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Biomedical subjects

B A Gordon

Publications and source records attributed to B A Gordon.

At least 37 records · Page 2Linked to original sources
PubMed1987

The hyperornithinemia, hyperammonemia, homocitrullinuria syndrome: an ornithine transport defect remediable with ornithine supplements.

The primary defect in patients presenting with a history of protein intolerance, mental retardation, and epilepsy of variable degree, with the unique triad of hyperornithinemia, hyperammonemia, and homocitrullinuria (the HHH syndrome) has been postulated to be a defect in translocation of ornithine into the mitochondria. In a 12-year-old boy with the HHH syndrome, the hyperammonemia observed following a protein load was prevented when the same load was given orally with a 1 mmol/kg of ornithine-HCl. At a dosage level of 0.5 to 1.0 mmol/kg/day of ornithine HCl, administered in 3 divided doses with meals, the patient's protein tolerance improved. As pretreatment hyperammonemia reverted to normal levels, the patient was able to cope with increased dietary protein and his growth accelerated. During the 2-year interval of the study, the ornithine HCl supplements were withdrawn on 2 occasions, and within a week the hyperammonemia recurred. Whereas cultured fibroblasts from the HHH patient were capable of oxidizing U-14C-glutamate to 14CO2 as rapidly as normal cells. 1-14C-ornithine or 5-14C-ornithine were oxidized at only 1/28 or 1/49 of the normal rate. Ultrastructural studies of the HHH cultured fibroblast mitochondria revealed distinctive alterations in size and shape; unusually long, branching, and "curling," HHH mitochondria also showed accelerated regressive changes.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Ultrastructural and biochemical aspects of the Sanfilippo syndrome,--type III genetic mucopolysaccharidosis.

The Sanfilippo Syndrome (SS) is a recessively inherited connective tissue disorder expressed in early life. It is classified as a genetic mucopolysaccharidosis (MPS) because the underlying defect involves the catabolism of heparan sulfate (HS), one of the glycosaminoglycans (GAG). Four variant forms, i.e., type A, B, C, and D, each associated with a different enzymatic defect, have been recognized in affected children. Biochemical studies show that characteristically HS accounts for most of the increased amounts of GAG excreted in the urine and those stored in viscera and brain. Gangliosides GM2, GM3 and GD2 are elevated considerably in the brain. Morphologically, the very water-soluble substances accumulating in the viscera are metachromatic, and consist ultrastructurally of finely granulo-floccular (or filamentous) material which is bound in cytoplasmic vacuoles. These substances are considered to represent the GAG. In the central nervous system (CNS) the stored substances are not soluble in water or alcohol and xylol, give a PAS-positive reaction, and stain for lipids and with luxol fast blue. Ultrastructurally, they consist of membranous arrays which often are of the "zebra body" variety. The CNS-inclusions are considered to represent the stored gangliosides; they were found also in small numbers in viscera of older children with SS. The search for a common denominator in the pathogenetic mechanism(s) culminating in both types of inclusions, continues.

Brain↗
PubMed1982

A variant form of metachromatic leukodystrophy without arylsulfatase deficiency.

The clinical, pathological, and biochemical findings in a young woman with a new variant of metachromatic leukodystrophy (MLD) are reported. The patient showed slow early development and deteriorated further during her first two decades. Nerve conductions were slow, and a sural nerve biopsy showed features of a sulfatide lipidosis. Urinary sulfatide excretion was comparable to that of patients with classic MLD, yet in vitro activity of arylsulfatase A and B and cerebroside sulfatase activity were normal. Skin fibroblasts cultured in medium supplemented with 3H-labeled sulfatide showed accumulation of labeled sulfatide in large amounts, implying a defect in sulfatide hydrolysis in vivo in spite of intact enzyme activity in vitro.

Adult↗
PubMed1982

Decreased transport of ornithine across the inner mitochondrial membrane as a cause of hyperornithinaemia.

Hyperornithinaemia due to a transport of ornithine across the inner mitochondrial membrane was demonstrated in three patients by measuring ornithine uptake by fibroblast mitochondria. Particulate compartments and soluble cytoplasm of fibroblasts were separated by a slight modification of the digitonin method of Zuurendonk and Tager. Patients' fibroblast pellet fraction contained significantly less radioactivity than control fibroblast pellet fraction after incubation of fibroblasts with [14C]-ornithine. Since neither of the patients was deficient in ornithine-delta-oxoacid aminotransferase, we concluded that in these hyperornithinaemia patients a defect exists for transport of ornithine across the inner mitochondrial membrane. The exact nature of this transport defect remains to be elucidated.

