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S Packman

Publications and source records attributed to S Packman.

At least 73 records · Page 4Linked to original sources
PubMed1984

Copper utilization in cultured skin fibroblasts of the mottled mouse, an animal model for Menkes' kinky hair syndrome.

An animal model for Menkes' kinky hair syndrome is provided by mice mutant at the X-linked mottled locus. Two mechanisms have been invoked to explain disease manifestations in mottled and in kinky hair syndrome: relative tissue copper deficiencies and corresponding reductions in cuproenzyme activities; or defective intracellular copper utilization, with impaired intracellular translocation to cuproenzymes or to copper-dependent processes. We addressed the second possibility through measurements of soluble superoxide dismutase (SOD-1) in cytosol extracts of confluent mottled (blotchy) cultured skin fibroblasts. At comparable intracellular copper concentrations over a broad range, SOD-1 specific activities in the mutant cells were not distinguishable from those in controls, or, in some instances, were actually higher. These data suggest that the excess copper anomalously sequestered in a cell expressing the mutation remains available for binding to a cytosolic cuproenzyme. When taken together with data in other systems, the results are consistent with the thesis that the basic lesion in blotchy may primarily affect copper transport or delivery to specific copper transport systems.

Animals↗
PubMed1984

Stable isotope dilution analysis of 3-hydroxyisovaleric acid in amniotic fluid: contribution to the prenatal diagnosis of inherited disorders of leucine catabolism.

A quantitative assay for 3-hydroxyisovaleric acid in amniotic fluid was developed using D6-3-hydroxyisovaleric acid as an internal standard. 3-Hydroxyisovaleric acid was isolated by liquid partition chromatography and the amount determined by selected ion monitoring, ammonia chemical ionization gas chromatography-mass spectrometry of the trimethylsilyl derivatives. The concentration of 3-hydroxyisovaleric acid in ten normal amniotic fluid was 4.52 +/- 1.73 mumol/l. The level was elevated eight-fold in the amniotic fluid from a pregnancy resulting in the birth of a child with biotin-responsive multiple carboxylase deficiency. The stable isotope dilution assay of 3-hydroxyisovaleric acid in amniotic fluid is a rapid, sensitive and accurate method for the prenatal diagnosis of this disorder, and may be of value in the prenatal diagnosis of other inherited disorders of leucine catabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed1984

Location of the retinoblastoma susceptibility gene(s) and the human esterase D locus.

Retinoblastoma occurs with increased frequency in children born with a deletion of the long arm of chromosome 13. Recent reviews have noted that the region 13q14 is consistently deleted in documented cases. Prometaphase and late prophase banding allowed Yunis and Ramsay to determine that a deletion in one patient included the sub-bands q14 . 12, q14 . 13, and q14 . 2, and a portion of q14 . 11 and q14 . 3. We report the results of similar cytogenetic techniques applied in the case of a 26 month old Caucasian female with unilateral retinoblastoma, moderate developmental delay, and subtle dysmorphology. Prometaphase banding of cultured skin fibroblasts revealed the karyotype: mos46,XX/46,XX,del(13)(q13 . 1q14 . 11). Only the sub-band q14 . 11 is deleted in both our patient and that of Yunis and Ramsay. The results are consistent with the localisation of the retinoblastoma susceptibility gene(s) in the sub-band 13q14 . 11. Electrophoretic analysis and activity assays of red blood cell esterase D are consistent with hemizygous expression of that marker in our proband. Comparison with published esterase D analyses in families with retinoblastoma permits the assignment of the esterase D locus to that same sub-band, 13q14 . 11.

Carboxylesterase↗
PubMed1984

Trace metal metabolism in cultured skin fibroblasts of the mottled mouse: response to metallothionein inducers.

