bluuebunny/crossref_metadata_2025_split huggingface dataset:
A male child with the rumpshaker mutation, X‐linked spastic paraplegia/Pelizaeus‐Merzbacher disease and lysinuria
Authors: Naidu S. , Dlouhy S.R. , Geraghty M.T. , Hodes M.E. 
Published: December 2002

AbstractA 3.5‐year‐old boy had intact cognition, delayed walking, progressive spastic paraparesis and congenital nystagmus. The mother denied family history of any neurological disorders, so an extensive work‐up was begun. Lysinuria, increased signal on cerebral T2‐weighted MRI imaging and the rumpshaker mutation (Ile186Thr) in his proteolipid protein gene, PLP, were found. When faced with these facts, the mother admitted that she was related to the family reported by Johnston and McKusick in 1962 and Kobayashi in 1994, in whom this mutation has been reported. This is the first report of an abnormal MRI scan in this family.
Molecular characterization of a unique patient with epimerase‐deficiency galactosaemia
Authors: Alano A. , Almashanu S. , Chinsky J. M. , Costeas P. , Blitzer M. G. , Wulfsberg E. A. , Cowan T. M. 
Published: December 2002

AbstractInherited deficiencies of UDP‐galactose 4‐epimerase (GALE) havebeen associated with two distinct phenotypes. The vast majority of North American patients are clinically asymptomatic, are identified through newborn screening programmes for classical galactosaemia, and are of African‐American descent. At least two symptomatic patients have been reported, one Pakistani and the other Asian Muslim, both with severe complications in the neonatal period and subsequent mental retardation. Through newborn screening, we have identified a GALE‐deficient patient who is of mixed Pakistani/caucasian ancestry. He was clinically well in the neonatal period on a lactose‐containing diet, and biochemical studies, including urine reducing sugars and galactitol, were consistent with a diagnosis of peripheral GALE deficiency. Although early developmental milestones were met normally, he now shows significant developmental delays in both motor and language skills. Mutational analysis revealed this patient to be a compound heterozygote at the GALE locus, with mutations N34S and L183P identified in the patient and confirmed in the parents. This report represents the first characterization of specific mutations ina GALE‐deficient patient in conjunction with biochemical and clinical pheno‐type, and facilitates further studies of the GALE enzyme and its role in the different clinical forms of epimerase‐deficiency galactosaemia.
In vivo measurement of ureagenesis with stable isotopes
Authors: Yudkoff M. , Daikhin Y. , Ye X. , Wilson J. M. , Batshaw M. L. 
Published: December 2002

AbstractWe have utilized stable isotopes to measure in vivo rates of urea‐genesis. In one testing procedure, 15NH4Cl was administered orally to con‐trols and to heterozygotes for ornithine transcarbamylase deficiency. Controls produced [15N]urea at a rate that was greater than that of symptomatic carriers, but indistinguishable from that of asymptomatic carriers. In contrast, both symptomatic and asymptomatic heterozygotes produced [5‐15N]glutamine more rapidly than the controls. Ureagenesis could also be measured by administering sodium [1‐13C]acetate to a healthy adult and measuring subsequent formation of [13C]urea. The latter approach involves the use of isotope ratio mass spectrometry to determine isotopic abundance. This technique is much more sensitive than gas chromatography–mass spectrometry for the measurement of isotopic label, a consideration that makes the method more suitable for the study of subjects in whom ureagenesis is severely compromised, for example the human male neonate with a near complete deficiency of ornithine transcarbamylase.
Amino acid and nucleotide sequences of human peroxisomal enoyl‐CoA hydratase : 3‐hydroxyacyl‐CoA dehydrogenase cDNA
Authors: Fukuda S. , Suzuki Y. , Shimozawa N. , Zhang Z. , Orii T. , Aoyama T. , Hashimoto T. , Kondo N. 
Published: December 2002

