bluuebunny/crossref_metadata_2025 huggingface dataset:
Progression of X‐linked adrenoleukodystrophy under interferon‐β therapy
Authors: Korenke G. C. , Christen H.‐J. , Kruse B. , Hunneman D. H. , Hanefeld F.
Published: December 2002

The cerebral phenotype of X‐linked adrenoleukodystrophy (ALD) is a rapidly progressive neurodegenerative disorder characterized by a cerebral inflammatory response and elevated very long‐chain fatty acids (VLCFA). Interferon‐β (INFB) is known to suppress the synthesis of tumour necrosis factor α and interferon‐γ, which have been reported to be elevated in the margin of the areas of demyelination in ALD brains. We report on treatment with interferon‐β in 8 patients with cerebral ALD, who additionally received glycerol trioleate/glycerol trierucate. INFB‐1a (Rebif, Serono, Switzerland) was given subcutaneously once a week, 3 million units for the first 3 months and 6 million units for the next 9 months. All patients showed an unimpeded progression of neurological symptoms during INFB therapy. Therapy was stopped within 6 months in 4 patients because of the fast neurological deterioration with loss of walking. In all patients the MRI demonstrated a progression of demyelination with a qualitatively unchanged gadolinium enhancement. Further studies are needed to elucidate the pathomechanism of demyelination in ALD in order to find an effective therapy for cerebral ALD patients.
Aspartylglucosaminuria among Palestinian Arabs
Authors: Zlotogora J. , Ben‐Neriah Z. , Abu‐Libdeh B. Y. , Zeigler M.
Published: December 2002

Aspartylglucosaminuria (AGU) is a rare disorder of glycoprotein metabolism caused by the deficiency of the lysosomal enzyme aspartylglucosaminidase (AGA). AGU is inherited as an autosomal recessive trait and occurs with a high frequency in Finland because of a founder effect. While very few patients with AGU have been reported from non‐Finnish origin, we diagnosed the disorder in 8 patients originating from 3 unrelated families, all Palestinian Arabs from the region of Jerusalem. The clinical diagnosis of AGU is often difficult, in particular early in the course of the disease, and most of the patients are diagnosed after the age of 5 years. However, since these patients excrete early large amounts of aspartylglucosamine in urine, biochemical screening is easy by urine chromatography.
Folate‐responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease)
Authors: Fowler B. , Schutgens R.B.H. , Rosenblatt D.S. , Smit G.P.A. , Lindemans J.
Published: December 2002

This first detailed report of a female patient with functional methionine synthase deficiency due to the cblE defect describes treatment with several vitamins and cofactors and clinical progress for 17 years. Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia, increased plasma free homocystine (> 20 µmol/L), low plasma methionine (< 10 µmol/L) and increased excretion of formiminoglutamate. On high‐dose folic acid, biochemical abnormalities such as formiminoglutamate excretion and homocystinuria nearly normalized, but clinical and haematological abnormalities remained. On replacement of folate with methylcobalamin, alertness, motor function, speech and the electroencephalogram improved, biochemical features were similar, but the mean corpuscular volume increased. The best control was observed on a combination of folate and methylcobalamin. At 17 years of age she remains severely mentally retarded.

In cultured fibroblasts methionine synthesis was reduced (0.03 nmol/mg/per 16h, controls 2.4‐6.9); methionine synthase activity was normal under high reducing conditions but decreased on limiting the reducing agent, dithiothreitol, to 5 mmol/L (18% of total, controls 51‐81%); formation of methylcobalamin was low (4.5% of total cobalamins, control 57.5%) and complementation studies indicated the cblE defect. Methionine formation showed only minor increases in cells grown in folate‐ or cobalamin‐supplemented medium. Serine synthesis, which was low in normal medium, increased with cobalamin supplementation. These studies suggest further heterogeneity within cblE mutants, show the difficulty of establishing the enzyme defect in vitro, and indicate a role for folate in addition to cobalamin in treatment.
Putative mechanisms for vascular damage by homocysteine
Authors: Bellamy M. F. , McDowell I. F. W.
Published: December 2002

In homocystinuria homocysteine appears to be directly toxic to the vasculature, but in mild hyperhomocysteinaemia a cause and effect relationship remains unproven. Evidence for a causal role is derived from recent primate and human studies in which endothelial dysfunction was produced by modestly elevated blood homocysteine concentrations. Endothelial dysfunction would account for an increased risk of both arterial and venous disease. A key abnormality may be impaired release and/or action of nitric oxide in response to flow. Other possible mechanisms include smooth muscle cell proliferation, extracellular matrix modification and lipoprotein oxidation. Although demonstrated in vitro, a role for lipoprotein oxidation in man has not been substantiated. However an effect of homocysteine on cellular redox status remains a possible mechanism. Homocysteine does not appear to alter circulating coagulation factors consistently, but may promote enhanced thrombin production indirectly by its effects on endothelium. Further studies are required to elucidate the pathological actions of homocysteine, concentrating on the effects of mild hyper‐homocysteinaemia on endothelial function in man.
A case of the carbohydrate‐deficient glycoprotein syndrome type 1 (CDGS type 1) with normal phosphomannomutase activity
Authors: Charlwood J. , Clayton P. , Johnson A. , Keir G. , Mian N. , Winchester B.
Published: December 2002

