bluuebunny/crossref_metadata_2025 huggingface dataset:
Transport of phytanic acid on lipoproteins in Refsum disease
Authors: Wierzbicki A. S. , Sankaralingam A. , Lumb P. J. , Hardman T. C. , Sidey M. C. , Gibberd F. B.
Published: December 2002

Patients with Refsum disease accumulate significant quantities of phytanic acid in adipose and neural tissue. The accumulation can be reversed by following a diet low in phytanic acid, yet the mechanism of transport of this fatty acid is obscure. We investigated the distribution of phytanic acid in different lipoprotein subfractions in 11 patients with Refsum disease and 9 unaffected siblings. Plasma phytanic acid was distributed on VLDL (16.2%±12.2%), IDL (1.77%±1.64%), LDL (34.8%±12.6%) and HDL (14.3%±7.87%). No correlations with any parameter were seen with total phytanic acid content. Weak nonsignificant correlations were found with the fractional distribution of phytanic acid and VLDL triglyceride (r=0.35; p=0.12) and plasma HDL‐cholesterol (r=0.32; p=0.16) and with LDL:HDL cholesterol ratio (r=0.33; p=0.14). Significant correlation of the fractional distribution of phytanic acid on lipoprotein particles was noted with the ratio of apolipoprotein B:apolipoprotein A1‐containing particles (r=0.46; p=0.03) and apolipoprotein B:apolipoprotein A1 in HDL2 (r=0.53; p=0.01). This suggests that the import–export balance for phytanic acid in plasma is related to forward and reverse cholesterol transport on lipoprotein particles, and only weakly to plasma cholesterol and triglycerides. These ratios of apolipoprotein particles may play a significant role in determining the rate of phytanic acid elimination in patients with Refsum disease.
Novel mutations in patients with fructose‐1,6‐bisphosphatase deficiency
Authors: Herzog B. , Wendel U. , Morris A. A. M. , Eschrich K.
Published: December 2002

Fructose‐1,6‐bisphosphatase (FBPase) deficiency is an autosomal recessive disorder of gluconeogenesis. Mutations have recently been identified in Japanese patients but none has been reported in patients of other ethnic backgrounds. We have undertaken sequence analysis on genomic DNA isolated from leukocytes of four patients with FBPase deficiency. Homozygous mutations were found in all four cases. One patient was homozygous for the common mutation identified in Japanese patients (960‐961insG in exon 7). The other three patients were all homozygous for novel mutations (35delA in exon 1, 778G→A in exon 6 and 966delC in exon 7). Normal and mutant FBPases were expressed in prokaryotic (E. coli TG2) and eukaryotic (COS1) cells. In cell‐free extracts the mutant proteins were enzymatically inactive, indicating that the mutations are responsible for the disease. In one affected family, molecular genetic analysis allowed the diagnosis to be excluded promptly in a newborn child 3 days after birth.
Biochemical monitoring of treatment for galactosaemia: Biological variability in metabolite concentrations
Authors: Hutcheson A. C. J. , Murdoch‐Davis C. , Green A. , Preece M. A. , Allen J. , Holton J. B. , Rylance G.
Published: December 2002

Red cell galactose 1‐phosphate (Gal‐1‐P) concentrations and urinary galactitol excretion have been suggested as biochemical indices of dietary compliance in classical transferase‐deficient galactosaemia. We report our experience of measuring both in 32 patients over 0–10.9 years (median 3.45). A total of 438 blood specimens for Gal‐1‐P and 383 urine specimens for galactitol assay were received; 317 pairs of specimens were collected at the same time. Concentrations of both analytes fell rapidly over the first 2–3 months following dietary intervention, to mean (geometric SD) levels of 225 (1.60) μmol/L red cells for Gal‐1‐P and 388 (1.19) μmol/mmol creatinine for galactitol. Concentrations then fell exponentially over the next 7–8 years, with times to half‐disappearance of 6.3 years for Gal‐1‐P and 6.4 years for galactitol, to levels of 104 (1.58) and 193 (1.36) respectively in patients aged over 10 years. Concentrations of both analytes were independent of the presence of the common Q188R mutation. Mean intra‐ and inter‐individual coefficients of variation (CV) across the range of values studied were 36% and 61% for Gal‐1‐P, and 37% and 42% for galactitol. Analytical CVs were 3.6% for Gal‐1‐P and 5.5% for galactitol, indicating that the major source of variability is biological. The correlation coefficient between Gal‐1‐P and galactitol in paired samples overall was 0.33; the regression equation being [Galactitol] = 0.84[Gal‐1‐P]+176. Serial measurements of both Gal‐1‐P and galactitol may be valuable in monitoring galactosaemia, but high intra‐individual biological variability limits their usefulness. Standardization of sample collection times may improve this. Further work is needed to assess the predictive values of both analytes for long‐term outcome.
Disorders of mitochondrial fatty acyl‐CoA β‐oxidation
Authors: Wanders R. J. A. , Vreken P. , den Boer M. E. J. , Wijburg F. A. , Van Gennip A. H. , IJlst L.
Published: December 2002