AbstractDeficiency of enoyl‐CoA hydratase : 3‐hydroxyacyl‐CoA dehydrogenase (peroxisomal bifunctional enzyme), one of the enzymes of the peroxisomal β‐oxidation system, leads to clinical manifestations resembling Zellweger syndrome with hypotonia, psychomotor delay, hepatomegaly, typical facial appearance and accumulation of very long‐chain fatty acids. The nucleotide sequence of the human peroxisomal enoyl‐CoA hydratase : 3‐hydroxyacyl‐CoA dehydrogenase cDNA has been reported by Hoefler and colleagues; however, we have found some amino acid differences from our originally isolated cDNA. Contrary to the findings described in a previous paper, we report here the cDNA sequence of human peroxisomal enoyl‐CoA hydratase : 3‐hydroxyacyl‐CoA dehydrogenase in which there are 9 authenticated amino acid alterations.
Gene transfer of the uroporphyrinogen III synthase cDNA into haematopoietic progenitor cells in view of a future gene therapy in congenital erythropoietic porphyria
Authors: Mazurier F. , Moreau‐Gaudry F. , Salesse S. , Barbot C. , Ged C. , Reiffers J. , de Verneuil H. 
Published: December 2002

AbstractCongenital erythropoietic porphyria (CEP) is an inherited metabolic disorder characterized by an overproduction and accumulation of porphyrins in bone marrow. This autosomal recessive disease results from a deficiency of uroporphyrinogen III synthase (UROIIIS), the fourth enzyme of the haem biosynthetic pathway. It is phenotypically heterogeneous: patients with mild disease have cutaneous involvement, while more severely affected patients are transfusion dependent. The cloning of UROIIIS cDNA and genomic DNA has allowed the molecular characterization of the genetic defect in a number of families. To date, 22 different mutations have been characterized. Allogeneic bone marrow transplantation is the only curative treatment available for the severe, transfusion‐dependent, cases. When bone marrow transplantation cannot be performed owing to the absence of a suitable donor, the autografting of genetically modified cells is an appealing alternative. The best approach to somatic gene therapy in this disease involves the use of recombinant retroviral vectors to transduce cells ex vivo, followed by autologous transplantation of the genetically modified cells. We investigated retroviral transfer in deficient human fibroblasts, immortalized lymphoblasts as well as bone marrow cells, and obtained a complete restoration of the enzymatic activity and full metabolic correction.Using K562 cells, an erythroleukaemic cell line, the expression of the transgene remained stable during 3 months and during erythroid differentiation of the cells. Finally, a 1.6‐ to 1.9‐fold increase in enzyme activity compared to the endogenous level was found in normal CD34+ cells, a population of heterogeneous cells known to contain the progenitor/stem cells for long‐term expression. The future availability of a mouse model of the disease will permit ex vivo gene therapy experiments on the entire animal.
Inborn errors of metabolism with a protein‐restricted diet: Effect on polyunsaturated fatty acids
Authors: Sanjurjo P. , Ruiz J. I. , Montejo M. 
Published: December 2002

AbstractPrevious studies have shown that phenylketonuric patients display a deficiency in long‐chain polyunsaturated fatty acids. A study has now been performed on 13 cases (5 with methylmalonic acidaemia and 8 with urea cycle disorders) whose dietary treatment also implies a limitation in protein‐rich food. Plasma and red‐cell phospholipid fatty acid profiles were studied. The most relevant results were a lower percentage of docosahexaenoic acid in plasma and red‐cell phospholipids (0.91% ± 0.53% vs 2.88% ± 1.17% and 2.07% ± 0.92% vs 3.62% ± 1.01% (p < 0.001)) and a lower percentage of arachidonic acid in plasma (5.22% ± 2.02% vs 8.3% ± 2.11% (p < 0.001)).A long‐chain polyunsaturated acid deficiency has also been confirmed in this group of metabolic patients and a dietary supplement is recommended since this population is subject to a special risk factor with regard to adequate psychomotor development. By extrapolating these data to the general population, the possibility can be inferred that long‐chain polyunsaturated fatty acids are semi‐essential in infant nutrition far beyond the breast‐feeding period.
Dihydropyridmidinase deficiency and congenital microvillous atrophy: Coincidence or genetic relation?
Authors: Assmann B. , Hoffmann G. F. , Wagner L. , Bräutigam C. , Seyberth H. W. , Duran M. , Van Kuilenburg A. B. P. , Wevers R. , Van Gennip A. H. 
Published: December 2002