The carbohydrate‐deficient glycoprotein syndrome (CDGS) is a group of disorders characterized biochemically by abnormal glycosylation of serum and cellular glycoproteins. It has been classified into four forms on the basis of the isoelectric focusing pattern of serum transferrin and differences in clinical presentation. A deficiency of phosphomannomutase (PMM) has been reported in most patients with type 1. Seven of our eight CDGS patients, classified clinically as type 1, were shown to have a deficiency of phosphomannomutase in their fibroblast or lymphoblastoid cells (0.04‐0.2 nmol/min per mg, compared with a control range of 1.0‐2.1 nmol/min per mg). The eighth patient, who had many clinical features of the severe neonatal form of CDGS type 1, but lacked definite signs of CNS and ocular involvement, had a normal phosphomannomutase activity in his fibroblasts. There were approximately equal amounts of disialo‐ and tetrasialotransferrin and only a trace amount of asialotransferrin in the serum and ascitic fluid of this patient. The disialo‐ and tetrasialotransferrin isoforms were purified by ion‐exchange chromatography and analysed by SDS‐PAGE. The disialotransferrin had a lower molecular mass than the tetrasialotransferrin, consistent with the absence of an N‐linked glycan. The N‐linked glycans released enzymically from both isoforms consisted exclusively of disialylated biantennary chains, suggesting that disialotransferrin results from underglycosylation, as in the PMM‐deficient CDGS type 1 patients. It is concluded that the clinical and biochemical phenotype in CDGS type 1 can result from more than one basic defect.
The fragile X syndrome
Authors: Hoogeveen A. T. , Oostra B. A.
Published: December 2002

The fragile X syndrome is caused by the amplification of a polymorphic CGG repeat in the 5′ untranslated region of the FMR1 gene and is the most common form of inherited mental retardation. When the repeat is amplified beyond 200 repeat units, the repeat and the FMR1 promoter region are methylated. As a result of this methylation the gene is silenced and no FMR1 gene product (FMRP) is translated. The lack of expression of FMRP in the fragile X syndrome causes the fragile X phenotype. A mouse model for the fragile X syndrome (knockout for FMRP) has been generated to study the pathological mechanisms leading to the symptoms seen in fragile X patients. FMRP is widely expressed in different tissues and localized predominantly in the cytoplasm associated with the 60S ribosomal subunit. The protein has RNA binding properties and possibly shuttles between cytoplasm and nucleus. The target signals necessary for this intracellular transport, like a nuclear location signal and a nuclear export signal, are present in FMRP. FMRP is also able to bind to other proteins by using specific sequence domains present in the protein. The coiled‐coil structures formed by these domains are known to be involved in protein‐protein interaction. In this review we postulate that FMRP is involved in the transport of RNA and/or proteins from the nucleus to the cytoplasm.
Inborn errors of signal transduction: Mutations in G proteins and G protein‐coupled receptors as a cause of disease
Authors: Spiegel A. M.
Published: December 2002

A vast array of neurotransmitters, polypeptide hormones and other extracellular signalling molecules utilize G protein‐coupled pathways for transmembrane signalling. In recent years, mutations in G protein‐coupled receptors and in G protein α subunits have been identified as the cause of a variety of human diseases. Both loss and gain of function mutations have been described in disorders such as Albright hereditary osteodystrophy, nephrogenic diabetes insipidus, McCune‐Albright syndrome, and familial male precocious puberty. Identification of mutations in G protein‐coupled receptors and in G proteins in human diseases has provided unique insights into G protein‐coupled signal transduction, has important implications for diagnosis and potentially for treatment, and should stimulate the search for additional defects in G protein‐coupled signal transduction in other diseases.
Commentary: Neonatal onset in fatty acid oxidation disorders: How can we minimize morbidity and mortality?
Authors: Riudor E.
Published: December 2002

Neonatal onset is one of the most severe forms of presentation in inborn errors of metabolism. In mitochondrial fatty acid oxidation disorders, neonatal onset is more frequent than commonly supposed, with high morbidity and mortality. Presentations include hypoketotic hypoglycaemia, which may be difficult to assess in the neonate because of its relative immaturity, metabolic acidosis, liver, muscle and/or cardiac involvement and even sudden death. In many cases diagnosed with a fatty acid oxidation defect a previous sibling had died suddenly in the neonatal period, emphasizing the severity of the neonatal presentation. Neonatal presentation has been described in the majority of fatty acid oxidation defects, as reviewed by Pollitt (1995) and Stanley (1995).
Glycogen storage disease type 1a in three siblings with the G270V mutation
Authors: Parvari R. , Isam J. , Moses S. W.
Published: December 2002

Glycogen storage disease type 1a (von Gierke disease, GSD1a) is caused by the deficiency of microsomal glucose‐6‐phosphatase (G6Pase) activity. The cloning of G6Pase cDNA and characterization of the human G6Pase gene enabled the identification of the mutations causing GSD1a. Here we report on the clinical and biochemical features of three GSD1a siblings of a Muslim Arab family with a G270V mutation. Two older patients presented with an unusually mild clinical and biochemical course.
From toxicological problem to therapeutic use: The discovery of the mode of action of 2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione (NTBC), its toxicology and development as a drug
Authors: Lock E. A. , Ellis M. K. , Gaskin P. , Robinson M. , Auton T. R. , Provan W. M. , Smith L. L. , Prisbylla M. P. , Mutter L. C. , Lee D. L.
Published: December 2002

NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4‐hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4‐hydroxyphenylpyruvate and 4‐hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4‐hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4‐hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.
One‐methyl group metabolism in non‐ketotic hyperglycinaemia: Mildly elevated cerebrospinal fluid homocysteine levels
Authors: Van Hove J. L. K. , Lazeyras F. , Zeisel S. H. , Bottiglieri T. , Hyland K. , Charles H. C. , Gray L. , Jaeken J. , Kahler S. G.
Published: December 2002

Non‐ketotic hyperglycinaemia (NKH) is a rare, severe brain disease caused by deficient glycine cleavage enzyme complex activity resulting in elevated glycine concentrations. Recent experience suggests that factors in addition to glycine kinetics are involved in its pathogenesis. The glycine cleavage reaction through the formation of methylenetetrahydrofolate is an important one‐methyl group donor. A deficiency in one‐methyl group metabolites, in particular of choline, has been hypothesized in NKH. We investigated metabolites involved in one‐methyl group metabolism in plasma and CSF of 8 patients with NKH, and monitored the effect of treatment with choline in one patient. Plasma and CSF choline and phosphatidylcholine concentrations were normal, except for a low plasma choline in the single neonate studied. Choline treatment did not change brain choline content, and was not associated with clinical or radiological improvement. Methionine concentrations and, in one‐patient, S‐adenosylmethionine and 5‐methyltetrahydrofolate concentrations were normal in CSF. Homocysteine concentrations in CSF, however, were slightly but consistently elevated in all four patients examined, but cysteine, cysteinylglycine and glutathione were normal. Serine is important in the transfer of one‐methyl groups from mitochondria to cytosol. Serine concentrations were normal in plasma and CSF, but dropped to below normal in CSF in three patients on benzoate treatment. These observations add to our understanding of the complex metabolic disturbances in NKH.
Animal models of lysosomal disease: An overview
Authors: Suzuki K. , Månsson J.‐E.
Published: December 2002

The relative rarity of human lysosomal disorders, extremely heterogeneous genetic background and ethical restrictions make well‐controlled studies difficult with human patients. Genetically authentic animal models complement human patients with their ready availability, homogeneous genetic background and the relatively flexible experimental designs. Spontaneous animal models of human lysosomal disorders are rare, particularly among small laboratory animals. However, the homologous recombination and embryonic stem cell technology has so far enabled us to duplicate almost all known human sphingolipidoses, two mucopolysaccharidoses and aspartylglycosaminuria in mice and more disorders are expected in the near future. This technology also allows generation of mouse mutants that are not known or are highly unlikely to exist in humans, such as ‘double‐knockouts’. Studies of lysosomal disease have come to the half‐way turning point of the marathon race from clincopathological descriptions, identification of affected compounds, enzymology, to the present gene‐level inquiries. The animal models will play an important role in our long journey from nucleic acids back to biology. While the utility of these mouse models is obvious, species differences in the brain development and metabolic pathways must be always remembered if the ultimate goal of the study is application to human patients. After all, the mouse is not human.
Renal transplantation in a patient with methylmalonic acidaemia
Authors: Van Calcar S. C. , Harding C. O. , Lyne P. , Hogan K. , Banerjee R. , Sollinger H. , Rieselbach R. E. , Wolff J. A.
Published: December 2002

Renal insufficiency is frequently reported in mutase‐deficient methylmalonic acidaemia. We present a case report of a patient with mut– methylmalonic acidaemia who developed chronic tubulointerstitial nephropathy during adolescence. At 24 years of age, she developed end‐stage renal failure and underwent renal transplantation. Both plasma and urine methylmalonic acid levels decreased significantly with improved renal function following transplantation. Complications included cyclosporin toxicity and development of diabetes. Renal, metabolic, and clinical status remained improved at 3 years after the kidney transplant.
Diffuse leukodystrophy in an infant with cytochrome‐c oxidase deficiency
Authors: Harpey J‐P. , Heron D. , Prudent M. , Charpentier C. , Rustin P. , Ponsot G. , Cormier‐Daire V.
Published: December 2002

A 25‐month‐old boy, born to consanguineous parents, had progressive spastic tetraplegia, and increased signal of the white matter on cerebral T2‐weighted magnetic resonance imaging indicative of diffuse leukodystrophy. Elevated blood and cerebrospinal fluid lactate levels pointed to a respiratory chain defect. Cytochrome‐c oxidase deficiency was demonstrated in cultured skin fibroblasts and skeletal muscle. This report extends the phenotype of COX deficiency in infancy. Systematic study of blood and CSF lactate should be carried out in every infant with leukodystrophy.
A simple screening test for fatty acid oxidation defects using whole‐blood palmitate oxidation
Authors: Seargeant L. E. , Balachandra K. , Mallory C. , Dilling L. A. , Greenberg C. R.
Published: December 2002

We report that measurement of whole‐blood palmitate oxidation is a rapid and inexpensive screening test for fatty acid oxidation defects. The assay has been adapted from published assays using cultured fibroblasts or isolated white blood cells. Micro whole‐blood samples are incubated with tritiated palmitic acid as substrate. The tritiated water produced is proportional to the mitochondrial β‐oxidation of palmitic acid. Patients with confirmed β‐oxidation defects show low whole‐blood palmitate oxidation.
Transcobalamin II deficiency with methylmalonic aciduria in three sisters
Authors: Bibi H. , Gelman‐Kohan Z. , Baumgartner E. R. , Rosenblatt D. S.
Published: December 2002