In recent years tremendous progress has been made with respect to the enzymology of the mitochondrial fatty acid β‐oxidation machinery and defects therein. Firstly, a number of new mitochondrial β‐oxidation enzymes have been identified, including very‐long‐chain acyl‐CoA dehydrogenase (VLCAD) and mitochondrial trifunctional protein (MTP). Secondly, the introduction of tandem MS for the analysis of plasma acylcarnitines has greatly facilitated the identification of patients with a defect in fatty acid oxidation (FAO). These two developments explain why the number of defined FAO disorders has increased dramatically, making FAO disorders the most rapidly growing group of inborn errors of metabolism. In this review we describe the current state of knowledge of the enzymes involved in the mitochondrial oxidation of straight‐chain, branched‐chain and (poly)unsaturated fatty acyl‐CoAs as well as disorders of fatty acid oxidation. The laboratory diagnosis of these disorders is described, with particular emphasis on the methods used to identify the underlying enzyme defect and the molecular mutations. In addition, a simple flowchart is presented as a guide to the identification of mitochondrial FAO‐disorders. Finally, treatment strategies are discussed briefly.
Long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency: Variable expressivity of maternal illness during pregnancy and unusual presentation with infantile cholestasis and hypocalcaemia
Authors: Ibdah J. A. , Dasouki M. J. , Strauss A. W.
Published: December 2002

Patients with long‐chain 3‐hydroxyacyl‐CoA dehydrogenase (LCHAD) deficiency present with a Reye‐like syndrome, cardiomyopathy, or sudden unexpected death. We describe an unusual presentation in a patient with unsuspected LCHAD deficiency. The proband presented at 2 months of age with an acute infantile hypocalcaemia and vitamin D deficiency associated with occult, unexplained cholestatic liver disease. Sudden, unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the prevalent LCHAD (1528G>C, E474Q) mutation. The mother had pre‐eclampsia during the third trimester of her pregnancy. In a subsequent pregnancy, she developed severe acute fatty liver of pregnancy (AFLP) and intrauterine fetal death at 33 weeks of gestation. In conclusion, infantile hypocalcaemia is an unusual phenotype associated with LCHAD deficiency. The maternal pregnancy history documents that fetal LCHAD deficiency is associated with a spectrum of maternal illnesses ranging from pre‐eclampsia to life‐threatening AFLP.
Automated mutation analysis
Authors: Ravine D.
Published: December 2002

Automated mutation analysis brings with it a vastly increased capacity in the number of test samples that can be processed at a time, as well as much improved test reproducibility. Until now, the introduction of automation into this field had been restricted to the use of semiautomated sequencing systems to make the most of the sequence information extractable from a single lane in an electrophoretic gel or in a polymer‐filled glass capillary. Much effort is now being directed into harnessing the potential of DNA microarrays (DNA chips) and there is increasing interest in the potential of matrix‐assisted mass spectrometry for determining the detail of large nucleic acid molecules. Meanwhile, there are other important recent developments already available, including robotic workstations, the further development of the allele‐specific oligonucleotide assay into microtitre formats, and its use with fluorescence for real‐time quantitative PCR analysis. Implementation of these developments in appropriate settings can further streamline the routine of molecular diagnostic laboratories, allowing them to take greater advantage of the recent surge of gene discoveries and their associated disease‐causing mutations.
Long‐term follow‐up following bone marrow transplantation for Hunter disease
Authors: Vellodi A. , Young E. , Cooper A. , Lidchi V. , Winchester B. , Wraith J. E.
Published: December 2002

Bone marrow transplantation (BMT) was performed in 10 patients with Hunter disease (mucopolysaccharidosis type II, iduronate‐2‐sulphatase deficiency). The donor was an HLA‐identical sibling in 2 cases, an HLA‐nonidentical relative in 6 cases, a volunteer unrelated donor in 1 case, and details were not available in 1 case. Only three patients have survived for more than 7 years post BMT; however, this high mortality probably resulted from poor donor selection. In two, there has been a steady progression of physical disability and mental handicap. One patient has maintained normal intellectual development, with only mild physical disability. It is possible that BMT may be useful in selected patients with MPS II.
Functional magnetic resonance imaging: Clinical applications and potential
Authors: Matthews P. M. , Clare S. , Adcock J.
Published: December 2002