AbstractWe describe a boy of consanguineous parents who suffered from intractable diarrhoea due to congenital microvillous atrophy, a recessively inherited autosomal disorder. He developed severe cholestatis starting at 2 weeks of age and leading to liver cirrhosis. His psychomotor development appeared only slightly delayed. At the age of 7 months he died due to septicaemia. In addition to disturbances of electrolyte balance and renal tubular function, which could be attributed to microvillous atrophy, marked elevations of dihydrouracil and dihydrothymine as well as moderately elevated excretion of uracil and thymine in urine were repeatedly demonstrated, suggesting a disorder of pyrimidine degradation. An enzymatic defect of 5,6‐dihydropyrimidine amidohydrolase (EC 3.5.2.2, dihydropyrimidinase, DHP) was demonstrated in liver biopsy. As both of these recessive disorders seem to be extremely rare, it remains speculative, whether he suffered from two independently inherited metabolic diseases or whether this represents a hitherto undescribed contiguous gene syndrome.
The heart and pericardial effusions in CDGS‐I (carbohydrate‐deficient glycoprotein syndrome type I)
Authors: Kristiansson B. , Stibler H. , Conradi N. , Eriksson B. O. , Ryd W. 
Published: December 2002

AbstractPericardial effusions were found in 6 of 10 children with carbohydrate‐deficient glycoprotein syndrome type I (CDGS‐I). In three cases pericardectomy was necessary. Blood concentrations of several glycoproteins and albumin were low. Similar abnormal isoforms of four glycoproteins were found in blood (B) and pericardial fluid (PF). There was a significant negative correlation between the mean concentration ratio PF/B and the molecular mass (MW) of 11 proteins. For proteins with MW <100 kDa there were significant correlations in the controls, but not in the patients, between the PF/B ratio and both the MW and the sialic acid contents in the (glyco‐)proteins. The pericardium exhibited focal mixed inflammatory changes with mesothelial proliferation, with widened endoplasmic reticulum and flocculent and/or lamellated material. Damage to a pericardial protein barrier is suggested to be involved in pericardial effusion in CDGS‐I.
Improvement in exercise tolerance in isovaleric acidaemia with L‐carnitine therapy
Authors: Lee P. J. , Harrison E. L. , Jones M. G. , Chalmers R. A. , Leonard J. V. , Whipp B. J. 
Published: December 2002

AbstractThe effect of 4 weeks' treatment with oral‐L‐carnitine (100 mg/kg per day) on carnitine status and metabolic parameters during an incremental ramp exercise test in a 12‐year‐old girl with isovaleric acidaemia was examined to determine its possible therapeutic role. The maximum work rate achieved increased from 110 to 120 watts; oxygen consumption at anaerobic threshold from 600 to 800 L/min; peak oxygen consumption from 1270 to 1450 L/min; and oxygen pulse, a measure of cardiac output, from 7.0 to 8.1 L/beat. These changes were associated with increases in plasma and urinary free and acyl carnitine concentrations but no change in physical activity. This observed effect of L‐carnitine on exercise performance may be on cardiac or skeletal muscle function or both. We conclude that, in this single patient with isovaleric acidaemia, L‐carnitine supplementation had objective benefits and further studies on more patients are warranted.
A novel acid α‐glucosidase mutation identified in a Pakistani family with glycogen storage disease type II
Authors: Kroos M. A. , Waitfield A. E. , Joosse M. , Winchester B. , Reuser A. J. J. , MacDermot K. D. 
Published: December 2002