Menkes' kinky hair syndrome is a lethal X-linked disorder marked by tissue-specific increases in copper content. An animal model of kinky hair syndrome is provided by mice mutant at the X-linked mottled locus. The basic defect is unknown. In order to discriminate among potential etiologies, we asked whether the expression of the mottled mutation causes abnormalities in the metabolism of trace metals other than copper in hemizygous mottled (blotchy) cultured skin fibroblasts, and whether we can differentiate mutant and normal cells according to their response to metal inducers of metallothionein. Blotchy fibroblasts accumulated up to 12 times more 64Cu than control (littermate) cells, over time and over a range of 64Cu concentrations. A saturable high affinity component to 64Cu accumulation over a fixed time interval was revealed in these studies. While 64Cu uptake kinetics were indistinguishable in mutant and control cells, the patterns of 64Cu exit differed. In both cell types, the rate of release of a rapidly exchangeable fraction of newly acquired 64Cu was similar. However, in mutant cells, a larger fraction of recently accumulated 64Cu is retained. In contrast to the results for 64Cu, accumulation and exit of 65Zn and 109Cd were not distinguishable in mutants and controls. With exposure to either a strong (cadmium) or weaker (zinc) inducer of metallothionein, 64Cu accumulation was increased in normal cells, while there was no change from the already elevated level of 64Cu accumulation in blotchy cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Pyruvate carboxylase activity in subacute necrotizing encephalopathy (Leigh's disease).

Leigh's disease is a heterogeneous group of disorders, in which clinical and biochemical features suggest abnormal pyruvate metabolism. In two patients with Leigh's disease, diagnosed according to rigorous clinical, radiographic, and histologic criteria, we tested the hypothesis that pyruvate carboxylase deficiency might be the primary etiology. Pyruvate carboxylase specific activities in extracts of cultured skin fibroblasts from both patients were in the normal range. These results, together with other evidence, suggest that isolated pyruvate carboxylase deficiency does not cause the Leigh's disease phenotype.

Brain Diseases↗
PubMed1984

Acetyl CoA carboxylase in cultured fibroblasts: differential biotin dependence in the two types of biotin-responsive multiple carboxylase deficiency.

In biotin-responsive multiple carboxylase deficiency, a characteristic organic aciduria reflects in vivo deficiency of mitochondrial propionyl CoA carboxylase, 3-methylcrotonyl CoA carboxylase, and pyruvate carboxylase. A possible primary or secondary defect in biotin absorption leads to an infantile-onset syndrome, while abnormal holocarboxylase synthetase activity has been identified in the neonatal-onset form. While distinct mitochondrial and cytosolic holocarboxylase synthetase biotinylation systems may exist in avian tissues, the system has not been characterized in humans. Toward this objective, we studied the biotin dependence of a cytosolic carboxylase, acetyl CoA carboxylase (ACC), in cultured skin fibroblasts of both types of multiple carboxylase deficiency. ACC specific activities in control and infantile-onset cells were not distinguishable at all biotin concentrations: with decreasing biotin availability (+ avidin), there were only modest decrements in ACC activity in both these cell types. In contrast, there were pronounced declines of ACC activity in neonatal-onset (holocarboxylase synthetase-deficient) cells after growth in low biotin concentrations, and activity was undetectable in + avidin. ACC activity was rapidly restored with biotin repletion to biotin-starved holocarboxylase synthetase-deficient cells, and this restoration was largely independent of protein synthesis. The behavior of the cytosolic carboxylase, ACC, is in all these respects identical to that of the mitochondrial carboxylases, an observation consistent with the existence of similar biotinylation mechanisms in the two cell compartments. Further, the data support the notion that at least some components of the holocarboxylase synthetase system are shared by mitochondria and cytosol in humans, and are consistent with the suggestion that restoration of activity in biotin-depleted cells represents biotinylation of preexisting enzyme protein. The modest decrements in ACC activity in normal and infantile-onset cells may be related to the compromised epidermal integrity observed in that form of multiple carboxylase deficiency. Finally, ACC and mitochondrial carboxylase activities were compared in cells from mutants representing a spectrum of clinical severity. Cells from later-onset patients of intermediate clinical severity were ultimately classifiable as putative holocarboxylase synthetase-deficient cells on chemical criteria. Accurate etiologic classification cannot be based on clinical presentation alone, and biochemical studies should be performed on all patients. Accordingly, we propose a classification of multiple carboxylase deficiency based on biochemical criteria.

Acetyl-CoA Carboxylase↗
PubMed1984

Central hypoventilation syndrome in pyruvate dehydrogenase complex deficiency.

