bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of chronic congenital lactic acidosis by oral administration of dichloroacetate
Authors: Kuroda Y. , Ito M. , Toshima K. , Takeda E. , Naito E. , Hwang T. J. , Hashimoto T. , Miyao M. , Masuda M. , Yamashita K. , Adachi T. , Suzuki Y. , Nishiyama K.
Published: June 2005

Sodium dichloroacetate (DCA) was administered orally at a dose of 50 mg per kg body weight twice or three times per day to a newborn infant with lactic acidosis of unknown cause (patient 1) and to a 15‐year‐old boy with mitochondrial encephalomyopathy associated with lactic acidosis (patient 2). In patient 1, during treatment with DCA, DCA accumulated in the blood judging from the findings that the urinary excretion of DCA increased cumulatively and the blood lactate level rapidly decreased to the normal range. In patient 2, the blood DCA level gradually increased during treatment to a concentration of 250 µgml−1 and the blood lactate level decreased and was maintained within the normal range. DCA was detected in the brain (25 µg g tissue−1) and the liver, kidney and muscle (33.8, 33.8 and 26.3 µg g tissue−1, respectively) obtained at autopsy of patient 1, and in the cerebrospinal fluid of patient 2 at a concentration of 125 µg ml−1 when the blood concentration was 250 µg ml−1. The lactate levels in the cerebrospinal fluid decreased from 7 and 4mmoll−1 to 2.4 and 2.6 mmoll−1 in patients 1 and 2, respectively. Thus DCA may be useful in clinical treatment of chronic congenital lactic acidosis because it seems to cross the blood‐brain barrier. However, it must be given at non‐toxic doses, determined by monitoring the concentrations of lactate and DCA in the blood, because orally administered DCA tends to accumulate in tissues.
Kinetic abnormalities of carbamyl phosphate synthetase‐I in a case of congenital hyperammonaemia
Authors: Qureshi I. A. , Letarte J. , Ouellet R. , Lemieux B. , Cathelineau L.
Published: June 2005

A sensitive direct colourimetric method has been employed to measure kinetic parameters and pH dependence of carbamyl phosphate synthetase‐I, in a liver sample from a 2 1/2‐month‐old girl, who died from complications of a late‐developing congenital hyperammonaemia. The residual activity of carbamyl phosphate synthetase‐I was 25%, whereas other urea cycle enzymes were within normal range. ApparentKm for ammonium ion (0.73 mmol/L) was significantly increased (normal range 0.24–0.51).Km for bicarbonate ion was normal, whileKm for NAG showed a slight variation from normal. The pH dependence curve of the patient's enzyme was flat, as compared to two controls showing pH optima at 7.8. Radial immunodiffusion (Mancini) of the abnormal enzyme against human enzyme antiserum gave a cross‐reacting material of 10–20%. The methodological approach presented can be used to characterize abnormal enzymes in cases of partial deficiency with only 100–200 mg of liver tissue.
Lysosomal protein degradation in experimental hyperphenylalaninaemia
Authors: Schröter J. , Schott K. ‐J. , Purtill M. ‐A. , Neuhoff V.
Published: June 2005

The influence of α‐methylphenylalanine‐induced hyperphenylalaninaemia (HYP) on the lysosomal protein degradation system in brain and liver of suckling rats was investigated. In both tissues cathepsind andl activities, measured at 5, 10 and 15 days post partum (p.p.), exhibited no differences between experimental and control animals.N‐Acetyl‐β‐d‐glucosaminidase (NAGase) activity in brain, measured at 10 and 15 days p.p., was not affected by HYP either. The release of valine and lysine from liver and brain homogenates respectively, serving as a measure for the lysosomal content of degradable proteins, was not influenced by HYP. Lysosomal integrity during incubation of homogenate was monitored by the recovery of NAGase activity in the cytosolic supernatant, and by the relative NAGase activity in total homogenates in the absence of the lysosome disrupting detergent Triton X‐100. In conclusion, experimental HYP appears unlikely to influence the lysosomal protein degradation system in brain and liver of suckling rats.
On the mechanism ofl‐alloisoleucine formation: Studies on a healthy subject and in fibroblasts from normals and patients with maple syrup urine disease
Authors: Schadewaldt P. , Hammen H. ‐W. , Dalle‐Feste C. , Wendel U.
Published: June 2005

l‐Alloisoleucine formation froml‐isoleucine was studiedin vitro andin vivo. When a healthy subject was loaded withl‐isoleucine, plasma levels ofl‐isoleucine and 3‐methyl‐2‐oxopentanoate (KMV), as well asl‐alloisoleucine, increased. Peak values were reached successively and were in the orderl‐isoleucine > > KMV > >l‐alloisoleucine. Metabolic clearance ofl‐isoleucine and KMV was rapid; clearance ofl‐alloisoleucine was considerably delayed. When human skin fibroblast cultures were challenged withl‐isoleucine, KMV accumulated at a gradually decreased rate, whereasl‐alloisoleucine accumulated at a gradually accelerated rate. KMV andl‐alloisoleucine formation were related and depended on thel‐isoleucine concentration applied. In cell lines derived from MSUD patients (classical form), metabolite formation was only about 2‐fold higher than in control strains. The relatively small difference between normal and MSUD fibroblastsin vitro as opposed to the striking differences between healthy subjects and MSUD patientsin vivo are discussed with respect to the significance of physiological mechanisms participating in the formation and degradation ofl‐alloisoleucine in man.
The effect of plasma valine, isoleucine and leucine on the control of the flux through tyrosine‐ and tryptophan‐hydroxylase in the brain
Authors: Hommes F. A. , Lee J. S.
Published: June 2005