Demonstration that contrast in magnetic resonance images can be generated based on differences in blood oxygenation has led to an explosion of interest in so‐called functional magnetic resonance imaging (FMRI). FMRI can be used to map increases in blood flow that accompany local synaptic activity in the brain. The technique has proved remarkably sensitive and has been used to map a broad range of cognitive, motor and sensory processes in the brain entirely non‐invasively. More recently, efforts have been made to extend this technique to the analysis of clinical problems. A major application is for presurgical localization of cerebral functions, e.g. in the surgical treatment of epilepsy. The technique also is beginning to provide information on functional consequences of abnormal brain development. Perhaps most exciting are applications to neurological impairments that are not associated with structural abnormalities, such as learning problems, dyslexia and movement disorders. It is possible that useful applications of FMRI may be found for directly mapping sites of action of CNS‐active drugs. Although the extent of the potential clinical applications of this new brain mapping technique is not clear, the widespread availability of MRI scanners suggests that the technique should in some form soon become a routine tool in major neuroradiological centres.
Intermittent jaundice in patients with acute leukaemia: A common mutation of the bilirubin uridine‐diphosphate glucuronosyltransferase gene among Asians
Authors: Kimura T. , Akaba K. , Ikegami T. , Akiba K. , Kanazawa C. , Katsuura M. , Shimizu Y. , Imaizumi M. , Lin C. , Hayasaka K.
Published: December 2002

The Gly71Arg mutation of the hepatic bilirubin UDP glucuronosyltransferase (B‐UGT) gene associated with Gilbert syndrome prevails among Japanese and its gene frequency is 0.13. Among 20 patients with acute leukaemia, 4 patients showed intermittent unconjugated hyperbilirubinaemia during the course of combined chemotherapy. The Gly71Arg mutation was detected in all 4 patients with hyperbilirubinaemia, but was not found in 16 patients without hyperbilirubinaemia. Two of them were heterozygotes and one was a homozygote for the Gly71Arg mutation, and the other was a compound heterozygote of the Gly71Arg mutation and TA insertion mutation in the TATA box of the B‐UGT gene. In addition to the complications leading to hyperbilirubinaemia, including liver damage due to drugs, viral infections or tumour cell infiltrations and alloimmune haemolysis, carrier status for the Gly71Arg mutation should be considered in a patient with leukaemia showing intermittent hyperbilirubinaemia during the course of chemotherapy, especially among Japanese, Koreans and Chinese owing to its prevalence in those populations.
Single‐cell analysis of mitochondrial DNA in patients and a carrier of the tRNALeu(UUR) gene mutation
Authors: Saitoh S. , Momoi M. Y. , Yamagata T. , Nakauchi H. , Nihei K. , Fujii M.
Published: December 2002

We examined heteroplasmy of mutated mitochondrial DNA in single peripheral lymphocytes derived from 4 individuals carrying the nt 3243 A‐to‐G mutation, including two patients with MELAS, a patient with cardiomyopathy, deafness and diabetes mellitus, and the asymptomatic mother of one of the MELAS patients. In these subjects, all lymphocytes examined were heteroplasmic to different degrees, with a wider range of heteroplasmy evident in the symptomatic patients than in the healthy carrier.
Increased Stability and Catalytic Efficiency of Yeast Hexokinase Upon Interaction with Zwitterionic Micelles. Kinetics and Conformational Studies
Authors: Guerra Rodrigo , Bianconi M. Lucia
Published: December 2002

The effect of ligands (glucose, ATP and Mg2+) and zwitterionic micellesof lysophosphatidylcholine (LPC) or N-hexadecyl-N,N-dimethyl-3-ammoniumpropanesulfonate (HPS) in the yeast hexokinase (HK) stability was studied at35°C. The thermal inactivation kinetics followed one-exponentialdecay. The effect of ligands on protecting the enzyme against inactivationfollowed the order: glucose>glucose/Mg2+>ATP/Mg2+≌Mg2+≌bufferonly. Both LPC and HPS micelles increased the enzyme stability only whenthe incubation medium contained glucose or glucose/Mg2+,suggesting that the protein conformation is a key prerequisite for theenzyme-micelle interaction to take place. This enzyme-micelle interactionresulted in an increased catalytic efficiency (with a decrease in Km forATP and increase in Vmax as well as in changes on the tertiary (intrinsicfluorescence) structure of the yeast hexokinase.
Central nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinaemia
Authors: Valtonen M. , Näntö‐Salonen K. , Jääskeläinen S. , Heinänen K. , Alanen A. , Heinonen O. J. , Lundbom N. , Erkintalo M. , Simell O.
Published: December 2002

In gyrate atrophy of the choroid and retina with hyperornithinaemia (GA), a genetically determined deficiency of ornithine {3}d‐aminotransferase activity leads to high ornithine concentrations in body fluids. GA is characterized by centripetally progressing retinal and choroidal destruction and selective atrophy with tubular aggregates in type II skeletal muscle fibres. These findings have been suggested to be mediated by hyperornithinaemia‐induced deficiency of high‐energy creatine phosphate. As abnormal brain magnetic resonance images and electroencephalograms are found in another disorder of creatine metabolism, guanidinoacetate methyltransferase deficiency, we investigated the central nervous system involvement in GA, which seems to be associated with a milder degree of phosphocreatine deficiency. We compared 23 untreated GA patients with age‐matched healthy controls, and with 9 patients who had received creatine or creatine precursor supplementation daily for several years. The mean age of the patients (32±18 years) was similar to that of the controls (36±22 years). The MRI or EEG findings of the patients on creatine supplementation did not differ from those of the untreated group. Brain MRI revealed degenerative lesions in the white matter in 50% of the GA patients, and 70% of the patients had premature atrophic changes, with a striking increase in the number of Virchow's spaces. Of the patients whose EEG was recorded, 58% had abnormal slow background activity, focal lesions or high‐amplitude β rhythm (>50μV). The EEG findings were not associated with the MRI changes or with the age or the sex of the patients. Early degenerative and atrophic brain changes and abnormal EEG are thus features of GA, in addition to the well‐characterized eye and muscle manifestations.
Apolipoprotein E polymorphism and serum concentrations in patients with glycogen storage disease type Ia
Authors: Trioche P. , Francoual J. , Capel L. , Odièvre M. , Lindenbaum A. , Labrune P.
Published: December 2002