AbstractA novel mutation, C118t, in exon 2 of the acid α‐glucosidase gene has been found in an infant with glycogen storage disease type II. This mutation is predicted to result in protein truncation. The phenotype was that of the severe infantile form of the disorder with lack of motor development, but with eye regard, social smile and vocalization. The parents were heterozygous for C118T and belong to an Islamic community opposed to termination of pregnancy. As the C118T mutation results in the loss of one of two AvaI sites present in an informative PCR product, reliable premarriage carrier detection became possible and was acceptable to the members of this extended family.
Niemann–Pick disease type C and defective peroxisomal β‐oxidation of branched‐chain substrates
Authors: Sequeira J. S. S. , Vellodi A. , Vanier M. T. , Clayton P. T. 
Published: December 2002

AbstractAn 18‐month‐old infant presented with hypotonia, motor delay, hepatosplenomegaly, rickets and steatorrhoea. Biochemical investigations revealed typical features of Niemann–Pick disease type C. In addition, there was evidence of defective peroxisomal β‐oxidation of branched‐chain substrates (3α,7α,12α‐trihydroxycholestanoic acid and pristanic acid). The steatorrhoea and fat‐soluble vitamin malabsorption responded well to bile acid therapy. Possible causes for the double defect are considered.
Aberrant phenylalanine metabolism in phenylketonuria heterozygotes
Authors: Guldberg P. , Henriksen K. F. , Lou H. C. , Güttler F. 
Published: December 2002

AbstractThe wide variation in phenylalanine hydroxylating capacity observed among patients with phenylketonuria (PKU) is primarily due to allelic heterogeneity at the phenylalanine hydroxylase (PAH) locus. In this study, we examined phenylalanine metabolism after an oral phenylalanine load in 148 carriers of known PAH gene mutations. As a group, heterozygotes formed less tyrosine than normozygotes (p<0.001), and there was a tendency that carriers of a severe PAH mutation formed less tyrosine than carriers of a mild mutation. Nevertheless, the interindividual variation was extensive, and we identified a group of individuals who formed no or very little tyrosine after the phenylalanine load. This tyrosine response was accompanied by a decreased ability to eliminate the phenylalanine test dose but did not correlate with the intrinsic severity of the mutant PAH allele. Examination of the entire coding region of the PAH gene revealed no additional sequence alterations in these subjects. Our data suggest that a subset of PKU heterozygotes have reduced phenylalanine hydroxylating capacity approaching or equalling the levels observed in genetic compounds with non‐PKU mild hyperphenylalaninaemia (MHP). Awareness of this phenotypic overlap between PKU carriers and genetic compounds with two mutant alleles may be useful for clinicians and paediatricians involved in diagnosis and genetic counselling.
Accurate detection of Smith–Lemli–Opitz syndrome carriers by measurement of the rate of reduction of the ergosterol C‐7 double bond in cultured skin fibroblasts
Authors: Honda M. , Tint G. S. , Shefer S. , Honda A. , Batta A. K. , Xu G. , Chen T. S. , Salen G. 
Published: December 2002

AbstractThe activity of ergosterol Δ7‐reductase (3β‐hydroxysteroid Δ7‐reductase) was measured in cultured skin fibroblasts from 7 controls, 10 Smith–Lemli–Opitz syndrome (SLOS) patients, and 10 parents (obligate carriers). The fibroblasts were exposed to delipidated medium supplemented with lovastatin for 24h and the enzyme activity was determined by incubating cell‐free homogenate with ergosterol (ergosta‐5,7,22‐trien‐3β‐ol) and measuring the mass of brassicasterol (ergosta‐5,22‐dien‐3β‐ol) formed by gas chromatography–mass spectrometry with selected‐ion monitoring. In carriers, the activity was significantly lower than in controls (22±2 vs 65±10 pmol/min per mg protein, p<0.0005), and no overlap was observed. The mean activity in carriers' fibroblasts was more than 100 times higher than in patients' cells (0.2 pmol/min per mg protein). The use of ergosterol avoids the many problems caused by the instability and lack of availability of radiolabelled 7‐dehydrocholesterol. The present method makes it possible to discriminate SLOS carriers from both controls and patients using a commercially available substrate and common analytical equipment.
Holoprosencephaly: A paradigm for the complex genetics of brain development
Authors: Roessler E. , Muenke M. 
Published: December 2002