The effect of increasing blood levels of valine, isoleucine and leucine on the fluxes through tyrosine and tryptophan hydroxylase in brain has been calculated and analysed in terms of flux control coefficients. It is concluded that any beneficial effect of increasing the concentration of these amino acids in phenylketonuria patients is not due to a decrease in brain phenylalanine or an improved neurotransmitter synthesis through tyrosine or tryptophan hydroxylase.
Quantitative analysis of disaccharides in the urine ofβ‐mannosidosis patients
Authors: Tjoa S. , Wenger D. A. , Fennessey P. V.
Published: June 2005

Until recently, there have not been any confirmed reports ofβ‐mannosidase deficiency in man. We have now analysed urine from two patients with confirmedβ‐mannosidase deficiency and have found Man‐β(1–4)GlcNAc concentrations of 65 and 73 mg/mmol creatinine. These levels are at least 12 times higher than those found in patients with other lysosomal storage diseases. The method we report for this analysis requires only 0.1 ml of urine and uses a gas chromatograph, area ratio, calibration curve for the quantitative analysis.
Muscle cell cultures in Menkes' disease: Copper accumulation in myotubes
Authors: van den Berg G. J. , Kroon J. J. , Wijburg F. A. , Sinjorgo K. M. C. , Herzberg N. H. , Bolhuis P. A.
Published: June 2005

We present64Cu uptake studies in cultured muscle cells from a one‐year‐old patient with Menkes' disease. The cultured muscle cells from the patient showed a five‐fold higher64Cu uptake than control muscle cells. Copper uptake in muscle cells was of the same magnitude as that found in fibroblasts from the patient and also from other Menkes' patients. The copper content of a muscle biopsy from the patient was twice that of a control biopsy. The enhanced uptake is probably copper specific, since zinc uptake was unaltered in both muscle cells and fibroblasts from the patient.

Cytochrome c oxidase in the muscle of the patient was reduced to one‐third of the value for controls, which is in agreement with the hypothesis that in Menkes' disease copper accumulates in a biologically non‐active form. However, in cultured muscle cells and fibroblasts from the patient the cytochrome c oxidase activity was in the normal range, probably because of the relatively large amount of copper already available in the culture medium.
Gyrate atrophy of the choroid and retina: 3 cases in one Italian family
Authors: Fois A. , Borgogni P. , Cioni M. , Mancini G. M. S. , Molinelli M. , Pizzetti M. , Bardelli A. M. , Biangini L. , Barberi L. , Malpassi C. , Harms E. , Kleijer W. J.
Published: June 2005

Conclusions

Our study reports the first comprehensive evaluation of HOGA in an Italian family, and is thus intended to alert Italian ophthalmologists and paediatricians to this potentially treatable condition in children with even apparently mild visual disturbances. The typical fundoscopic findings make diagnosis possible. Extensive epidemiological investigations could be justified to determine the incidence of this disorder in Italy.
Four cases of hyperphenylalaninaemia: Studies during pregnancy and of the offspring produced
Authors: Koch R. , Blaskovics M.
Published: June 2005

Four cases of variant hyperphenylalaninaemia during pregnancy are presented. Babies born to mothers with blood phenylalanine concentrations of 4–8 mg/dl were normal and did not exhibit significant microcephaly, although one did have a major congenital anomaly (exstrophy of the bladder). The mother with blood phenylalanine concentrations of 6–12 mg/dl during pregnancy delivered three of four infants with mild microcephaly but normal intellectual function. The data suggest that phenylalanine concentrations of 4–8 mg/dl are reasonable and desirable during pregnancy in hyperphenylalaninaemic women. Furthermore, the data do not support or refute the justification hypothesis of Bessmanet al.
The use of deuterated phenylalanine for thein vivo assay of phenylalanine hydroxylase activity in children
Authors: Matalon R. , Matthews D. E. , Michals K. , Bier D.
Published: June 2005

Fifteen children, five with phenylketonuria (PKU), five with hyperphenylalaninaemia, and five phenotypically normal but at risk of being carriers for PKU, were given [ring2H5]phenylalanine orally in amounts ranging from 75 mg/kg to 10 mg/kg. Plama was assayed for [2H5]phenylalanine and [2H4]tyrosine at hourly intervals, the amino acids being measured as theN‐acetyl, n‐propyl esters by gas chromatography‐mass spectroscopy. The results obtained were calculated as the log of the ratio [2H5]phenylalanine: [2H4]tyrosine in the plasma. The five patients with PKU had ratios of infinity because no [2H4]tyrosine was measured in their plasma during the experimental period. The patients with hyperphenylalaninaemia had log ratios over 2.00 throughout the assay period. Among the five normal children three are considered to be carriers for PKU as the logarithms of the [2H5]phenylalanine: [2H4]tyrosine ratios were 1.77, 1.73, and 1.33 and remained over 1.00 during the assay period. The other children had log ratios of 1.16 and 1.00 at the first hour which dropped below 1.00 subsequently, suggesting normal activity of phenylalanine hydroxylase.
Standardized loading test with protein for the differentiation of phenylketonuria from hyperphenylalaninaemia
Authors: Lutz P. , Schmidt H. , Frey G. , Bickel H.
Published: June 2005

Eighty‐nine protein‐loading tests were performed in 80 patients with an increased blood phenylalanine concentration. The amount of protein corresponding to 0.18g phenylalanine/kg body weight per day was calculated and given for 3 days, during which time eight phenylalanine and eight tyrosine blood concentrations were determined. Nine numerical evaluations were checked for discrimination between phenylketonuria and hyperphenylalaninaemia. The two most powerful discriminants were the phenylalanine blood concentration after 72 hours (sample taken in the morning of the 4th day after the beginning of the load) with a limit value of 15 mg/dl (0.91 mmol/l), and the mean value of the 5th to 8th phenylalanine values, also with a limit value of 15 mg/dl. In only eight of the 80 patients would the final diagnosis not have been established by the loading test.
Organic aciduria in neonatal multiple carboxylase deficiency
Authors: Sweetman L. , Nyhan W. L. , Sakati N. A. , Ohlsson A. , Mange M. S. , Boychuk R. B. , Kaye R.
Published: June 2005