The presentation and treatment of a central hypoventilation syndrome in a boy with pyruvate dehydrogenase complex (PDHC) deficiency are reported. Dephosphorylated PDHC was assayed in disrupted fibroblasts after pretreatment with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor. Maximal specific activity of activated patient PDHC was 10% to 30% of control values. Patient PDHC activity was not increased by alterations in concentrations of pyruvate or cofactors (thiamine pyrophosphate [TPP], coenzyme A [CoA], oxidized form of nicotinamide adenine dinucleotide [NAD+]). Clinically, normalization of plasma lactate by a high-lipid diet did not prevent slowly progressive neurologic decline. The patient manifested intermittent ataxia, episodic profound weakness, moderate psychomotor retardation, ophthalmoplegia, and retinal pigment epithelial changes. A true central hypoventilation syndrome was documented on the basis of rigorous radiologic, electrophysiologic, and pulmonary function criteria. Theophylline, progesterone, and ritalin neither altered ventilatory response to CO2 nor permitted weaning from the ventilator. In contrast, peripheral chemoreceptor stimulants (intravenous doxapram; oral almitrine) effected an acute doubling of minute ventilation with appropriate decreases in PaCO2. However, a positive response to long-term therapy with almitrine could not be unequivocally shown. It was concluded that measurement of disrupted fibroblast PDHC following dichloroacetate activation constitutes an accurate assay for PDHC deficiency. PDHC deficiency must be considered in the differential diagnosis of the central hypoventilation syndrome; this appears to be the first report of such an association. Finally, a therapeutic trial of a peripheral chemoreceptor agonist is warranted in the management of central hypoventilation syndrome.

Almitrine↗
PubMed1984

Curious neurologic sequelae in galactosemia.

Two siblings with classic transferase deficiency galactosemia that was detected at birth have been treated with lactose restriction since the neonatal period. Both patients developed a unique and progressive neurologic syndrome of mental retardation, tremor, and ataxia. Careful review of the family history and medical records, the absence of metabolic disturbances other than those related to galactosemia, and the aggregate physical findings and neurodiagnostic studies ruled out other neurologic disorders in these siblings. It is therefore proposed that these patients represent a subgroup of transferase-deficient galactosemic patients, who develop characteristic neurologic sequelae with conventional dietary management. The existence of this subgroup should be considered in evaluations of therapeutic responses in cohorts of patients with galactosemia. Further, galactosemia should be included in the differential diagnosis of tremor and ataxia in the setting of mental retardation.

Adolescent↗
PubMed1983

Cadmium, zinc, and copper metabolism in the mottled mouse, an animal model for Menkes' kinky hair syndrome.

Studies of uptake and release of 64Cu, 109Cd, and 65Zn in suckling C57BL/6J male mice revealed kinetics and distributions that differed for each metal both within and among the organs analyzed, suggesting distinct, albeit overlapping, mechanisms for transport and binding of each metal. In mutants, there were tissue-specific increases in copper-binding capacity. In hemizygotes (Moblo/y) accumulation of 64Cu was increased in kidney, lung, and duodenum. In heterozygotes (Moblo/+), 64Cu content was increased in kidney, with a smaller increase in lung, and no change in duodenal Cu. Decreased 64Cu accumulation was seen in liver in both hemi- and heterozygotes. In contrast, 64Zn and 109Cd accumulation in organs of heterozygote mice was not significantly distinguishable from normal. In skin and connective tissues there is excessive accumulation of 64Cu in Moblo/+ and Moblo/y, no abnormality in heterozygote 65Zn accumulation, but a clear decrease in heterozygote 109Cd content. In both mutant kidney and liver, there was an aberrant subcellular distribution of 64Cu, with the major fraction of sequestered 64Cu in the cytosol. Our studies establish that in spite of the ubiquity of metallothioneins and the structural similarities of those that have been characterized, there is specificity and functional heterogeneity in metal binding among tissues. The aggregate data suggest that there are unique regulatory mechanisms for the metabolism of copper and zinc, while there exists, in part, an inverse relationship between the binding of copper and cadmium. Our data further suggest that the blotchy mutation involves a specific cytosolic copper storage or transport protein also capable of binding cadmium.

Animals↗
PubMed1983

Alopecia and periorificial dermatitis in biotin-responsive multiple carboxylase deficiency.