AbstractHoloprosencephaly (HPE) is the most common major developmental defect of the forebrain in humans. Clinical expression is variable, ranging from a small brain with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial HPE. Significant aetiological heterogeneity exists in HPE and includes both genetic and environmental causes. Recently, defects in the cell signalling pathway involving the Sonic Hedgehog (SHH) gene, as well as defects in the cholesterol biosynthesis, have been shown to cause HPE in humans. These discoveries and current genetic approaches serve as a paradigm for studying normal and abnormal brain morphogenesis.
Studies on the oxidation of phytanic acid and pristanic acid in human fibroblasts by acylcarnitine analysis
Authors: Verhoeven N. M. , Jakobs C. , Ten Brink H. J. , Wanders R. J. A. , Roe C. R. 
Published: December 2002

AbstractThe α‐oxidation of phytanic acid and the β‐oxidation of pristanitc acid were investigated in cultured fibroblasts from controls and patients affected with different peroxisomal disorders using deuterated substrates. Formation of [ω‐2H6]4,8‐dimethylnonanoylcarnitine ([ω‐2H6]C11‐carnitine) from [ω‐2 H6]phytanic acid and [ω‐2H6]pristanic acid was used as marker for these processes. Analysis was performed by tandem mass spectrometry.In normal cells, formation of [ω‐2H6]C11‐carnitine from both [ω‐2H6]phytanic acid and [ω‐2H 6]pristanic acid was observed. When peroxisome‐deficient fibroblasts were incubated with these substrates, [ω‐2H6]C11‐carnitine was not detectable or, in two cases, very low, which results from deficiencies in both peroxisomal α‐ and β‐oxidation. In cells with an isolated β‐oxidation defect at the level of the peroxisomal bifunctional protein, formation of [ω‐2H6]C11‐carnitine could also not be detected.Cells with an isolated defect in the α‐oxidation of phytanic acid, obtained from patients affected with Refsum disease (McKusick 266500) or rhizomelic chondrodysplasia punctata (McKusick 215100), did not form [ω‐2H6]C11 ‐carnitine from [ω‐2H6]phytanic acid. The observed formation of [ω‐2H6]C11‐carnitine from [ω‐2H6]pristanic acid in these cells is in accordance with a normal peroxisomal β ‐oxidation in these disorders.This study shows that separate incubation of fibroblasts with [ω‐2H 6]phytanic acid and [ω‐2H6]pristanic acid, followed by acylcarnitine analysis in the medium by tandem mass spectrometry, can be used for screening cell lines for deficiencies in the peroxisomal α‐ and β‐oxidation pathways.
Four novel mutations at the cystathionine β‐synthase locus causing homocystinuria
Authors: Coudé M. , Aupetit J. , Zabot M. T. , Kamoun P. , Chadefaux‐Vekemans B. 
Published: December 2002