A Samoan patient and a Saudi‐Arabian patient were found to have abnormalities in the pattern of organic acid metabolites characteristic of 3‐methylcrotonylglycinuria, propionic acidaemia and lactic acidosis. Both patients died early in life. The metabolic pattern is diagnostic of multiple carboxylase deficiency and an enzymatic diagnosis was made in a subsequent affected sibling of the first patient. Deficiency of the three carboxylases suggests a primary defect in the metabolism of biotin which is required for their activity. The importance of the recognition of the clinical picture is highlighted by the fact that this lethal disease is readily treated with biotin. These patients have prominent skin lesions which can serve as alerting signs for the diagnosis.
Normal 2‐aminobutyrate oxidation and increased valine oxidation in fibroblasts deficient in pyruvate dehydrogenase
Authors: Borud O. , Pettersen J. E.
Published: June 2005

Human skin fibroblasts deficient in pyruvate dehydrogenase and five normal control strains were incubated with one of the following labelled substrates:dl‐[1‐14C]‐2‐amino‐n‐butyric acid,dl‐[3‐14C]‐2‐amino‐n‐butyric acid,dl‐[1‐14C]leucine,l‐[1‐14C]valine,l‐[1‐14C]alanine, and [1‐14C]pyruvate. The rate of14CO2‐production in the deficient cells was normal from 2‐aminobutyrate and leucine, increased from valine, and decreased from alanine and pyruvate. These results indicated that in human skin fibroblasts the decarboxylation of 2‐oxobutyrate is catalysed by an enzyme system different from the pyruvate dehydrogenase complex.
In vivo disposal of phenylalanine in phenylketonuria: A study of two siblings
Authors: Treacy E. , Pitt J. J. , Seller K. , Thompson G. N. , Ramus S. , Cotton R. G. H.
Published: June 2005

Mutation at the phenylalanine hydroxylase (PAH) locus is a cause of hyperphenylalaninaemia. Genotype‐phenotype correlation relative to the predicted PAH activity may differ at the metabolite level and at the IQ level in untreated phenylketonuria. Discordant metabolic phenotypes have been noted in siblings; influences on transport and metabolism of phenylalanine determining homeostasis may account for differing metabolic phenotypes. We report two siblings of different sex and identical genotype at the PAH locus who demonstrate a difference in phenylalanine disposal. A stable isotope infusion of [2H5]phenylalanine was used to measure protein turnover, phenylalanine hydroxylation and excretion of phenylalanine transamination metabolites. The siblings were observed to have identical hydroxylation rates under the experimental conditions of the study while manifesting differences in renal excretion rates of phenylalanine transamination metabolites and protein accretion.
A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency
Authors: Vreken P. , Van Kuilenburg A. B. P. , Meinsma R. , Smit G. P. A. , Bakker H. D. , De Abreu R. A. , van Gennip A. H.
Published: June 2005

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterized by thymine‐uraciluria and associated with a variable clinical phenotype. In order to identify the molecular defect underlying complete DPD deficiency in a Dutch patient previously shown to have a 165 base pair deletion in the mature DPD mRNA, we cloned the genomic region encompassing the skipped exon and its flanking intron sequences. Sequence analysis revealed that the patient was homozygous for a single G→A point mutation in the invariant GT dinucleotide splice donor site downstream of the skipped exon. The same mutation was identified in another, unrelated, Dutch patient. Because this mutation destroys a uniqueMaeII restriction site, rapid screening using restriction enzyme cleavage of the amplified genomic region encompassing this mutation is possible. Analysis of 50 controls revealed no individuals heterozygous for this mutation
Bone marrow involvement and obstructive jaundice in Farber lipogranulomatosis: clinical and autopsy report of a new case
Authors: Nowaczyk M. J. M. , Feigenbaum A. , Silver M. M. , Callahan J. , Levin A. , Jay V.
Published: June 2005

We report a case of Farber lipogranulomatosis in a girl with hepatosplenomegaly, macular cherry‐red spot, and subcutaneous nodules who developed liver dysfunction with jaundice and ascites, and myelophthisic anaemia because of infiltration of bone marrow with storage cells. Acid ceramidase assay confirmed the diagnosis. We conclude that the bone marrow dysfunction and cherry‐red spot are features of type IV Farber lipogranulomatosis that have not been previously recognized, and should be added to the clinical phenotypic description.
NADH‐coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings
Authors: Pitkanen S. , Feigenbaum A. , Laframboise R. , Robinson B. H.
Published: June 2005

Twelve patient cell lines with biochemically proven complex I deficiency were compared for clinical presentation and outcome, together with their sensitivity to galactose and menadione toxicity. Each patient had elevated lactate to pyruvate ratios demonstrable in fibroblast cultures. Each patient also had decreased rotenone‐sensitive NADH‐cytochromec reductase (complexes I and III) with normal succinate cytochromec reductase (complexes II and III) and cytochrome oxidase (complex IV) activity in cultured skin fibroblasts, indicating a deficient NADH‐coenzyme Q reductase (complex I) activity. The patients fell into five categories: severe neonatal lactic acidosis; Leigh disease; cardiomyopathy and cataracts; hepatopathy and tubulopathy; and mild symptoms with lactic acidaemia. Cell lines from 4 out of the 12 patients were susceptible to both galactose and menadione toxicity and 3 of these also displayed low levels of ATP synthesis in digitonin‐permeabilized skin fibroblasts from a number of substrates. This study highlights the heterogeneity of complex I deficiency at the clinical and biochemical level.
Neutral lipid storage disease with ichthyosis: Lipid content and metabolism of fibroblasts
Authors: Williams M. L. , Monger D. J. , Rutherford S. L. , Hincenbergs M. , Rehfeld S. J. , Grunfeld C.
Published: June 2005