Transcobalamin II (TC II) is a plasma protein that binds vitamin B12 (cobalamin, Cbl) and facilitates cellular Cbl uptake by receptor‐mediated endocytosis. In autosomal recessive TC II deficiency, intracellular Cbl deficiency results in an early onset of megaloblastic anaemia that may be accompanied by neurological abnormalities. Inadequate treatment may lead to neurological abnormalities. We describe three sisters, the daughters of first cousins of Moroccan origin, with TC II deficiency requiring continuous and long‐term vitamin B12 treatment. The diagnosis was suspected from the finding of low unsaturated vitamin B12 binding capacity and confirmed by absence of detectable TC II by radioimmunoassay and by inability of cultured fibroblasts to synthesize TC II.
Artefactual pyruvate and 2‐oxobutyrate produced by trimethylsilylation of methylmalonic and ethylmalonic acids in the presence of oxygen
Authors: Mamer O. A. , Choiniere L. , Boismenu D. , Lepine F.
Published: December 2002

Trimethylsilylation of methylmalonic and ethylmalonic acids in the presence of headspace atmospheric oxygen is shown to produce the trimethylsilyl derivatives of pyruvic and 2‐oxobutyric acids, along with 2‐hydroxy‐2‐methylmalonic and 2‐hydroxy‐2‐ethylmalonic acids, respectively. This may lead to overestimation of these keto acids, if they were not oximated in the original sample, and the mistaken reporting of the 2‐hydroxymalonates.
Cell-Type Dependence of Stability Modulation of Lectin-initiated Contacts by Impairment of Multivalent Carbohydrate Binding and Intracellular Signaling
Authors: Timoshenko A. V. , Gorudko I. V. , André S. , Gabius H.-J.
Published: December 2002

Initial ligand selection and the intermolecular spatial arrangement ofglycan-lectin complexes are assumed to be essential to induce formationof stable cell aggregates by a lectin. To distinguish effects of thesetwo processes, the tetrameric mistletoe lectin and its isolated B-chainwere used. A reduced impact of multivalency for Ehrlich ascites tumorcells in contrast to rat thymocytes was revealed. Signaling is thusinitiated in a cell-type-dependent manner. Using selective metabolicinhibitors to reduce signal transfer for aggregate stability, decreasein cellular SH-group level was shown to be a common effect accompanyingsuppression of lectin-dependent aggregate stability. The resultsunderscore an intrinsic variability in the relative importance oflectin-dependent glycan aggregation on the cell surface for triggeringpost-binding lectin effects.
A review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delC)
Authors: Wevers R. A. , de Rijk‐van Andel J. F. , Bräutigam C. , Geurtz B. , van den Heuvel L. P. W. J. , Steenbergen‐Spanjers G. C. H. , Smeitink J. A. M. , Hoffmann G. F. , Gabreëls F. J. M.
Published: December 2002

An overview is given of the current knowledge on the human tyrosine hydroxylase gene and on the biochemical aspects of diagnosing defects in this gene. Diagnostic biochemical findings are described in four cases of genetically confirmed tyrosine hydroxylase deficiency. Decreased CSF levels of homovanillic acid (HVA) and 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG), together with normal pterin and CSF tyrosine and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations are the diagnostic hallmarks of tyrosine hydroxylase deficiency. At the metabolite level the diagnosis can only be made reliably in CSF. Strict adherence to a standardized lumbar puncture protocol and adequate reference values are essential for diagnosis of this “new” treatable neurometabolic disorder. Measurements of HVA, vanillylmandelic acid (VMA) or catecholamines in urine are not relevant for diagnosing tyrosine hydroxylase deficiency. The diagnosis should be considered in all children with unexplained hypokinesia and other extrapyramidal symptoms. Three of our patients are homozygous for a mutation in exon 6 (698G>A) of the tyrosine hydroxylase gene and one patient was compound heterozygous for the same mutation and a novel truncating mutation in exon 3 (291delC).
Adolescent myopathic presentation in two sisters with very long‐chain acyl‐CoA dehydrogenase deficiency
Authors: Merinero B. , Pascual Pascual S. I. , Pérez‐Cerdá C. , Gangoiti J. , Castro M. , Garcia M. J. , Pascual Castroviejo I. , Vianey‐Saban C. , Andresen B. , Gregersen N. , Ugarte M.
Published: December 2002

Two sisters were investigated at the ages of 20 and 13 years owing to persistently increased serum creatine kinase and recurrent episodes of rhabdomyolysis after emotional stress in the older and myalgias in the younger. The finding of increased levels of cis‐5‐tetradecenoic acid (C14:1) in plasma, severe hypocarnitinaemia and the absence of a pathological dicarboxylic aciduria in both sisters suggested a very long‐chain acyl‐CoA dehydrogenase (VLCAD) deficiency. Reduced [1‐14C]palmitate oxidation and deficient mitochondrial VLCAD activity in fibroblasts were found. Mutation analysis revealed compound heterozygosity for Asp365His and Arg410His changes. This late‐onset, milder clinical presentation differs from the other two more severe infantile phenotypes described, since there is no hypoglycaemia or cardiac disease. Fatty acid oxidation defects should be investigated in all cases with rhabdomyolysis beginning in adolescence or early adulthood.
Urinary organic acid screening in children with developmental language delay
Authors: Michelson M. , Harel S. , Gutman A. , Lerman‐Sagie T.
Published: December 2002

