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Cross-correctional studies in inborn errors of vitamin B12 metabolismByck, Susan January 1989 (has links)
No description available.
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Studies on mammalian 25-hydroxyvitamin D3-24-hydroxylaseMandla, Suzan (Suzan G.) January 1992 (has links)
No description available.
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Prolidase deficiency : studies in human dermal fibroblastsBoright, Andrew Pepler January 1988 (has links)
No description available.
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Chemical pathology analysis of inborn errors of metabolism for expanded newborn screening in Hong KongMak, Miu., 麥苗. January 2012 (has links)
Inborn errors of metabolism (IEM) are under international spotlight because of the recent tremendous development in expanded newborn screening (NBS) and molecular genetics. IEM is a difficult subject involving more than 1,000 different disorders with protean clinical presentations and complicated diagnostic pathways. Cumulative incidence of IEM was reported up to 1 in 800. Patients can be affected in any ages.
High clinical suspicion alone is not sufficient to reduce morbidities and mortalities. Notably, some IEM are amenable to treatment with promising outcome. Local data regarding the disease spectrum and incidences is largely lacking. Public awareness and readiness for expanded NBS is unknown. This renders difficulties in the consideration of expanded NBS in Hong Kong.
In this study, laboratory data of classical IEM from 2005 to 2009 were retrospectively analyzed (Chapter 2). Local incidence was 1 in 4,122 and that of hyperphenylalaninemias was 1 in 29,542, similar to worldwide figures. Majority (69%) was amino acid disorders, 12% was organic acidemias and 19% was fatty acid oxidation defects. Most of these diseases are effectively amenable to treatment.
Local cases including hyperphenylalaninemia, tyrosinemia type I, arginase deficiency, ornithine transcarbamylase deficiency, very long-chain acyl-CoA dehydrogenase deficiency, tyrosine hydroxylase deficiency, thermolabile carnitine palmitoyltransferase II variants and adults IEM with X-linked adrenoleukodystrophy, cerebrotendinous xanthomatosis, familial transthyretin amyloidosis, Wilson disease and PANK2-associated young-onset Parkinsonism were described (Chapters 1.1.3 and 3).
Electronic chemical pathology consultation service and dried blood spot metabolic screening were implemented (Chapter 4). There were 279 consultations and 158 screening in a 12-month period. Major referral reasons were developmental delay, neurological defects and unexplained biochemical abnormalities. The incidence in high risk screening was 1 in 158. A non-derivatized tandem mass spectrometry assay for amino acids and acylcarnitines was evaluated for its precision, accuracy and reference intervals (Chapter 5). The concordance rate was 100% in inter-laboratory comparison and external quality assurance programs. The method was proven to be accurate, rapid and affordable. It is suitable for large volume testing and emergency diagnostic needs.
A feasibility study of a hospital-based expanded NBS service model was conducted on 360 newborns (Chapter 6). More than 90% of babies were older than 48 hours before discharge and were fit for blood collection. The service model consisted of parent education, consent, postnatal sample collection, technical analysis, clinical interpretation, reporting and follow-up actions.
Questionnaire on the knowledge and attitude towards IEM and expanded NBS was surveyed on 172 parents to investigate the psychological, social and ethical aspects (Chapter 7). Here, 99.4% demanded more education on expanded NBS; 97.6% supported to implement the program; 97.7% supported population screening even though some diseases are incurable. Availability of treatment is not the most important pre-requisite for NBS; 93.9% accepted the possibility of false positive and false negative results. Acceptance towards expanded NBS among parents was high.
Our data indicate that IEM is not uncommon in Hong Kong and it is indisputable for the introduction of a local expanded NBS program. Our data serve as groundwork for policy decision and further discussion on expanded NBS. / published_or_final_version / Pathology / Master / Doctor of Medicine
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Cross-correctional studies in inborn errors of vitamin B12 metabolismByck, Susan January 1989 (has links)
Human skin fibroblasts derived from patients with all 7 known inborn errors of vitamin B$ sb{12}$ metabolism have been studied for functional integrity of methylmalonyl CoA mutase and methionine synthase. Cocultivation of cblC and cblF fibroblasts in the absence of polyethylene glycol resulted in a twofold increase over the expected in both ($ sp{14}$C) propionate and ($ sp{14}$C) methyltetrahydrofolate incorporation into acid-precipitable material, suggesting that metabolic cooperation between cells occurs. CblD fibroblasts, which are biochemically similar to cblC cells (Goodman et al, 1970; Willard et al, 1977), do not cooperate metabolically when mixed with cblF cells. Partial correction in phenotype was seen in mixtures of cblD and cblG cells, but not cblC and cblG cells. These observations lend further support for the division of cblC and cblD disease into two discrete complementation classes. Cocultivation of cblF fibroblasts with both cblE and cblG cells also resulted in partial correction in phenotype. / ($ sp{14}$C) Propionate incorporation in both cblC and cblF cells exposed to conditioned medium from control cells was increased more than twofold. ($ sp{14}$C) methyltetrahydrofolate incorporation in cblC cells exposed to conditioned medium from cblF cells was increased twofold. This suggests the presence of a diffusible factor correcting the defect in the mutant cell lines.