Neutral lipid storage disease with ichthyosis is a newly recognized heritable disorder characterized by widespread cellular triglyceride storage. Lipid metabolism in fibroblasts cultured from three affected family members was studied. The stored lipid is triglyceride composed of an unremarkable fatty acid profile and derived from both exogenously‐supplied and endogenously‐synthesized fatty acids. Lipid storage could not be corrected by prolonged culture in lipid‐depleted media. Acetyl CoA carboxylase activity and β‐oxidation of palmitate were both normal. Taken together, these studies exclude a primary defect of fatty acid uptake, over‐synthesis or impaired β‐oxidation. Moreover, triacylglycerol lipase activity of homogenates of fibroblasts from patients with NLSDI examined over the range of pH 3.5–8.5 was normal.
Group work with adolescent PKU girls and their mothers
Authors: Cohen B. E. , Weiss R. , Hadar R. , Normand M. , Shiloh S. , Elhanati D.
Published: June 2005

Group therapy was the method chosen for working with PKU girls and their mothers in improving their knowledge of maternal PKU and the prevention of unplanned pregnancies. It was found effective in relieving anxiety, and the importance of including the mothers in the group was critical.
Rapid diagnosis of medium‐chain acyl CoA dehydrogenase deficiency by measurement ofcis‐4‐decenoic acid in plasma
Authors: Heales S. J. R. , Woolf D. A. , Robinson P. , Leonard J. V.
Published: June 2005

Plasma concentrations of octanoate andcis‐4‐decenoate were measured by gas chromatography‐mass spectrometry in children with deficiencies of medium‐chain acyl‐CoA dehydrogenase (MCAD), long‐chain 3‐hydroxyacyl‐CoA dehydrogenase (3LHAD) and multiple acyl‐CoA dehydrogenase (MAD) deficiency. Children receiving medium‐ and long‐chain lipid supplements were also studied. Octanoate was elevated in all but one of the children with MCAD deficiency, in MAD deficiency and in children receiving medium‐chain triglyceride supplementation.Cis‐4‐decenoate was only elevated in MCAD and MAD deficiency. It is concluded that measurement of plasmacis‐4‐decenoate provides a sensitive and specific test for defects of medium‐chain acyl CoA dehydrogenase.
N‐acetylglutamate synthetase deficiency: Clinical and laboratory observations
Authors: Pandya A. L. , Koch R. , Hommes F. A. , Williams J. C.
Published: June 2005

Two male siblings presented in the first 6 weeks of life with emesis, diarrhoea, metabolic acidosis and lethargy. A male sibling had previously died at 14 months of age from liver failure of unknown aetiology. Both of the current cases had mild hyperammonaemia with normal orotic acid, organic acid and argininosuccinic acid levels. Citrulline and arginine levels were normal or mildly decreased. One of the brothers was biopsied and had no detectableN‐acetylglutamate synthetase activity and normal values for other enzymes of the urea cycle in liver. Treatment with a low‐protein diet and sodium benzoate/sodium phenylacetate resulted in near normal blood ammonia levels, except during viral illness. Subsequent neurological development has been normal to mildly delayed. These patients differ from those previously decribed withN‐acetylglutamate synthetase deficiency in that their presentation and subsequent course were relatively benign.
Possible deleterious effect ofL‐carnitine supplementation in a patient with mild multiple acyl‐CoA dehydrogenation deficiency (ethylmalonic‐adipic aciduria)
Authors: Green A. , Preece M. A. , de Sousa C. , Pollitt R. J.
Published: June 2005

A patient with riboflavin‐responsive mild multiple acyl‐CoA dehydrogenation deficiency of the ethylmalonic‐adipic aciduria type experienced a recurrence of spontaneous hypoglycaemic episodes whilst being given supplementaryL‐cartinine. This phenomenon is explicable in terms of the known biochemical features of this condition and suggests caution in the carnitine supplementation of patients with defective oxidation of medium‐ or short‐chain fatty acyl‐CoA esters. This patient excreted excessive phenylpropionylglycine after an oral phenylpropionic acid load. Thus the phenylpropionic acid loading test is not completely specific for primary medium‐chain acyl‐CoA dehydrogenase deficiency as has been supposed.
Biochemical characterization of β‐hexosaminidase in different biological specimens from eleven patients with GM2‐gangliosidosis B1 variant
Authors: Ribeiro M. G. , Pinto R. A. , Dos Santos M. R. , Maia M. , Sá Miranda M. C.
Published: June 2005

GM2‐gangliosidosis B1 variant is thought to be a rare disorder with a wide geographical and ethnic distribution. We report the biochemical findings obtained in different specimens from a group of 11 B1 variant patients originating from the north of Portugal. The biochemical data obtained seem to indicate that only one of these patients is a genetic compound presenting a clinical and biochemical pattern similar to the majority of B1 variant patients described in the literature, but somewhat different from the profile presented by the other patients reported here, who are homozygous for the ‘DN‐allele’.
Heterozygous carriers of classical phenylketonuria in a sample of the turkish population: Detection by a spectrofluorimetric method
Authors: Güneral F. , Özalp İ. , Tatlidil H.
Published: June 2005