The prevalence of 3‐methylglutaconic aciduria was evaluated among children with developmental language disorders. A urine specimen was obtained from 40 children referred for developmental language delay to the Tel‐Aviv Child Development Center during 12/96–6/97 and from 50 age‐matched controls. Urine organic acids were analysed by gas chromatography–mass spectrometry. Urinary 3‐methylglutaconic acid was quantified. A mildly increased excretion of 3‐methylglutaconic acid was found in 8 children with developmental language delay. The combined excretion of 3‐methylglutaconic and 3‐methylglutaric acid was increased in 9 patients. There were no differences in the excretion of other organic acids. The patients with elevated 3‐methylglutaconic acid did not differ from the other patients with developmentallanguage disorders in any of the parameters evaluated. Mildly elevated urinary levels of 3‐methylglutaconic acid may be a marker of a still undefined metabolic disorder presenting with developmental language delay. A further study in large groups of children with different developmental disorders is mandatory.
Genomics, mutations and the Internet: The naming and use of parts
Authors: Scriver C. R. , Nowacki P. M.
Published: December 2002

Mutations are the source of genetic variation and diversity; by their effect, some are neutral, others are pathogenic. In contemporary genetics, mutations appear at the interface between genomics (structural and functional) and genetics (heredity), where they serve gene discovery and mapping (genomics) and generate challenges to modify their phenotypic effects (medical genetics). Assuming the human genome harbours 80000 transcribed genes each possessing at least 100 different (germline) alleles in a typical population, how then to record and recover data on at least 8 million human alleles? Bioinformatics is the essential resource to create the corresponding accessible digital libraries (genomic and locus‐specific mutation databases) for this purpose, a goal to which The HUGO Mutation Database Initiative (Science 279: 10–11, 1998) aspires. Guidelines now exist for naming alleles (Hum Mutat 11: 1–3, 1998). The principles behind the practice are illustrated by PAHdb (http://www.mcgill.ca/pahdb), a prototype locus‐specific mutation database (NAR 26: 220–225, 1998), and by prototype genomic mutation databases (HGMD (NAR 26: 285–287, 1998), http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html; the EBI mutation database, http://www2.ebi.ac.uk/mutations/; and OMIM, http://www.ncbi.nlm.nih.gov/Omim.html).
Population newborn screening for inherited metabolic disease: Current UK perspectives
Authors: Green A. , Pollitt R. J.
Published: December 2002

Some of the generally accepted criteria for screening programmes are inappropriate for newborn metabolic screening as they ignore the family dimension and the importance of timely genetic information. Uncritical application of such criteria creates special difficulties for screening by tandem mass spectrometry, which can detect a range diseases with widely different natural histories and responsiveness to treatment. Further difficulties arise from increasing demands for direct proof of the effects of screening on long‐term morbidity and mortality. The randomized controlled trial is held to be the gold standard, but for ethical and practical reasons it will be impossible to achieve for such relatively rare diseases. This approach also oversimplifies the complex matrix of costs and benefits of newborn metabolic screening. A more workable approach could involve Bayesian synthesis, combining quantitative performance data from carefully designed prospective pilot studies of screening with existing experience of the natural history, diagnosis, and management of the individual disorders concerned.
Towards metabolic sink therapy for mut methylmalonic acidaemia: Correction of methylmalonyl‐CoA mutase deficiency in T lymphocytes from a mut methylmalonic acidaemia child by retroviral‐mediated gene transfer
Authors: Chang C.‐C. , Hsiao K.‐J. , Lee Y.‐M. , Lin C.‐M.
Published: December 2002

The pathology associated with mut methylmalonic acidaemia (MMA) is caused by systemic accumulation of methylmalonate. Therefore, removal of methylmalonate from the circulation of affected individuals by an engineered metabolic system is proposed as a potential treatment. The haematopoietic cell is a potential site for such a metabolic system because of its direct contact with the accumulated metabolite and the demonstrated safety and ease in utilizing this cell. In this study, we assessed the feasibility of developing a haematopoietic cell‐based methylmalonate sink by analysing propionate/methylmalonate metabolism in a variety of haematopoietic cells. The results show that propionate metabolism and methylmalonyl‐CoA mutase (MCM) activity are intact in primary T cells, EBV‐B cells, and CD34+ haematopoietic stem cell‐derived granulocytes, whereas they are defective in those from a mut MMA child. Moreover, normal T and EBV‐B cells clear methylmalonate from the medium at a significant rate. Transduction of MCM‐deficient T cells with a recombinant retrovirus encoding the human MCM cDNA results in correction of propionate metabolism. These results establish the basis for developing haematopoietic cell‐based metabolic sink therapy for mut MMA by T lymphocyte/haematopoietic stem cell‐directed gene transfer.
High plasma leucine concentrations without neurological symptoms in a patient with classical maple syrup urine disease
Authors: Skladal D. , Grissenauer G. , Konstantopoulou V. , Felker S. , Sperl W.
Published: December 2002

It has been found that the amino acid analyser used in this study systematically overestimated plasma leucine at high concentrations. The concentration reported as 2249 μmol/L had a true value of 1430 μmol/L and leucine values reported as >2000 μmol/L were approximately 1500 μmol/L.
Short‐term effect of captopril on microalbuminuria in children with glycogen storage disease type Ia
Authors: Özen H. , Ciliv G. , Koçak N. , Saltik İ. N. , Yüce A. , Gürakan F.
Published: December 2002