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Metabolic studies of prolidase deficiency in cultured human fibroblastsDolenga, Michael Peter January 1991 (has links)
Prolidase deficiency (McKusick 26413) is a rare autosomal recessive disorder characterized by iminodipeptiduria, skin lesions and mental retardation. The enzyme prolidase hydrolyzes dipeptides containing C-terminal proline or hydroxyproline. / The results presented here indicate that prolidase plays a major role in the recycling of dipeptide bound proline. Control fibroblasts were able to use iminodipeptides in lieu of proline to sustain normal growth and protein synthesis whereas prolidase deficient cells were not. / Iminodipeptides added to the media of control and mutant cells showed no adverse effects on protein synthesis or cell growth. These results are consistent with a mechanism of biochemical pathology in which proline deprivation caused by the enzyme deficit is the cause of damage to skin cells. / Prolidase regulation by product and substrate was studied. A two fold decrease of prolidase activity was observed in fibroblasts grown in excess proline. However, cells grown in medium in which iminodipeptides replaced proline showed no significant difference in prolidase activity.
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Intragenic complementation in methylmalonyl CoA mutaseFarah, Rita S. January 1994 (has links)
Methylmalonic aciduria (MMA) is an autosomal recessive metabolic disorder with an incidence of 1 in 48,000, which may be due to a defect in the mitochondrial homodimeric enzyme methylmalonyl CoA mutase (mut MMA). mut MMA is subdivided into $mut sp circ$ and $mut sp-$ subclasses on the basis of complementation analysis; $mut sp circ$ cell lines have very low incorporation of ($ sp{14}$C) from propionate into acid precipitable material while incorporation in $mut sp-$ cells is increased when cells are incubated in cobalamin. Intragenic complementation was first observed with WG 1130, a $mut sp circ$ fibroblast line with a homozygous R93H mutation, that is capable of complementing MCM activity when fused with some $mut sp circ$ and some $mut sp-$ cells (1). Extensive intragenic complementation in mut MMA was subsequently observed. Fibroblasts cultured from thirteen unrelated patients (6 $mut sp-$, 7 $mut sp circ$) were fused in all possible pairwise combination and MCM activity was assayed in the heterokaryons by measuring the incorporation of ($ sp{14}$C) from propionate into acid precipitable material. Intragenic complementation, indicated by stimulation of ($ sp{14}$C) -propionate incorporation following cell fusion with polyethylene glycol, was observed in fusions involving twelve of the thirteen strains. Of these thirteen strains, mutations have been identified in six; four have a homozygous mutation (WG 1130 (R93H), WG 1511 (H678R), WG 1610 (G717V), WG 1609 (G630E)), and two cell lines are compound heterozygous (WG 1681 (G623R and G703R), WG 1607 (W105R and A377E)); the remainders are yet to be determined. These intragenic complementations will provide information for grouping the mutations in defined domains in order to correlate structure and function of MCM.