Blood obtained by finger prick from 209 presumed normal homozygotes and 42 heterozygotes for classical PKU was analysed for plasma phenylalanine (Phe) and tyrosine (Tyr) by a fluorimetric method. Subjects were tested near midday and 3 hours after a protein‐rich breakfast. The plot of Phe/Tyr (micromolar ratio) against Phe2/Tyr, permitted the detection of 11 heterozygotes among 209 controls. The accuracy of this method was checked by computation of a stepwise multivariate discriminant analysis, using Phe and Tyr (µmol/L), Phe/Tyr micromolar ratio and Phe2/Tyr as variables. Ten of the 11 subjects were recovered with a percentage of correct classification of over 90%, while one case had a percentage of 89.45%. The PKU gene frequency was found to be 1/19. This emphasizes the importance of a screening programme for PKU gene carrier status in Turkey.
Agoraphobia in phenylketonuria
Authors: Waisbren S. E. , Levy H. L.
Published: June 2005

We describe agoraphobia as a complication of phenylketonuria (PKU) in young adults. The five patients have classic PKU and received phenylalanine‐restricted diet only in childhood. Only one has normal intelligence. All but one were also depressed. All were anxious. Three of the five had initiated the phenylalanine‐restricted diet after 3 months of age. Two returned to the phenylalanine‐restricted diet with dramatic reduction of symptoms.

The frequency of manifestations of agoraphobia was also examined in 50 young women with PKU enrolled in a longitudinal study of psychosocial factors in maternal PKU, 47 of their acquaintances and 49 women with diabetes. All were administered a test of agoraphobic‐avoidant behaviour. The women with PKU appeared to be more prone to social withdrawal and fear of leaving home. Twenty per cent were within the agoraphobia range of the Mobility Inventory. Those still on diet and those with non‐PKU hyperphenylalaninaemia reported less avoidant behaviour than those who had terminated the diet in childhood.

These results suggest that young adults with PKU are at risk for agoraphobia but that return to the phenylalanine‐restricted diet may be an effective treatment.
Registers for inherited metabolic diseases
Authors: Holton J. B.
Published: June 2005

The use of a register for inherited metabolic diseases has many potential benefits, but it is particularly important to define clear objectives, to ensure that the design of the register should allow these objectives to be achieved and to take account of the many problems which may be encountered. The possibility that there may be alternative ways of achieving the same results should be considered.
Analbuminaemia: a natural model of metabolic compensatory systems
Authors: Baldo‐Enzi G. , Baiocchi M. R. , Vigna G. , Andrian C. , Mosconi C. , Fellin R.
Published: June 2005

Important clinical signs are usually not present in analbuminaemia, a congenital condition inherited as an autosomal recessive trait, but several biochemical alterations in proteins, cholesterol, phospholipids and plasma beta lipoproteins have been observed.

We studied two sibs, R.U. and R.R., with this disease and observed a striking increase in the variables mentioned above as well as a high LDL fraction with concomitant increase in apo B; increases in HDL3 and apo A‐I and A‐II levels were also observed. The lipoproteins, however, were not altered in morphology but showed a slight increase in lipid/protein ratio. Post‐heparin lipolytic activity was normal in the male patient and reduced in the female while LCAT enzyme activity instead was increased in both. Fatty acids bound to phospholipids and serum cholesterol were mostly monounsaturated. Free fatty acid concentration was normal and they appeared mostly bound to the LDL and HDL3 fractions, which are increased in this disease and appear to replace albumin in one of its main carrier functions.
Galactose metabolism in transferase‐deficient galactosaemic and normal long‐term lymphoid cell lines
Authors: Beratis N. G. , Wilbur L.
Published: June 2005

The activity (mean±SD) of galactose‐1‐phosphate uridyl transferase in two long‐term lymphoid cell lines from Caucasian patients with transferase deficiency galactosaemia, a heterozygote, and eight normal subjects was 0, 78 and 168±55 nmol UDPG consumed (mg protein)−1h−1, respectively. Also, no activity was found in erythrocytes and cultured fibroblasts from the patients. A small number of cells of the galactosaemic lines cultured in medium, in which galactose was substituted for glucose, survived for 37 days. Normal and galactosaemic lines incubated withD‐galactose‐[1‐14C] liberated 218.2±65.6 and 18.1 pmol14CO2 (mg cellular protein)−1 (6h)−1, respectively. The evolution of14CO2 fromD‐glucose‐[1‐14C] was similar in normal and galactosaemic lines. In the presence of [3H] galactose the radioactivity incorporated into TCA‐precipitated material of the galactosaemic lines was 6.8% of the normal lines. Approximately 26% and 1.3% of the total radioactivity was incorporated into molecular species with a molecular weight greater than 400000 daltons in normal and galactosaemic cells, respectively. Similar molecules were identified in the cell‐free medium of both normal and deficient cells except for an 18000 daltons molecule identified only in the medium of the normal cells. These findings indicate that a small amount of galactose is metabolized in galactosaemic lines with no transferase activity.
Intermittent hypermethioninaemia associated with normal hepatic methionine adenosyltransferase activity: Report of a case
Authors: Jhaveri B. M. , Buist N. R. M. , Gaull G. E. , Tallan H. H.
Published: June 2005

A 5‐month‐old infant was found to have hypermethioninaemia (0.8 µmol/ml) that has persisted intermittently (0.02–1.3 µmol/ml) over a period of 3 years. She presented with developmental delay and failure to thrive associated with gross abuse and neglect. Histological examination of the liver revealed inflammation of the portal triads. The activity of hepaticl‐methionine‐S‐adenosyltransferase (EC 2.5.1.6) was normal. Whether the biochemical findings were the cause or the result of the hepatic damage is uncertain, but the minimal histological findings in the liver suggest a primary biochemical defect.
Isovaleric acidaemia presenting with dwarfism, cataract and congenital abnormalities
Authors: Duran M. , Bruinvis L. , Ketting D. , Wadman S. K. , van Pelt B. C. , Batenburg‐Plenter A. M.
Published: June 2005