In patients with glycogen storage disease type Ia (glucose‐6‐phosphatase deficiency), serum triglyceride concentrations are markedly raised, whereas phospholipids and cholesterol levels are only moderately elevated. In addition, both VLDL and LDL lipoprotein fractions are raised. Despite these abnormalities, endothelial vascular dysfunction and atherosclerosis seem to be rare in such patients. In view of the crucial role of apolipoprotein E (apoE) in lipid metabolism, we studied both apoE polymorphism (40 patients) and serum concentration (20 patients) in patients with glycogen storage disease type Ia. The distribution of each allele at the apoE locus was similar to that reported in the general population, whereas serum apoE concentrations were raised in our patients. Raised apoE levels in the serum could play an important role in counterbalancing the at‐risk‐for‐atherosclerosis lipid profile of patients with glycogen storage disease type Ia. Moreover, E3 and E4 polymorphisms, predominant in our patients, have a high triglyceride binding capacity and are thus able to increase triglyceride clearance. However, the origin of raised concentrations of apoE is not completely clear though, bearing in mind previous reports regarding serum protein concentrations in such patients, increased hepatic synthesis is likely.
Congenital porto–left renal venous shunt as a cause of galactosaemia
Authors: Mizoguchi N. , Sakura N. , Ono H. , Naito K. , Hamakawa M.
Published: December 2002

Congenital porto–left renal venous (PRV) shunt was found to be the cause of galactosaemia in four galactosaemic neonates detected by mass screening (Paigen method). The patients did not have hereditary galactosaemias and were diagnosed as having galactosaemia of unknown cause, because porto–systemic venous (PS) shunts had not been recognized. At the time of diagnosis, hypergalactosaemia was not severe (0.44–0.55 mmol/L; 8–10 mg/dl) and plasma concentration of total bile acids (TBA) did not suggest a PS shunt (46–50 μmol/L). However, slightly but consistently increased concentrations of galactose and TBA strongly suggested the presence of a PS shunt, and careful ultrasonographic investigation revealed PRV shunt. We conclude that PRV shunt should be suspected in patients with hypergalactosaemia of unknown cause.
The increased sensitivity of neurons with elevated glucocerebroside to neurotoxic agents can be reversed by imiglucerase
Authors: Pelled D. , Shogomori H. , Futerman A. H.
Published: December 2002

We have recently demonstrated that incubation of cultured rat hippocampal neurons with conduritol β‐epoxide (CBE), an inhibitor of glucocerebrosidase, the enzyme defective in Gaucher disease, results in changes in intracellular morphology and in functional calcium stores. Changes in levels of functional calcium stores are directly related to neuronal cell death. We now show that neurons incubated with either CBE or a non‐hydrolysable analogue of GlcCer (glucosylthioceramide), are more sensitive to the toxic effects of high concentrations of glutamate and of a variety of metabolic inhibitors. A linear relationship exists between level of accumulation of GlcCer and the extent of neuronal cell death. The deleterious effects of elevated GlcCer levels can be completely reversed by addition of human glucocerebrosidase (imiglucerase) to the culture medium. Imiglucerase is internalized to lysosomes, where it presumably degrades excess GlcCer. This suggests that the limited success of enzyme replacement therapy in neuronopathic forms of Gaucher disease is not due to lack of efficacy of glucocerebroside in degrading GlcCer in neurons of the central nervous system, and adds impetus to attempts to develop ways to efficiently deliver glucocerebrosidase to the brains of neurologically compromised Gaucher disease patients.
Biochemical and molecular basis for mitochondrial cardiomyopathy in neonates and children
Authors: Marin‐Garcia J. , Ananthakrishnan R. , Goldenthal M. J. , Pierpont M. E.
Published: December 2002

