B-oxidation (TB-OX & PB-OX), and pyruvate dehydrogenase activity (PDH) in fibroblasts from a patient (P) with neonatal adrenoleukodystrophy and controls (C). CoA content was determined after perchloric acid extraction by a fluorometric enzymatic cycling method. Total CoA content for P, C in nmol/mg protein: Acyl CoA 0.129 ± 0.069, 0.045 ± 0.007, p 0.02; acetyl CoA 0.258 ± 0.077, 0.115 ± 0.04, p<0.01; CoASH 0.003; 0.048. PB-OX was measured in the presence of rotenone and antimycin a. TB-OX in nmol/mg/min (PB-OX, % of TB-OX); P, C 0.198 ± 0.042 (39%), 0.184 ± 0.043 (47%) and PDH in nmol/mg/min; P, C 0.11 ± 0.02, 0.24 ± 0.01, P < 0.004. The increase in acyl CoA and acetyl CoA/CoASH ratio in P may result in decreased mitochondrial PDH activity. P also exhibits clinical evidence of mitochondrial dysfunction characterized by carnitine deficiency. Therefore, the defects in lipid metabolism caused by the peroxisomal disorder of P may contribute to secondary mitochondrial disorders documented clinically and biochemically.

1294 ORAL ETHER LIPID THERAPY IN PATIENTS WITH ZELLWEGER SYNDR0ME OR ZELLWEGER-LIKEIDISORDERS

Patients with the cerebrohepatorenal syndrome of Zellweger (ZS) lack peroxisomes and certain peroxisomal enzymes such as dihydroxyacetone phosphate acyltransferase (DHAP-AT) in their tissues. Deficiency of this necessary enzyme for glycerol ether lipid biosynthesis provides a biochemical criterion for diagnosing patients with more subtle alterations of peroxisome function and suggests a therapeutic strategy for ZS patients. We describe the oral administration of an emulsion of alkyl glycerols to two patients with ZS-one with classic manifestations and 9% of control fibroblast DHAP-AT activity, the other with 30% of control fibroblast DHAP-AT activity and milder disease. Case 1 had classic ZS and received oral ether lipids during intervals from age 4 months to her death at age 10 months. Case 2 had hypotonia, peripheral retinal pigmentary changes, hepatomegaly, developmental delay with minimal dysmorphic features and has received oral ether lipids from age 15 months to his present age of 20 months. In case 1, treatment produced a qualitative in-, crease in erythrocyte plasmalogens but little evidence for clinical benefit. In case 2, dramatic improvement in muscle strength and vision were noted after instituting therapy. These results suggest the need for controlled evaluation of glycerol ether lipid therapy in selected patients with peroxisomal disorders.