Isovaleric acidaemia was diagnosed in a 9‐year‐old girl with an unusual clinical presentation. She was severely mentally retarded, had an extreme growth retardation, bilateral cataracts, multiple fractures of the long bones, vitium cordis and malformations of the head. Frequent infections occurred since early childhood. The relevance of these findings is discussed.
Allopurinol challenge test in children
Authors: Burlina A. B. , Ferrari V. , Dionisi‐Vici C. , Bordugo A. , Zacchello F. , Tuchman M.
Published: June 2005

The allopurinol challenge test was performed on 44 healthy subjects (28 children and 16 adolescents) in order to establish normal values of urinary orotic acid excretion following allopurinol ingestion in the paediatric population. The subjects were divided into three groups according to their age: 6 months to 6 years; 6 years to 10 years; and 10 years to 17 years. They were given 100 mg, 200 mg, or 300 mg of allopurinol, respectively (based on age) in a single oral dose. Maximum peak urinary orotic acid levels following ingestion of allopurinol were 13.0 (n=14), 9.3 (n=14), and 10.2 (n=16) µmol/mmol creatinine in the three groups, respectively. In all children tested the peak orotic acid level was 3.1±2.7 µmol/mmol creatinine (mean ± SD,n=44). This allopurinol challenge test was also performed in six children with ureacycle disorders, including five females with ornithine transcarbamylase (OTC) deficiency, all of whom demonstrated abnormally elevated levels of urinary orotic acid (peak levels of 26–134 µmol/mmol creatinine) following allopurinol ingestion.
Fructose and glucagon loading in siblings with fructose‐1,6‐diphosphatase deficiency in fed state
Authors: Nagai T. , Yokoyama T. , Hasegawa T. , Tsuchiya Y. , Matsuo N.
Published: June 2005

Hypoglycaemia induced by fructose administration is one of the diagnostic clues to fructose‐1,6‐diphosphatase (FDPase) deficiency (McKusick 229700). However, the pathological mechanism of this reactive hypoglycaemia is not fully known. This paper describes two siblings with FDPase deficiency, diagnosed enzymatically in leukocytes, who failed to correct reactive hypoglycaemia after glucagon administration even in the fed state, supporting a possibility that disturbed hepatic phosphorylase activity may be a main cause of reactive hypoglycaemia.
In vivo13C‐NMR evaluation of glycogen content in a patient with glycogen storage disease
Authors: Labrune Ph. , Jehenson Ph. , Syrota A. , Odièvre M.
Published: June 2005

Glycogen storage disease was suspected in a 10‐month‐old boy. Initial technical problems did not permit the determination of the precise enzyme deficiency, and type VI glycogen storage disease was only diagnosed at the age of 2 years. In the mean time, natural abundance13C nuclear magnetic resonance evaluation of muscular and hepatic glycogen content indicated normal muscular glycogen and increased hepatic glycogen in our patient, a finding which strongly argued for the diagnosis of type VI glycogen storage disease. Even though the use of nuclear magnetic resonance might seem, in this situation, a somewhat circuitous means of reaching the diagnosis, it appears that nuclear magnetic resonance could provide a useful tool for a non‐invasive diagnosis of glycogen storage diseases.
Mevalonate kinase assay using DEAE‐cellulose column chromatography for first‐trimester prenatal diagnosis and complementation analysis in mevalonic aciduria
Authors: Hoffmann G. F. , Brendel S. U. , Scharfschwerdt S. R. , Shin Y. S. , Speidel I. M. , Gibson K. M.
Published: June 2005

Mevalonic aciduria due to mevalonate kinase deficiency, an inherited defect of cholesterol biosynthesis, has presented with clinical variability in 10 patients from 7 families. We sought to define a genetic basis for this heterogeneity by determining mevalonate kinase activity in fibroblast heterokaryons obtained by polyethylene glycol fusion. To this end we developed a DEAE‐cellulose (Cl−) column chromatography procedure for assessing mevalonate kinase in cell extracts that would allow multiple rapid analyses. Fusion of control fibroblasts with those from affected patients from six families with mevalonate kinase deficiency yielded 37% of the mean control activity. None of the fusions between the six cell lines of patients resulted in measurable mevalonate kinase activity. Using the chromatographic procedure, we developed an optimized assay for mevalonate kinase in biopsied chorionic villi.Km values for chorionic villi were similar to those obtained in fibroblasts. Mevalonate kinase activity in biopsied chorionic villi showed a linear increase (0.75–4.3 nmol/min per mg protein) with gestational age from 7 to 14 weeks. Using the optimized assay in biopsied chorionic villi we performed a first‐trimester prenatal diagnosis in a pregnancy at risk for mevalonate kinase deficiency and correctly diagnosed an unaffected fetus. The availability of an optimized assay for mevalonate kinase in biopsied chorionic villi should allow reliable first‐trimester prenatal diagnosis for families at risk.
Elevated plasma carnitine in the hepatic form of carnitine palmitoyltransferase‐1 deficiency
Authors: Stanley C. A. , Sunaryo F. , Hale D. E. , Bonnefont J. ‐P. , Demaugre F. , Saudubray J. ‐M.
Published: June 2005

In a boy with a defect in fatty acid oxidation due to the hepatic form of carnitine palmitoyltransferase‐1 deficiency, plasma carnitine concentrations were found to be twice normal. The elevation in plasma carnitine levels was accompanied by an unusually high renal threshold for free carnitine, suggesting a secondary increase in carnitine transport. Similar to other fatty acid oxidation disorders involving the carnitine cycle, urinary dicarboxylic acids were not abnormally elevated during illnesses. The combination of elevated plasma carnitine levels and absence of dicarboxylic aciduria may help to distinguish the hepatic form of carnitine palmitoyltransferase‐1 deficiency from other defects in fatty acid oxidation.
Phosphorylase kinase in leukocytes and erythrocytes of a patient with glycogen storage disease type IX
Authors: Bashan N. , Potashnik R. , Ehrlich T. , Moses S. W.
Published: June 2005