Defects in myocardial bioenergetics have been reported in patients with cardiomyopathy but their molecular basis and role in pathophysiology remain unclear. We sought to establish a molecular basis for cardiac mitochondrial respiratory enzyme abnormalities frequently present (75%) in a group of 16 children (including 2 neonates) with end‐stage cardiomyopathy. Decreased specific activity levels were found in complexes I, III, IV and V but not in II, the only complex that is entirely nuclear encoded. Sequence analysis of cardiac mtDNA revealed 4 patients harbouring heteroplasmic mtDNA mutations in cytb, tRNAArg, and ND5 at highly conserved positions. These mutations were present neither in controls nor in patients without enzymatic defect. In addition, 4 patients exhibited marked reduction in cardiac mtDNA levels. The basis for respiratory enzyme abnormalities can be explained in a subset of our patients as a result of either pathogenic mtDNA mutation or depletion. Patients harbouring both DNA and enzymatic defects fulfil rigorous criteria defining mitochondrial cardiomyopathy.
Brain phenylalanine concentration in the management of adults with phenylketonuria
Authors: Moats R. A. , Koch R. , Moseley K. , Guldberg P. , Guttler F. , Boles R. G. , Nelson M. D.
Published: December 2002

Diagnosis by newborn screening and the implementation of a phenylalanine‐restricted diet have resulted in normal neurological development in approximately 10 000 persons with phenylketonuria (PKU) in the United States. While it is accepted that a phenylalanine‐restricted diet is necessary in childhood, the recommended concentration of phenylalanine in the blood varies. Clinicians now must make recommendations for adults with PKU who probably tolerate higher levels of phenylalanine than children. This factor, quality of life issues, the expense of the diet, and varying genetic and socio‐economic backgrounds, make the choice of dietary recommendations difficult.

Molecular analysis of the mutations in PKU has provided insight but has not resulted in clear recommendations for phenylalanine concentration in the blood. Magnetic resonance imaging has provided the recognition that white‐matter changes are present in PKU. However, owing to poor correlation of white‐matter changes with clinical factors, analysis of white‐matter changes has not proved useful. We hypothesize that measurement of brain phenylalanine directly will aid in clinical decision making.

Twenty‐one subjects with PKU had blood and brain phenylalanine measured simultaneously. Fifteen were randomly selected, 2 were examined for clinical reasons and 4 exceptional patients were chosen because they had maintained high IQs, despite having high historic blood concentrations and having been off the diet for at least 10 years. The correlation of blood and brain phenylalanine is in general poor. However, the four exceptional patients all had relatively low concentrations of phenylalanine in their brains compared to their blood. We suggest that their good clinical status, despite high historic blood levels, is due to their comparatively low brain levels of phenylalanine. We further suggest that measurement of brain phenylalanine concentration is useful in the management of PKU patients.
Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue‐ or age‐related variation
Authors: White S. L. , Shanske S. , McGill J. J. , Mountain H. , Geraghty M. T. , DiMauro S. , Dahl H.‐H. M. , Thorburn D. R.
Published: December 2002

Two pathogenic mitochondrial DNA mutations, a T‐to‐G substitution (8993T>G) and a T‐to‐C substitution (8993T>C), at nucleotide 8993 have been reported. We describe 13 pedigrees with mitochondrial DNA mutations at nucleotide 8993; 10 pedigrees with the 8993T>G mutation and three with the 8993T>C mutation. Prenatal diagnosis of the nucleotide 8993 mutations is technically possible. However, there are three major concerns: (i) that there is variation in mutant loads among tissues; (ii) that the mutant load in a tissue may change over time; and (iii) that the genotype–phenotype correlation is not clearly understood. We have used the 13 pedigrees to determine specifically the extent of tissue‐ and age‐related variation of the two mutations at nucleotide 8993 in the mitochondrial DNA. The tissue variation was investigated by analysing two or more different tissues from a total of 18 individuals. The age‐related variation of the mutation was investigated by comparing the amount of both mutations in blood taken at birth and at a later age. No substantial tissue variation was found, nor was there any substantial change in the proportion of either mutation over periods of 8–23 years in the four individuals studied. In addition, we noted that two features were remarkably common in families with nucleotide 8993 mutations, namely (i) unexplained infant death (8 cases in 13 pedigrees), and (ii) de novo mutations (5 of the 10 8993T>G pedigrees).
Lysosomal transport disorders
Authors: Mancini G. M. S. , Havelaar A. C. , Verheijen F. W.
Published: December 2002

In the group of lysosomal storage diseases, transport disorders occupy a special place because they represent rare examples of inborn errors of metabolism caused by a defect of an intracellular membrane transporter. In particular, two disorders are caused by a proven defect in carrier‐mediated transport of metabolites: cystinosis and the group of sialic acid storage disorders (SASD). The recent identification of the gene mutations for both disorders will improve patient diagnosis and shed light on new physiological mechanisms of intracellular trafficking.
Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone
Authors: Lerman‐Sagie T. , Rustin P. , Lev D. , Yanoov M. , Leshinsky‐Silver E. , Sagie A. , Ben‐Gal T. , Munnich A.
Published: December 2002