Amino Acid Metabolism, Inborn Errors↗
PubMed1982

Deficiency of the hexosaminidase A activator protein in a case of GM2 gangliosidosis; variant AB.

A patient is described whose clinical course and pathologic features, including massive brain storage of GM2 ganglioside in grey matter, are identical with those of classical Tay-Sachs disease despite normal levels of beta -N-acetyl hexosaminidase and normal isozyme distribution. The kinetic properties and thermolability of the patient's hexosaminidase are normal. Crude extracts of a postmortem sample of patient's liver can catalyze the hydrolysis of 5.1 pmoles of labeled GM2 ganglioside/16 h/mg of protein (control liver = 69.9 pmoles/16 h/mg). Addition of partially purified human liver hexosaminidase A activator protein stimulated the hydrolysis of substrate by the patients liver extract by 27-fold compared to 3-fold for control livers. Measurement of "activator" in enriched fractions of patient's and control liver showed a reduced (25-30% of control) amount of stimulation of hexosaminidase A catalyzed hydrolysis of GM2 ganglioside as well as of Asialo-GM2 ganglioside. The addition of sphingomyelin to reaction mixtures, which is known to inhibit surfactant stimulation of hexosaminidase A, reduced activation of hexosaminidase A by patient's liver preparation to undetectable levels. Polyacrylamide gel electrophoresis of enriched preparations of control and patient's liver showed a rapidly migrating protein band in control liver corresponding to the activator protein and the absence of this protein band in the patient's liver.

Brain↗
PubMed1981

The AB-variant of metachromatic leukodystrophy (postulated activator protein deficiency). Light and electron microscopic findings in a sural nerve biopsy.

THe histopathological findings in a sural nerve biopsy of a new distinct variant of metachromatic leukodystrophy (MLD) are compared to those of classical MLD. The clinical and histological features are typical of a sulfatide lipidosis, yet in vitro activities of arylsulfatases A and B and cerebroside sulfatase are normal. Intact skin fibroblasts, when cultured in a medium supplemented with labelled sulfatide, show impaired in vivo sulfatide hydrolysis. A deficiency of the requisite activator protein is postulated.

Adult↗
PubMed1981

Ultrastructure of hepatic mitochondria in a child with hyperornithinemia, hyperammonemia, and homocitrullinuria.

Ultrastructural studies of hepatic tissue obtained at biopsy from a nine year old severely retarded boy with hyperornithinemia, hyperammonemia, and homocitrullinuria showed mitochondria of bizarre shapes and unusual internal features. Among the latter were tubules extending throughout the length of the large mitochondria that on cross section had a rosette-like arrangement; the presence of a periodic, approximately 300 A thick, sievelike membrane interposed between the tubules and the inner mitochondrial membrane; and "bulges" of mitochondrial matrix occasionally formed between these two membranes. Since to be metabolized ornithine must enter the mitochondria, the hyperornithinemia is regarded as a reflection of its inability to reach the mitochondrial interior. It is speculated that among other possible causes, the unusual sievelike membrane may be the barrier to ornithine's access to the mitochondrion.

Amino Acid Metabolism, Inborn Errors↗
PubMed1980

Unusual clinical and ultrastructural features in a boy with biochemically typical mannosidosis.

A 4 1/2-year-old boy with a history of recurring respiratory tract infections and seizures, and evidence of severe retardation of psychomotor development and growth, lacked the coarse facial features, skeletal changes and other clinical stigmata generally associated with mannosidosis, but the total alpha-mannosidase activity in his leukocytes, cultured fibroblasts and liver were no more than 10% of the control mean. Studies of the residual alpha-mannosidase enzyme suggest a specific deficiency of the thermostable isoenzyme with an acidic pH optimum. The alpha-mannosidase in the fibroblasts of our and another (control) patient with mannosidosis had a reduced affinity for the substrate 4-methylumbelliferyl-alpha-D-mannoside. Light microscopy of the liver biopsy showed an increase in connective tissue often distorting the hepatic architecture; numerous tiny vacuoles, small dense and lipid bodies in most hepatocytes, and similar but more extensive changes in sinusoidal cells; and sinusoidal pools of hepatocytic debris. Electron microscopy of hepatocytes revealed vacuoles similar but not identical to those described in reported mannosidosis patients, and in addition several forms of secondary lysosomes; prominent peroxisomes (microbodies); increased numbers of profiles of smooth endoplasmic reticulum; dilated rough endoplasmic reticulum containing traces of fine granulo-fibrillar material; increased numbers of rosettes of alpha particles of glycogen and reduced numbers of mitochondria with alterations in their distribution, size and configuration. It is believed that the usual clinical and hepatic ultrastructural features in our patient reflect another variant of mannosidosis.