A variant form of phosphorylase kinase deficiency is described and studied using erythrocyte and leukocyte enzyme activities.
N‐acetylaspartic aciduria due to aspartoacylase deficiency — a new aetiology of childhood leukodystrophy
Authors: Hagenfeldt L. , Bollgren I. , Venizelos N.
Published: June 2005

We describe a male infant with psychomotor retardation and leukodystrophy who excretes large quantities ofN‐acetylaspartate in his urine. A high CSF/plasma concentration ratio ofN‐acetylaspartate indicates that this substance originates in the brain. Fibroblasts from the patient are deficient in aspartoacylase activity. It is proposed that the dysmyelination in the patient may be due to failure ofN‐acetylaspartate to serve as a carrier of acetyl groups from mitochondria to the cytosol for lipogenesis.
Adenine phosphoribosyltransferase deficiency: a case diagnosed by GC‐MS identification of 2,8‐dihydroxyadenine in urinary crystals
Authors: Christensen E. , Brandt N. J. , Laxdal T.
Published: June 2005

Light microscopy of the urinary sediment from a child suffering from urinary tract disease showed massive crystalluria. Most of the sediment consisted of characteristic round and brownish crystals. 2,8‐Dihydroxyadenine was identified in the crystals by means of gas chromatography‐mass spectrometry. The diagnosis of adenine phosphoribosyltransferase deficiency was established by the finding of a very low activity of this enzyme in erythrocytes from the patient, and of half the normal activity in the parents.

The patient was first treated with a diet low in purine and with a high liquid intake. She stayed symptomless on this regimen, but the crystalluria persisted. On low doses of allopurinol the crystalluria disappeared.
Characterization of α‐mannosidase in feline mannosidosis
Authors: Raghavan S. , Stuer G. , Riviere L. , Alroy J. , Kolodny E. H.
Published: June 2005

Acidic α‐mannosidase deficiency has been identified in a family of Blue Persian cats. Characterization of the residual activity revealed that theKm for the substrate, 4‐methylumbelliferyl‐α‐d‐mannoside, increased approximately three‐fold with a severe deficiency inVmax (1–2%) in homogenates of liver and brain of affected cats compared with controls. The residual activity at pH 4.0 in liver homogenates from affected cats is very thermolabile at 51°C while the control activity is stable at this temperature for 1h. Subcellular fractionation of liver was performed from a control and diseased cat in order to compare the properties of the different α‐mannosidases localized in these fractions. The residual activity present in the lysosomal fraction from diseased cat liver showed altered pH optimum, two‐fold increase inKm with a severely reducedVmax and increased thermolability compared with the activity in the lysosomal fraction from control liver. The thermal inactivation pattern andKm of the residual activity in the lysosomal fraction is different from the non‐lysosomal α‐mannosidase in the liver of the affected cat. This suggests that the residual activity in the lysosomal fraction of the liver from the affected cat is not due to contamination of non‐lysosomal α‐mannosidase in this fraction. Whether this residual activity represents the properties of the mutant enzyme or yet another minor normal component of lysosomes different from the major inactive mutant or absent lysosomal enzyme remains to be elucidated.
Newborn urine screening experience with over one million infants in the Quebec Network of Genetic Medicine
Authors: Lemieux B. , Auray‐Blais C. , Giguère R. , Shapcott D. , Scriver C. R.
Published: June 2005

We screened urine for chemical individuality in over 1 million newborn infants, by various chromatographic (thin‐layer), chemical and spectrophotometric methods, 12 procedures in all. The programme is part of the Quebec Network of Genetic Medicine. Voluntary urine screening began in 1971 and has evolved with changes in choice of tests and times of sample collection. Urine samples were collected on filter paper at either 5, 14 or 21 days after birth; results were best with the 21‐day test. Compliance is over 94% with the latter and over 98% with requests for repeat samples. Screening is centralized in one laboratory; follow‐up diagnosis, counselling and management are done at four regional centres. Incidence of phenotypes ranged from 1:4300 live births (for expressed cystinuria alleles) to 1 per million (for hyperargininaemia). Over 20 inherited Mendelian disorders were identified. 30 patients required aggressive medical management. We show how this programme can be used for neuroblastoma screening.
Biochemical genetics of HPRTCapeTown: is the defect in the HPRT gene?
Authors: Galloon T. , Harley E. H.
Published: June 2005

HPRTCapeTown shows low levels of purine salvage in cultured cells which is associated with the unusual property of substrate inhibition by its purine substrates in erythrocyte haemolysates. Since it is not certain that the defect is in the HPRT gene, we studied enzyme kinetics in cell‐free preparations of erythrocytes and transformed lymphoblasts from both the proband and his obligate heterozygote daughter and studied purine salvage in intact cells. Substrate inhibition was demonstrated in erythrocyte and lymphoblast cell‐free extracts from the proband and his daughter and lymphoblasts from the daughter showed similar growth properties in selective media to her father. These results were all consistent with the defect being in the HPRT gene.
Lesch‐nyhan syndrome: Growth delay, testicular atrophy and a partial failure of the 11β‐hydroxylation of steroids
Authors: Watts R. W. E. , Harkness R. A. , Spellacy E. , Taylor N. F.
Published: June 2005

There is a failure of growth in hypoxanthine guanine phosphoribosyltransferase deficiency; slow weight gain is marked after the second year of age but is apparent in the birth weights of all eight of our patients for whom we have data. However, head growth and bone development are less affected than weight.

A partial defect in the adrenocortical 11β‐hydroxylation of steroids was demonstrated after ACTH stimulation in all four patients studied. This hydroxylation takes place in mitochondria the function of which is modulated by purine nucleotide concentrations; this may be the link with the enzyme defect.