Idebenone, a synthetic analogue of coenzyme Q10, has been shown to improve cardiac function in patients with Friedreich ataxia and a deficiency of respiratory chain complexes I–III. We describe a woman with severe combined right and left heart failure due to a mitochondrial cardiomyopathy. The patient underwent an endomyocardial biopsy as part of an evaluation for cardiac transplantation. It showed severely decreased respiratory complex activities dependent on CoQ, pointing to CoQ depletion. Following idebenone treatment there was a dramatic improvement in her clinical status with resolution of the heart failure.
Behavioural and emotional problems in early‐treated adolescents with phenylketonuria in comparison with diabetic patients and healthy controls
Authors: Weglage J. , Grenzebach M. , Pietsch M. , Feldmann R. , Linnenbank R. , Denecke J. , Koch H. G.
Published: December 2002

Even early‐treated patients with phenylketonuria (PKU) have a higher risk of psychosocial maladjustment. This study was performed to determine whether emotional and behavioural problems are specific in phenylketonurics and whether they depend on the quality of biochemical control. This comparative study covered 42 PKU patients aged 10–18 years (mean 14.7 years) and 42 diabetic patients matched for sex, age and socioeconomic status. Patients' groups were compared with a control sample of healthy controls (n=2900) from an epidemiological study. We used the Child Behavior Check List (CBCL) according to Achenbach, intelligence quotient (IQ) test according to Weiss, and monitoring of blood phenylalanine concentrations and HBA1 concentrations. Internalizing problems such as depressive mood, anxiety, physical complaints or social isolation were significantly elevated in both phenylketonuric and diabetic patients, whereas externalizing problems were not. The two patient groups did not differ significantly either in the degree or in the pattern of their psychological profile. In both groups no significant correlations could be computed between the psychological characteristics and the biochemical control, the IQ, and the socioeconomic status. No patient was undergoing psychiatric treatment or psychotherapy. Our results strongly support a psychological perspective for the development of behavioural and emotional problems in both phenylketonuric and diabetic patients. Thus, medical treatment should be accompanied by psychological support for the families.
Behaviour and school achievement in patients with early and continuously treated phenylketonuria
Authors: Stemerdink B. A. , Kalverboer A. F. , van der Meere J. J. , van der Molen M. W. , Huisman J. , de Jong L. W. A. , Slijper F. M. E. , Verkerk P. H. , van Spronsen F. J.
Published: December 2002

Thirty patients with early and continuously treated phenylketonuria (PKU) between 8 and 20 years of age were compared with 30 controls, matched individually for age, sex, and educational level of both parents, on behaviour rating scales for parents and teachers as well as a school achievement scale. PKU patients, as a group, demonstrated more problems in task‐oriented behaviour and average academic performance than did matched controls. Interestingly, whereas male PKU patients were rated significantly lower on introversion by their teachers, female patients were rated significantly higher on introversion and lower on extraversion than matched controls. This sex difference was also reflected in the relationship between measures of dietary control and the behaviour clusters, suggesting that male and female patients respond differently to elevated Phe levels or the stress associated with PKU. The teacher rating on average academic performance of the PKU patients was associated with recent level of dietary control, which suggests that it might be improved by more strict adherence to the diet. In addition, academic performance correlated negatively with the behaviour cluster negative task orientation. Further studies are recommended to obtain a more complete evaluation of this relationship and to replicate the current findings on larger samples.
Genotypes and phenotypes of patients in the UK with carbohydrate‐deficient glycoprotein syndrome type 1
Authors: Imtiaz F. , Worthington V. , Champion M. , Beesley C. , Charlwood J. , Clayton P. , Keir G. , Mian N. , Winchester B.
Published: December 2002

18 UK patients (14 families) have been diagnosed with the carbohydrate‐deficient glycoprotein syndrome (CDGS), type 1, on the basis of their clinical symptoms and/or abnormal electrophoretic patterns of serum transferrin. Eleven out of the 16 infants died before the age of 2 years. Patients from 12 families had a typical type 1 transferrin profile but one had a variant profile and another, who had many of the clinical features of CDGS type 1, had a normal profile. Eleven of the patients (10 families) with the typical type 1 profile had a deficiency of phosphomannomutase (PMM), (CDGS type 1a) but there was no correlation between residual enzyme activity and severity of disease. All these patients were compound heterozygotes for mutations in the phosphomannomutase (PMM2) gene, with 7 out of the 10 families having the common R141H mutation. Eight different mutations were found, including three novel ones. There was no correlation between genotype and phenotype, although siblings had similar phenotypes. Three patients, including the one with the normal transferrin profile, did not have a deficiency of phosphomannomutase or phosphomannose isomerase (CDGS 1b).
Acylcarnitines in plasma and blood spots of patients with long‐chain 3‐hydroxyacyl‐coenzyme A dehydrogenase defiency
Authors: Van Hove J. L. K. , Kahler S. G. , Feezor M. D. , Ramakrishna J. P. , Hart P. , Treem W. R. , Shen J.‐J. , Matern D. , Millington D. S.
Published: December 2002