Early signs of renal dysfunction in glycogen storage disease type Ia (GSD Ia) are glomerular hyperfiltration and proteinuria. In a non‐randomized study, the effect of captopril on the improvement of proteinuria in GSD Ia patients with microalbuminuria was investigated. A positive effect has been shown for the insulin‐dependent diabetes mellitus patients. Microalbuminuria was defined as albumin/creatinine ratio (mg/mmol) more than 2.5 in spot urine. Nineteen (52.7%) out of 36 patients had microalbuminuria, and 8 patients received captopril at a dose of 1mg/kg per day. Microalbuminuria was evaluated periodically during the follow‐up period. Of the captopril‐treated patients, one was lost to follow‐up. In the remaining 7 patients, urinary albumin excretion normalized in 3 patients (42.9%) and decreased at least by 50% in another 3 patients (42.8%) after 6 months of treatment. One patient, who was the oldest, did not have any benefit. In untreated patients, only two patients had a decrease in microalbuminuria of more than 50%. Patients with microalbuminuria had significantly higher blood lactate (p<0.05) and plasma triglyceride (p<0.01) concentrations and significantly lower blood bicarbonate concentration (p<0.05) than those patients without it. Additionally, the patients with microalbuminuria had been diagnosed earlier than those without microalbuminuria (p<0.05). Patients with microalbuminuria have more severe clinical and laboratory findings than those without microalbuminuria. Captopril at a dose of 1 mg/kg per day seems to be effective in at least 50% of GSD Ia patients with microalbuminuria.
Mutation detection in 65 families with a possible diagnosis of ornithine carbamoyltransferase deficiency including 14 novel mutations
Authors: Genet S. , Cranston T. , Middleton‐Price H. R.
Published: December 2002

The high new mutation rate and the wide spectrum of mutations found in patients with ornithine carbamoyltransferase (OCT) deficiency means that direct mutation analysis is essential for providing accurate carrier detection and prenatal diagnosis in affected families. We present our strategy for mutation detection in the OCT gene and summarize the results from 31 families with a confirmed diagnosis and 34 families with a suspected diagnosis of OCT deficiency, and describe 14 previously unreported mutations.
Genetic analysis of phytosterolaemia
Authors: Togo M. , Toda T. , Nguyen L. A. , Kubota S. , Tsukamoto K. , Satoh H. , Hara M. , Iso‐o N. , Noto H. , Kimura S. , Nakahara K. , Seyama Y. , Hashimoto Y.
Published: December 2002

Two women with multiple xanthomas, intermittent arthritis and thrombocytopenia were diagnosed as phytosterolaemia, an autosomal‐recessive lipid storage disease, based on their increased serum concentrations of β‐sitosterol, campesterol and sitostanol. The gene responsible for this disease is located within a distance of 18 cM between microsatellite markers of D2S1788 and D2S1352 at chromosome 2p21. We genotyped the patients and their family members with 16 microsatellite markers around this locus. The results from the homozygosity mapping of one family suggested that the gene was located within the distance of 12.6 cM between D2S2328 and D2S1352. We have shortened the genetic distance by 5.4 cM.
Gene therapy/cell therapy for lysosomal storage disease
Authors: Eto Y. , Ohashi T.
Published: December 2002

Lysosomal storage diseases (LSD) are considered to be appropriate disorders for gene therapy/cell therapy. We are attempting to treat one of these disorders using a mouse model, the Sly mouse. This is an authentic model for human β‐glucuronidase deficiency, MPS VII. We have carried out two types of experimental protocols; in vivo gene therapy and ex vivo gene therapy using Sly mice. For in vivo gene therapy, we produced a recombinant adenovirus that expresses human β‐glucuronidase and administered this to Sly mice intravenously. The β‐glucuronidase activities in liver and spleen were elevated to 40% and 20%, respectively, of the heterozygote enzyme level at day 16. Expression persisted for at least 35 days. Pathological abnormalities improved in these tissues and urinary glycosaminoglycan excretion was reduced in treated animals. ex vivo gene therapy/cell therapy was carried out using macrophages obtained by cultivation of bone marrow cells. Non‐myeloablated macrophages from normal mice were transplanted into Sly mice, and after 7 days donor cells had populated the liver and spleen. The human β‐glucuronidase (HBG) activity was increased in liver and spleen, although these enzyme activities subsequently fell by 38 days. The pathological improvement in Sly mice was evident at day 38 post transplantation. Furthermore, the macrophages from Sly mice were treated with retrovirus/adenovirus vector expressing HBG activity and the glycosaminoglycan accumulation was markedly decreased after 5 weeks. These data suggest that genetically engineered macrophage transplantation may be a very useful form of ex vivo gene therapy for lysosomal storage diseases. We also discuss the possible treatment of the CNS involvement in lysosomal storage diseases by gene therapy/cell therapy.
Novel mutations in two Japanese cases of glycogen storage disease type IIIa and a review of the literature of the molecular basis of glycogen storage disease type III
Authors: Fukuda T. , Sugie H. , Ito M.
Published: December 2002