AbstractWe describe four new mutations in the cystathionine β‐synthase gene: three point mutations localized in exons 3, 9 and 10 and one mutation in exon 12 which results in stop codon. Homocystinuria due to cystathionine β‐synthase (CBS, EC.4.2.1.22) deficiency (McKusick 236200), is the most common autosomal recessive inborn error of the transsulphuration pathway. Homocystinuric patients exhibit mental retardation, psychotic behaviour, dislocated lenses, vascular disease, osteoporosis and skeletal abnormalities. About 50% of affected subjects show biochemical improvements when treated with pyridoxine, the precursor of the CBS cofactor pyridoxal 5′‐phosphate. The severity of the disease varies among the patients: pyridoxine‐responsive patients usually have a milder clinical phenotype than pyridoxine‐nonresponsive patients. Human CBS cDNA has been cloned and its complete sequence, with minor differences in the coding region, has been published by three teams (Chassé et al 1995; Kraus et al 1993; Kruger and Cox 1994). The screening for mutations in homocystinuric patients has led to the identification of more than 50 mutations (Aral et al 1997; Dawson et al 1996; De Franchis et al 1994; Gallagher et al 1995; Hu et al 1993; Kluijtmans et al 1995; Kozich et al 1993; Kozich and Kraus 1992; Kraus 1994; Marble et al 1994; Shih et al 1995; Sebastio et al 1995; Sperandeo et al 1995). Two mutations are found to be most prevalent: (a) I278T only in pyridoxine‐responsive patients; (b) G307S mutation, the leading cause of homocystinuria in Ireland and in patients of ‘Celtic origin’ (Gallagher et al 1995). We describe here four novel mutations at the CBS locus.
Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin
Authors: Enns G. M. , Barkovich A. J. , Rosenblatt D. S. , Fredrick D. R. , Weisiger K. , Ohnstad C. , Packman S. 
Published: December 2002

AbstractCobalamin C (cblC) defects result in decreased activity of both methylmalonyl‐CoA mutase and N5‐methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase), with subsequent methylmalonic aciduria and homocystinuria. Patients typically show failure to thrive, developmental delay and megaloblastic anaemia. Vitamin B12 therapy has been beneficial in some cases. We report a now 4‐year‐old Hispanic girl with cblC disease documented by complementation analysis, with progressive neurological deterioration and worsening head MRI changes while on intramuscular hydroxocobalamin begun at age 3 weeks. Oral carnitine and folic acid were added at age 1 year. Blood levels of methylmalonic acid were reduced to treatment ranges. In the absence of acute metabolic crises, she developed microcephaly, progressive hypotonia and decreased interactiveness. Funduscopic examination was normal at age 13 months. At age 19 months, she developed nystagmus, and darkly pigmented fundi and sclerotic retinal vessels were observed on examination. Her neonatal head MRI was normal. By age 1 year, the MRI showed diffuse white‐matter loss, with secondary third and lateral ventricle enlargement, a thin corpus callosum, and normal basal ganglia. At age 15 months, progression of the white‐matter loss, as well as hyperintense globi pallidi, were present. Interval progression of both grey‐ and white‐matter loss was seen at age 27 months. We therefore caution that progressive neurological deterioration and head MRI abnormalities may still occur in cblC disease, despite early initiation of hydroxocobalamin therapy and improvement in toxic metabolite concentrations in physiological fluids.
Large heterozygous deletion masquerading as homozygous missense mutation: A pitfall in diagnostic mutation analysis
Authors: Zschocke J. , Quak E. , Knauer A. , Fritz B. , Aslan M. , Hoffmann G. F. 
Published: December 2002

AbstractThe clinical use of molecular analyses in recessive disorders relies onthe exact characterization of both mutant alleles in the affected patient. Thiscan be problematic when only part of the gene is examined or when relevant DNA alterations are not recognized by standard methods. We present a child in whom phenylketonuria was apparently caused by homozygosity for the mutation E390G in exon 11 of the phenylalanine hydroxylase (PAH) gene. However, the clinical severity of the disease was not quite as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene. Presence of a large deletion involving exons 9, 10 and 11 of the phenylalanine hydroxylase gene was confirmed by long‐range PCR. Diagnostic DNA analyses should include a comprehensive examination of the whole relevant gene in the patient and confirmation of carrier status in both parents.