The acylcarnitines in plasma and blood spots of 23 patients with proven deficiency of long‐chain 3‐hydroxyacylcoenzyme A dehydrogenase were reviewed. Long‐chain 3‐hydroxyacylcarnitines of C14:1, C14, C16 and C18:1 chain length, and long‐chain acylcarnitines of C12, C14:1, C14, C16, C18:2 and C18:1 chain length were elevated. Acetylcarnitine was decreased. In plasma, elevation of hydroxy‐C18:1 acylcarnitine over the 95th centile of controls, in combination with an elevation of two of the three acylcarnitines C14, C14:1 and hydroxy‐C16, identified over 85% of patients with high specificity (less than 0.1% false positive rate). High endogenous levels of long‐chain acylcarnitines in normal erythrocytes reduced the diagnostic specificity in blood spots compared with plasma samples. The results were also diagnostic in asymptomatic patients, and were not influenced by genotype. Treatment with diet low in fat and high in medium‐chain triglyceride decreased all disease‐specific acylcarnitines, often to normal, suggesting that this assay is useful in treatment monitoring.
Psychiatric symptoms of inherited metabolic disease
Authors: Estrov Y. , Scaglia F. , Bodamer O. A. F.
Published: December 2002

Inborn errors of metabolism often present with a variety of psychiatric symptoms. With improved diagnosis and treatment options, many patients have increased lifespans; consequently, issues of long‐term quality of life are coming to the forefront. Mental health concerns are among these issues. To demonstrate the connection between the course of metabolic disease and its psychiatric manifestations, four different inborn errors of metabolism are reviewed: phenylketonuria, Wilson disease, acute intermittent porphyria, and metachromatic leukodystrophy.
Rolipram does not normalize very long‐chain fatty acid levels in adrenoleukodystrophy protein‐deficient fibroblasts and mice
Authors: Netik A. , Hobel A. , Rauschka H. , Molzer B. , Forss‐Petter S. , Berger J.
Published: December 2002

In its severe form, X‐linked adrenoleukodystrophy (X‐ALD) is a lethal neurodegenerative disorder with inflammatory demyelination, in which defective peroxisomal β‐oxidation causes accumulation of very long‐chain fatty acids (VLCFA) in tissues and plasma, in particular in the nervous system and adrenal glands. Recently, several drugs have been reported to reduce VLCFA in cultured human fibroblasts of X‐ALD patients, and therefore to be potential candidates for novel therapeutic treatments in X‐ALD. Among the most promising of these substances is the antidepressant rolipram, because of favourable adverse event profile in clinical studies and its additionally reported anti‐inflammatory action. To further elucidate the effects of rolipram on peroxisomal β‐oxidation and VLCFA accumulation, we administered rolipram orally in the diet to ALD protein‐deficient mice and ALD protein‐deficient cultured human and mouse fibroblasts and assayed the accumulation of VLCFA. In contrast to the previously reported reduction of VLCFA, our data did not demonstrate a decrease in VLCFA content either in vivo or in vitro. NMR spectroscopic analysis verified the structural integrity and purity of the rolipram used here, thus excluding inauthenticity as a reason for the discrepancy. We therefore suggest that rolipram should be excluded from the current list of potential therapeutic agents for X‐ALD.
Blood lipids and endothelial function in glycogen storage disease type III
Authors: Hershkovitz E. , Donald A. , Mullen M. , Lee P. J. , Leonard J. V.
Published: December 2002

We have assessed early indicators of arterial disease in patients with glycogen storage disease type III (GSD III; McKusick 232400), investigating the plasma lipid and lipoprotein profile and endothelial function. Eleven patients, aged 10–39 years, were recruited together with age‐, sex‐ and smoking status‐matched controls. Brachial artery responses were assessed by high‐resolution ultrasonographic measurement of the diameter of the brachial artery at baseline, after reactive hyperaemia and in response to sublingual glyceryl trinitrate (GTN).

The means of plasma cholesterol (total and HDL and LDL subfractions), triglycerides, apo‐A1, apo‐B, Lp(a) and the atherogenic index were similar in both groups. Cardiac troponin I was below the lower limits of detection (<0.03g/L) in all subjects. The GSD III patients had similar body mass index (BMI) and brachial artery diameter to the control group (BMI 22.6±5.6 vs 22.3±5kg/m2; brachial artery diameter 3.4±0.5 vs 3±0.7mm). When compared to the baseline diameter, the maximal flow‐mediated dilatation of the brachial artery after reactive hyperaemia was 9.3±2.1% (mean±SD) in the GSD III patients and 6.5±3.5% in the control group, a difference of 1.8% (95% CI 0.07% to 5.5%). The maximal dilatation of the brachial artery after GTN administration was 18.3±6.4% in the GSD III patients and 17.9±6.5% in the control group, a difference of 0.4% (95% CI –6.9% to 7.7%.