We report two novel mutations in two Japanese patients with glycogen storage disease type IIIa (GSD IIIa). In addition, we review the literature on mutations in GSD III to understand better the molecular basis of GSD III. In our first case, the homozygous A‐to‐C mutation at the acceptor site of intron 5 (IVS5–2A>C) was identified. This leads to the skipping of exon 6 and the predicted mutant protein was found to be 68 amino acids shorter than normal. This is the first report of skipping exon 6, which encodes one of the putative active sites, resulting in a profoundly deleterious effect on debrancher activity. In our second case, the homozygous deletion of an A at position 4234 (4234delA) was identified; this induces a frameshift resulting in the appearance of a stop codon at amino acid position 1276 (1276X). In patients with GSD IIIa, several mutations of the debrancher gene located in the C‐terminal region containing putative glycogen binding domains have been identified as well as 4234delA in our second case. On the other hand, specific localization of the mutations within exon 3 was proposed in patients with GSD IIIb.
Cerebral metabolic changes in biotinidase deficiency
Authors: Schürmann M. , Engelbrecht V. , Lohmeier K. , Lenard H. G. , Wendel U. , Gärtner J.
Published: December 2002

Clinical and metabolic changes in the central nervous system are described in a patient with biotinidase deficiency before and after biotin treatment. Lactate, pyruvate and 3‐hydroxyisovaleric acid as metabolic disease markers were measured in blood, cerebrospinal fluid and brain tissue by biochemical analyses or localized magnetic resonance proton spectroscopy. The patient improved markedly with biotin treatment. Nevertheless, neurological sequelae and abnormal intracerebral lactate concentrations persisted despite normalized metabolic disease markers in extracerebral fluids. Therefore, localized in vivo measurements of intracerebral metabolites may be a valuable tool for elucidating the pathogenesis of biotinidase deficiency.
Effect of plasma α‐tocopherol on leukotriene E4 excretion in genetic vitamin E deficiency
Authors: Kohlschütter A. , Mayatepek E. , Finckh B. , Hübner C.
Published: December 2002

Studying the biological effects of vitamin E in humans is difficult because conditions involving vitamin E deficiency are usually associated with chronic multiple pathology. Genetic vitamin E deficiency caused by a deficient α‐tocopherol transport protein offers unique possibilities for study of vitamin E effects since the patients can be studied in good general health. In such a patient we manipulated plasma α‐tocopherol levels in a wide range by varying oral α‐tocopherol supplements and measured urinary leukotriene E4 (LTE4) concentrations. LTE4 excretion proved inversely correlated to plasma α‐tocopherol levels. This strongly suggests that in genetic vitamin E deficiency, α‐tocopherol influences formation of leukotrienes in vivo.
Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin
Authors: Kleijer W. J. , Keulemans J. L. M. , van der Kraan M. , Geilen G. G. , van der Helm R. M. , Rafi M. A. , Luzi P. , Wenger D. A. , Halley D. J. J. , van Diggelen O. P.
Published: December 2002

Sixty‐four unrelated patients with infantile Krabbe disease (globoid cell leukodystrophy, GLD) of Dutch (n=41) or other European origin (n=23) were screened for the presence of a large 30kb deletion starting in intron 10 (IVS 10del30kb), a base substitution 1538T(T513M) and a polymorphism, 502T. The deletion and the T513M mutation were present in 52% and 8.5%, respectively, of the 82 GALC alleles of the Dutch patients. The 502T polymorphism, which had an allele frequency of 5.3% in a Dutch control panel, occurred in 65% of the GLD alleles. Analysis of patients and both parents in 26 of the families showed that del30kb was invariably associated with 502T. However, 502T was also present on 40% of the GLD alleles with an as yet unidentified mutation, which is 7.5 times higher than its frequency in controls. This suggests that besides del30kb at least one other relatively frequent mutation has arisen on the 502T GALC allele. A relatively high incidence of del30kb was also found in 23 other European (non‐Dutch) patients (allele frequency 35%), but T513M did not occur in this group. Practical examples described in this report illustrate the potential usefulness of mutation analysis in many families with Krabbe disease for heterozygote detection and prenatal diagnosis.
Primary hyperoxaluria type 1: Diagnostic relevance of mutations and polymorphisms in the alanine:glyoxylate aminotransferase gene (AGXT)
Authors: Tarn A. C. , von Schnakenburg C. , Rumsby G.
Published: December 2002

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism caused by deficiency of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). The disease shows considerable phenotypic, enzymatic and genetic heterogeneity. To date, 7 polymorphisms and 11 point mutations have been described in the gene encoding AGT. We report on the prevalence of these polymorphisms and mutations in 79 patients with PH1 with the aim of assessing their diagnostic relevance. A strong association of the C154T, intron 1 insertion and C386T polymorphisms is confirmed and this linkage extends to include the type 1 variant of a polymorphic tandem repeat in intron 4. Only 64 of 158 (40%) PH1 alleles have one of the defined mutations, with the G630A mutation accounting for 39 of these and T853C for 14. Overall only 20 (25%) of the patients studied had the genetic basis of their disease fully explained: 7 were homozygous for the G630A mutation, 5 were homozygous for the T853C mutation, 1 was homozygous for the C819T mutation, and 7 had two different mutations identified and were presumed to be compound heterozygotes. Only the two more frequent G630A and T853C mutations are of general diagnostic relevance for mutation screening. It seems likely that there are a significant number of other mutations, perhaps family‐specific, still to be described. There was no apparent difference in the types of mutations in patients presenting in the first year of life (36%), suggesting that other factors, such as periods of dehydration or urinary tract infections, might contribute more to the clinical manifestation than genotype.
Urinary uracil concentrations are a useful guide to genetic disorders associated with neurological deficits and abnormal pyrimidine metabolism
Authors: Davies P.M. , Fairbanks L.D. , Dulby J.A. , Simmonds H.A.
Published: December 2002