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The molecular characterization of mutations at the methylmalonyl CoA mutase locus involved in interallelic complementation /Qureshi, Amber A. (Amber Ateef) January 1993 (has links)
Methylmalonic aciduria is an autosomal recessive metabolic disorder, which may be due to a defect in the methylmalonyl CoA mutase (MCM) apoenzyme. The mut$ sp circ$ mutation is characterized by undetectable enzyme activity in cell extracts, and by the low incorporation of ($ sp{14}$C) propionate in the presence of hydroxocobalamin in culture. A mut$ sp circ$ fibroblast cell line, WG 1681, from an African-American male infant was shown to complement another mut$ sp circ$ cell line, WG 1130. Subsequent cloning and sequencing of cDNA from WG 1681 identified two previously described homozygous polymorphisms: H532R and V671I(1). In addition, compound heterozygosity was observed for two novel changes at highly conserved sites: G623R and G703R. Hybridization of allele specific oligonucleotides to PCR amplified MCM exons from WG 1681 and family members identified a clinically normal mother, sister and half-brother as carriers of the G703R change in cis with both polymorphisms. The putative father was not identified as a carrier of the G623R change. transfection of each change, singly and in cis with both polymorphisms, into GM1673 cells demonstrated a lack of stimulation of ($ sp{14}$C) propionate uptake in the absence and presence of OH-Cbl, in comparison to controls. Co-transfection of each separate mutation with the previously identified R93H mutation of WG 1130 (2) stimulated propionate uptake. These results indicate that G623R and G703R are novel mutations responsible for deficient MCM activity and the mut$ sp circ$ phenotype in WG 1681, and both mutations are independently capable of complementing the R93H mutation of WG 1130.
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Studies on mammalian 25-hydroxyvitamin D3-24-hydroxylaseMandla, Suzan (Suzan G.) January 1992 (has links)
This thesis describes three studies on mammalian 25-hydroxyvitamin D$ sb3$-24-hyroxylase (24-hydroxylase), the first enzyme in the C24-oxidation pathway, a major catabolic pathway for vitamin D metabolites in kidney and other target tissues for vitamin D hormone. The first study examines the involvement of protein kinase C in the regulation of 24-hydroxylase activity in mouse kidney. Evidence is presented supporting a stimulatory role for protein kinase C in the regulation of constitutive, but not inducible, renal 24-hydroxylase. The kinase is also implicated in the aberrant expression of renal vitamin D metabolism in the mutant X-linked hypophosphatemic (Hyp) mouse. The second study investigates the mechanism(s) by which forskolin, a classic activator of adenylate cyclase, inhibits 24-hydroxylase activity in mouse kidney. Both the traditional cAMP-dependent mechanism and a novel cAMP-independent mode of action are observed. A direct interaction between forskolin and the substrate binding site of 24-hydroxylase is suggested for the latter based on kinetic analyses and structural similarities between the diterpene and the steroid substrate for the hydroxylase. The third study addresses the structural relationship between renal 1-hydroxylase and renal and target cell 24-hydroxylase(s) by assessing 24-hydroxylase activity in patients with vitamin D dependency rickets type I (VDDR-I), a Mendelian disorder of 1-hydroxylase function. Both constitutive renal 24-hydroxylase, indirectly ascertained through measurement of circulating levels of relevant vitamin D metabolites, and inducible target cell 24-hydroxylase, directly measured in cultured skin fibroblasts, are shown to be intact in VDDR-I patients undergoing calcitriol therapy. These findings suggest that the 1- and 24-hydroxylase activities likely represent or contain distinct gene products.
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Prolidase deficiency : studies in human dermal fibroblastsBoright, Andrew Pepler January 1988 (has links)
Prolidase deficiency (MIM 26413), an autosomal recessive phenotype, is caused by rare alleles at a locus on chromosome 19cent.-q13.2. The clinical phenotype is pleiotropic (affecting skin, brain, etc.) and of variable expressivity (benign to early death). I established skin fibroblast cultures from 6 homozygous probands and 6 obligate heterozygotes, purified prolidase (E.C. 3.4.13.9, a homodimer) from normal human fibroblasts, raised a monospecific rabbit antiserum to the subunit, and studied its biosynthesis. Pulse-chase immunoprecipitation experiments showed that the subunit is synthesized in the cytosol as a 58 KDa. polypeptide and not processed further. Homozygous prolidase-deficient cell strains expressed 3 classes of mutant alleles which by complementation analysis mapped to one locus. The alleles were designated CRM$-$ (nul), CRM+ activity/size variant, and CRM+ activity variant. Heterozygotes carrying CRM$-$ alleles have heat stable prolidase (50$ sp circ$C, 1hr); heterozygotes carrying CRM+ variant alleles have heat labile enzyme. The finding implies that variant CRM+ allele(s) can confer negative allelic complementation on the dimeric enzyme (dominant relative phenotype). CRM$-$ homozygous cells contain varying amounts of an alternative imidodipeptidase-like activity. The variant prolidase allele (major gene) and amount of alternative "prolidase" activity (modifier gene) are apparently both determinants of the associated clinical phenotype in prolidase deficiency. I obtained and sequenced a tryptic peptide from human kidney prolidase for synthesis of oligonucleotide probes in the future.
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