Three siblings with infantile-onset biotin-responsive multiple carboxylase deficiency are described. Recognition of the characteristic dermatologic manifestations, alopecia and periorificial dermatitis, should result in early diagnosis and institution of potentially lifesaving therapy with biotin. Other metabolic disorders may present a similar clinical picture. Immunologic dysfunction and/or aberration in lipid or branched chain amino acid metabolism may be the common pathophysiologic link in some or all of these disorders.

Alopecia↗
PubMed1982

Biochemical evidence for diverse etiologies in biotin-responsive multiple carboxylase deficiency.

Biotin-responsive multiple carboxylase deficiency can be categorized by clinical criteria into a neonatal-onset disorder and distinct syndrome of infantile onset. Pedigrees in each instance are consistent with autosomal recessive inheritance. For a neonatal-onset proband, the sensitivity to relative biotin deprivation and the rapid clinical response to biotin supplementation are reflected by in vitro studies. Specific activities of biotin-dependent pyruvate carboxylase, propionyl CoA carboxylase, and 1-methylcrotonyl CoA carboxylase are 0.8 to 16% of mean control values after growth of fibroblasts in intermediate and very low biotin concentrations. Following relative biotin depletion, pyruvate carboxylase activity returns to normal after only 14 hr of growth in biotin-supplemented medium. In contrast, carboxylase activities in fibroblasts of an infantile-onset proband remain normal at very low biotin concentrations, even when avidin is added to the growth medium. The clinical heterogeneity, taken together with the distinct responses of cultured skin fibroblasts to biotin deprivation in vitro, probably reflect fundamentally different etiologies for the two categories of biotin-responsive multiple carboxylase deficiency.

Adult↗
PubMed1982

Brain pyruvate carboxylase and the pathophysiology of biotin-dependent diseases.

Given the cerebellar symptomatology of biotin-dependent diseases and other lactic acidoses, we hypothesized that cerebellar pyruvate carboxylase activity might be differentially low or especially sensitive to cofactor deprivation. Accordingly, pyruvate carboxylase activity was measured in selected areas of normal and biotin-deficient rat brain. Control cerebellar hemisphere and vermis specific activities were identical, and slightly higher than cerebral and brainstem activities. In biotin-deficient rats, hepatic pyruvate carboxylase activity was 3% of control, whereas pyruvate carboxylase activities of all brain sections were 53 to 71% of control. Brain histology was normal. Cerebellar pyruvate carboxylase activity is therefore not distinctly low or labile and is in fact preferentially maintained despite severe cofactor deprivation.

Animals↗
PubMed1981

Deletions of different segments of the long arm of chromosome 4.

We report the clinical and chromosomal findings in 8 patients with deletions of the long arm of chromosome 4. Four of these patients appear to have terminal deletions beginning in band 4q31, and therefore, lack the digital 1/3 of the long arm of chromosome 4. We confirm that deletion of 4q31 leads to qter causes a recognizable syndrome, and we further define the phenotype of that syndrome. A 5th patient has a horter terminal deletion, ie, 4q33 leads to qter. This deletion causes a milder phenotypic expression than that seen in the severe 4q terminal-deletion syndrome. The remaining 3 patients have interstitial deletions of the long arm of the 4th chromosome, including segments 4q21.1 leads to q25, 4q21.3 leads to q26, and 4q27 leads to q31.3. The phenotypic expression noted in these patients is variable in differs from the 4q terminal-deletion syndrome.

Abnormalities, Multiple↗
PubMed1980

Intermittent ataxia and immunodeficiency with multiple carboxylase deficiencies: a biotin-responsive disorder.

A small group of inborn errors of metabolism are manifested by intermittent cerebellar ataxia. We have previously reported a family with an inherited metabolic defect resulting in multiple carboxylase deficiencies which were responsive to pharmacological doses of biotin. Affected children presented with a skin rash, infections, acute intermittent ataxia, and lactic acidosis. Two affected siblings died prior to diagnosis and therapy, and a detailed postmortem examination was performed on one of them. The brain was characterized by atrophy restricted to the superior vermis of the cerebellum, a finding strikingly similar to that found in chronic alcoholism. Intermittent ataxia would suggest a potentially treatable metabolic disease, and clinical evaluation should include studies of intermediary metabolism and immune function.

Biotin↗