Elevated urinary uracil concentrations are characteristic of genetic deficiencies of enzymes catalysing the first two steps of the pyrimidine degradative pathway (Van Gennip et al 1993), dihydropyrimidine dehydrogenase (DPD) and dihydropyrimidinase (DHP). DPD is rate limiting for the whole pathway. Homozygotes are detected by the raised levels of uracil and thymine in urine. The pyrimidine synthetic route shares a common intermediate. carbamoyl phosphate, with the urea cycle. In urea‐cycle disorders such as ornithine carbamoyltransferase (OCT) deficiency, orotic aciduria resulting from an increased flux through the pathway has been used to detect hemizygotes or carriers following a protein, or more recently, an allopurinol load (Sebesta et al 1994). This paper demonstrates that uracil may be an even more useful guide to OCT carrier status and compares urinary uracil with concentrations found in genetic pyrimidine defects associated with neurological deficits.
Inherited metabolic diseases affecting the carrier
Authors: Endres W.
Published: December 2002

The objective of this review is to draw attention to those inherited metabolic traits which are potentially harmful also for the carrier, and to outline preventive measures, at least for obligate heterozygotes, i.e. parents of homozygous children. Concerning carriers of food‐dependent abnormalities, early vascular disease in homocystinuria, hyperammonaemic episodes in ornithine transcarbamylase deficiency, presenile cataracts in galactosaemia as well as galactokinase deficiency, spastic paraparesis in X‐linked adrenoleukodystrophy, and HELLP syndrome in mothers of babies with long‐chain 3‐hydroxyacyl‐coenzyme A dehydrogenase deficiency have to be mentioned. In the group of food‐independent disorders, clinical features in carriers may be paraesthesias and corneal dystrophy in Fabry disease, lens clouding in Lowe syndrome, lung and/or liver diseases in α1‐antitrypsin deficiency, and renal stones in cystinuria type II and III. Finally, two monogenic carrier states are known which in pregnant indi‐viduals could possibly afflict the developing fetus, i.e. heterozygosity for galactosaemia and for phenylketonuria. Elevated levels of galactose‐1‐phosphate have been found in red blood cells of infants heterozygous for galactosaemia born to heterozygous mothers. Aspartame in very high doses is reported to increase blood phenylalanine levels in heterozygotes for phenylketonuria, thus being a risk for the fetus of a heterozygous mother. For some of these carrier states preventive measures can be recommended, e.g. restriction of lactose in parents and heterozygous grandparents of children with galactosaemia and galactokinase deficiency as well as transiently in infants heterozygous for galactosaemia, dietary supplementation with monounsaturated fatty acids in symptomatic carriers for X‐linked adrenoleukodystrophy, avoidance of smoking and alcohol in heterozygotes for α1‐antitrypsin deficiency, avoidance of episodes of dehydration in heterozygotes for cystinuria, and restriction of aspartame in p regnant women.
Methylmalonic acidaemia with bilateral globus pallidus involvement: A neuropathological study
Authors: Larnaout A. , Mongalgi M. A. , Kaabachi N. , Khiari D. , Debbabi A. , Mebazza A. , Ben Hamida M. , Hentati F.
Published: December 2002

A 16‐month‐old boy was hospitalized because of a 1‐day history of severe ketoacidosis with lethargy, hypotonia, vomiting, and important dyspnoea. Organic acid assay by gas chromatography–mass spectrometry confirmed the diagnosis of methylmalonic acidaemia (MMA). On the sixteenth day, he developed an acute extrapyramidal disorder. The CT scan of the brain disclosed bilaterally symmetric lucency of basal ganglia. He died at 17 months of age. Post‐mortem neuropathological examination, showed severe necrosis with spongiosis, cystic cavitation and numerous lipid‐laden macrophages of the globi pallidi, and mild spongiosis of subthalamic nuclei, mammillary bodies, portion of internal capsule adjacent to globus pallidus, superior cerebellar peduncles and tegmentum of brainstem. Pallidal infarction, a focal ischaemic lesion, demonstrates that ischaemia/energy depletion may be important in the etiology of the neuropathology of MMA.
Bone marrow transplantation for Maroteaux–Lamy syndrome (MPS VI): Long‐term follow‐up
Authors: Herskhovitz E. , Young E. , Rainer J. , Hall C. M. , Lidchi V. , Chong K. , Vellodi A.
Published: December 2002

We describe the results of bone marrow transplantation (BMT) in four patients with mucopolysaccharidosis type VI (MPS VI, McKusick 253200) – Maroteaux–Lamy disease. The indications for transplantation were cardiomyopathy in three patients and severe obstructive sleep apnoea in one. The follow‐up period ranges between 1 and 9 years, and three of the patients are at mainstream schools. In all of the patients the facial features have become less coarse and the cardiac manifestations have improved or remained stable. However, skeletal changes have persisted or even progressed, although posture and joint mobility have improved and all the patients have remained ambulatory and active. BMT appears to prolong survival and improve the quality of life in MPS VI patients, but careful selection of patients is essential.