Testicular atrophy at autopsy was found in two pubertal age boys and seven patients aged 12–17 years had no signs of puberty. All five boys aged 3–11 years showed less than the normal mean response of plasma testosterone concentration to human chorionic gonadotrophin despite the normal histological appearance of the testes of one 6‐year‐old‐boy. Follicle stimulating hormone responses to gonadotrophin releasing hormone are probably less than in normal in at least three of the seven prepubertal boys. The absence of the normally high activities of hypoxanthine guanine phosphoribosyltransferase in testes appears to inhibit their ability to respond to gonadotrophin.
Acid β‐mannosidase of human plasma: Influence of age and sex on enzyme activity
Authors: Cooper A. , Hatton C. , Sardharwalla I. B.
Published: June 2005

Optimum conditions for assay of human plasma β‐mannosidase activity were determined. Maximum activity was observed at pH 3.0–3.4, the apparentKm was 0.9 mmol L−1 and enzymatic hydrolysis was linear for at least 60 min. Assays were performed on plasma from two siblings with the recently described condition β‐mannosidosis and their parents and controls. Both β‐mannosidosis patients showed a marked deficiency of β‐mannosidase activity. Control samples showed no variation between sexes (p>0.05) but enzyme activity varied significantly with age (p<0.05). Highest activity was observed in the 0–1 year age group, activity then decreasing to adulthood, Both mother and father of the affected individuals showed reduced activity (34% and 53%, respectively) compared to age‐matched controls. This suggests that heterozygote detection in this condition is possible using plasma, provided the variation of activity with age is taken into consideration.
Impaired glucose transport in polymorphonuclear leukocytes in glycogen storage disease Ib
Authors: Bashan N. , Potashnik R. , Hagay Y. , Moses S. W.
Published: June 2005

A study of 2‐deoxyglucose transport into polymorphonuclear leukocytes (PMN) was performed in three patients with glycogen storage disease (GSD) type Ib. The rate of 2‐deoxyglucose transport into GSD Ib PMN was 30% of that of cells of normal controls. In GSD Ib lymphocytes, transport was normal.

Km for 2‐deoxyglucose in the PMN of one patient was within the normal range.

The reduced transport was not due to the elevation in Km for 2‐deoxyglucose nor to the decreased rate of phosphorylation of 2‐deoxyglucose. The striking limitation of glucose transport across the cell membrane may account for the impairment of leukocyte function which is characteristic of GSD Ib.
Prevalence of different types of lysosomal storage diseases in saudi arabia
Authors: Ozand P. T. , Gascon G. , Al Aqeel A. , Roberts G. , Dhalla M. , Subramanyam S. B.
Published: June 2005

The frequency of different types of lysosomal storage diseases in 125 referred cases, collected over three years, was compared to the occurrence elsewhere. The data suggest that mucopolysaccharidosis (MPS) type IVA (Morquio disease), multiple sulphatase deficiency, Niemann‐Pick disease type B, GM2 gangliosidosis type ‘0’ (Sandhoff disease), and ceroid lipofuscinosis (Jansky‐Bielschowsky and Batten‐Spielmeyer‐Vogt syndromes) are encountered frequently in Saudi Arabia, as compared to other storage diseases. In contrast, some other diseases such as the adult variant of Gaucher's disease were not observed. Half of the GM2 gangliosidosis type ‘0’ cases originated from one large tribe in the country. Other conditions did not show tribal predilection. The ceroid lipofuscinosis cases in Saudi Arabia originated from four large families. Consanguineous marriages taking place within tribal boundaries probably account for the pattern observed.
β‐Mannosidase deficiency: Heterogeneous manifestation in the first female patient and her brother
Authors: Kleijer W. J. , Hu P. , Thoomes R. , Boer M. , Huijmans J. G. M. , Blom W. , Van Diggelen O. P. , Seemanova E. , Macek M.
Published: June 2005

β‐Mannosidase deficiency was demonstrated in fibroblasts of a girl who showed severe psychomotor retardation, bone deformities and gargoylism and recurrent skin and respiratory infections and who died at 20 years of age from bronchopneumonia. This first demonstration of a female patient confirms the autosomal recessive inheritance of β‐mannosidosis. Further investigation of this gipsy family revealed β‐mannosidosis in an older brother with a milder manifestation of gargoyl facial dysmorphology, mental retardation, hearing impairment and recurrent infections. β‐Mannosidase activity was completely deficient in his cultured skin fibroblasts, leukocytes and plasma. In urine a characteristic disaccharide was present. Heterozygote levels of β‐mannosidase were found in fibroblasts and/or plasma of the parents and one sister.
Restriction fragment length polymorphisms among Japanese detected with a dihydropteridine reductase cDNA gene probe
Authors: Hayasaka K. , Narisawa K. , Ohura T. , Ogawa E. , Dahl H. ‐H. M.
Published: June 2005

Using a human dihydropteridine reductase (DHPR) cDNA, the frequency of restriction fragment length polymorphisms (RFLPs) with restriction endonucleases AvaII, MspI, NcoI and HinfI was estimated in unrelated, unaffected Japanese. The allele frequencies are different from those found in Caucasians, especially with MspI and HinfI. However, approximately 60% of Japanese are heterozygous for at least one of the RFLPs and analysis of one family with DHPR deficiency was shown to be informative. RFLP linkage analysis will be useful in the Japanese population as previously reported for Caucasians.
Prenatal exclusion of ornithine transcarbamylase (OTC) by using RFLP analysis
Authors: Liechti S. , Dionisi Vici C. , Bachmann C. , Mazziotta M. R. M. , Bartuli A. , Sabetta G.
Published: June 2005

The use of restriction fragment length polymorphism studies for prenatal exclusion of OTC deficiency in a carrier mother is reported.