Abnormalities, Multiple↗
PubMed1979

Amino-acid metabolism and liver ultrastructure in hyperornithinemia with gyrate atrophy of the choroid and retina.

Three patients with the rare hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA) syndrome were studied to elucidate the metabolic derangement and its pathologic concomitants. Tenfold elevations of blood ornithine levels, decreases in lysine levels, and hitherto unreported decreases in blood glutamate and glutamine concentration were observed. The output of ornithine from muscle kidney and splanchnic beds was curtailed or reversed after intravenous glucose. Levels of ornithine in venous blood declined after oral glucose, and rose after intravenous arginine. Increased amounts of 3-amino-2-piperidone were found in the urine, but these did not increase after the arginine-induced increase in ornithine levels. Liver biopsies in two patients revealed a marked alteration in mitochondrial ultrastructure. These studies extend the knowledge of the metabolic and pathologic derangements in HOGA. These findings are consistent with a disorder of ornithine-ketoacid transaminase, but such a disorder might not account for all the observations.

Adult↗
PubMed1977

Ornithine methyl ester. An unusual metabolite encountered in the urine of patients with a urea cycle disorder characterized by hyperammonemia, hyperornithinemia and homocitrullinuria.

In the urine of six subjects with a urea cycle disorder characterized by hyperammonemia, hyperornithinemia and homocitrullinuria, an unusual ninhydrin-reaction compound was encountered. This unknown on hydrolysis yielded ornithine as the only amino acid and, on dansylation studied, yielded didansyl ornithine. The metabolite from urine has been shown to have the same chromatographic mobility as ornithine methyl ester on paper cellulose thin layer, and ion exchange chromatography. When trimethylsily derivatives were prepared the unknown and the ornithine methyl ester standard had similar mobility on gas chromatography. Identification of the unknown as the ornithine methyl ester was confirmed by gas chromatography-mass spectrometric analysis. In the patients' urines the concentration of methyl ornithine ranged from 70 to 368 microne moles/g creatinine.

Amino Acid Metabolism, Inborn Errors↗
PubMed1976

Methylmalonic acidemia controlled with oral administration of vitamin B12.

A 3-month-old male infant had two episodes of fever, projectile vomiting, dehydration, generalized fine tremors and gross metabloic ketoacidosis. Methylmalonic acid was found in high concentration in both serum and urine, although the concentration of serum vitamin B12 was normal. A therapeutic trial of vitamin B12, administered parenterally, reduced greatly the methylmalonic aciduria. The patient has since been given vitamin B12 supplements continuously, initially 1 mg intramuscularly every other day, then 15 mg/d orally, and the protein in his diet was subsequently restricted. The most effected control of the methylmalonic aciduria was achieved with the combined regimen of oral vitamin therapy and dietary protein restriction. His physical and intellectual development have progressed normally and he has survived several acute respiratory tract infections without recurrence of metabolic acidosis.

Acidosis↗
PubMed1976

Ultrastructure and peroxidase of leucocytes in five patients with juvenile form of ceroid lipofuscinoses.

Peripheral leucocytes obtained from five patients with clinical histories and funduscopic findings typical of the juvenile form of the so-called neuronal ceroid lipofuscinosis (NCLF) (synonym: Spielmeyer-Vogt disease) were assayed for peroxidase activity and examined by electron microscopy. The peroxidase levels were considerably lower in three but normal in two patients. Ultrastructurally, the lymphocytes of all five patients showed the presence of tubulo-membranous cytosomes many displaying the fingerprint images at present regarded as being typical for the NCLF. The possible implications of the discrepancy between the morphological observations and the enzymatic findings are discussed.

Adolescent↗
PubMed1975

Defective heparan sulfate metabolism in the Sanfilippo syndrome and assay of this defect in the assessment of the mucopolysaccharidoses patient.

The Sanifilippo syndrome is an inherited dementia caused by defective degradation of heparan sulfate. In the course of its catabolism the heparan sulfate polymer must be desulfated. Heparan sulfate sulfatase activity was demonstrated in homogenates of normal tissues and cultured skin fibroblasts, and in normal urine. This activity was found to be grossly depressed or absent in necropsy specimens of liver and spleen from two Sanfilippo patients. The heparan sulfate sulfatase activity was not demonstrable in urine from eleven, or cultured fibroblasts from four Sanfilippo patients. Activities of alpha-N-acetyl-glucosaminidase, the site of the metabolic defect in the Sanfilippo B variant were either normal or slightly elevated in the Sanfilippo tissues and cultured fibroblasts whereas the mean level in the urine of our Sanfilippo patients was about one-third of that encountered in control urines.

Acetylglucosaminidase↗