In conclusion, we found no evidence of abnormal plasma lipid and lipoprotein profile or endothelial dysfunction in patients with GSD III. They are unlikely to be at increased risk of premature atherosclerosis.
Features of carnitine palmitoyltransferase type I deficiency
Authors: Olpin S. E. , Allen J. , Bonham J. R. , Clark S. , Clayton P. T. , Calvin J. , Downing M. , Ives K. , Jones S. , Manning N. J. , Pollitt R. J. , Standing S. J. , Tanner M. S.
Published: December 2002

Carnitine palmitoyltransferase type I (CPT I) is unique among long‐chain fatty acid oxidation enzymes in that there are two tissue‐specific isoforms, ‘hepatic’ and ‘muscle’, which are encoded by two separate genes. The ‘hepatic’ isoform is expressed in liver, kidney and fibroblasts and at low levels in the heart, while the other isoform occurs in skeletal muscle and is the predominant form in heart. Reported patients with CPT I deficiency lack activity of the hepatic isoform and present before 30 months of age with hypoketotic hypoglycaemia, hepatomegaly with raised transaminases, seizures and coma. We discuss four new cases in three families showing, variously, renal tubular acidosis, transient hyperlipidaemia and, paradoxically, myopathy with elevated creatinine kinase or cardiac involvement in the neonatal period as additional features that deserve wider recognition.
Acylcarnitines in fibroblasts of patients with long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency and other fatty acid oxidation disorders
Authors: Shen J. J. , Matern D. , Millington D. S. , Hillman S. , Feezor M. D. , Bennett M. J. , Qumsiyeh M. , Kahler S. G. , Chen Y.‐T. , Van Hove J. L. K.
Published: December 2002

Mitochondrial fatty acid oxidation disorders cause hypoglycaemia, hepatic dysfunction, myopathy, cardiomyopathy and encephalopathy. Despite their recognition for more than 15 years, diagnosis and treatment remain difficult. To help design rational diagnostic and therapeutic strategies, we studied the pathophysiology of accumulating metabolites in a whole‐cell system. Acylcarnitines were quantified in cells and media of cultured fibroblasts after incubation with L‐carnitine and fatty acids. Following incubation with palmitate, long‐chain 3‐hydroxyacyl‐CoA dehydrogenase (LCHAD)‐deficient fibroblasts compared with controls showed elevation of hydroxypalmitoyl‐ and palmitoylcarnitine and reduction of C10‐ and shorter acylcarnitines, and following incubation with linoleate an increase in C14:2‐, C18:2‐ and hydroxy‐C18:2‐acylcarnitines and reduction in C10:1‐acylcarnitines. Hydroxyacylcarnitines remained more intracellular compared to corresponding saturated acylcarnitines. Incubation with decanoate and octanoate showed absence of hydroxylated acylcarnitines and correction of secondary metabolic disturbances, suggesting that optimal treatment should include medium‐chain triglycerides of these chain lengths. Fibroblasts of patients with other fatty acid oxidation disorders showed distinct elevations of disease‐specific acylcarnitines. This acylcarnitine analysis allows the diagnosis of LCHAD deficiency and its differentiation from other fatty acid oxidation disorders, which can pose difficulties in vivo. The strategy has allowed in‐depth analysis with different substrates, providing suggestions for the rational design of treatment trials.
Do Coping Styles Differ Across Sociocultural Groups? The Role of Measurement Equivalence in Making This Judgment
Authors: Prelow Hazel M. , Tein Jenn-Yun , Roosa Mark W. , Wood Jennifer
Published: December 2002

Cross‐sociocultural group measurement equivalency is an important issue that generally has not been studied in the coping literature. Measurement equivalency of the COPE (Carver, Scheier, & Weintraub, 1989) was assessed across two sociocultural groups, a sample of 100 Anglo middle‐class divorced mothers and a sample of 122 low‐income Mexican American/Mexican immigrant mothers. A series of restrictive confirmatory factor analyses revealed that seven of the COPE's subscales may be measuring the same underlying construct across populations. However, scores derived from the subscales may not represent the same magnitude of the construct in these two groups. This study makes an important first step in furthering the understanding of coping strategies in low‐income Mexican American/Mexican immigrant mothers. This study also illustrates the importance of testing for measurement equivalency before conducting comparative research in disparate populations.
The Roles of Ethnicity and School Context in Predicting Children's Victimization by Peers
Authors: Hanish Laura D. , Guerra Nancy G.
Published: December 2002

This study examines the prevalence, stability, and contextual correlates of peer victimization in a sample of African‐American, Hispanic, and non‐Hispanic White urban elementary school‐age children. A total of 1956 children (40% African‐American, 42% Hispanic, and 18% White) attending any 1 of 14 public elementary schools located in one large and one mid‐sized Midwestern city participated in this study. Peer ratings of victimization were obtained at two points in time, separated by a 2‐year period. Findings revealed that risk for being victimized by peers varied by ethnicity and by school context. Hispanic children had lower victimization scores than did either African‐American or White children. These findings, however, were moderated by school context, such that attending ethnically integrated schools was associated with a significantly higher risk of victimization for White children and a slightly lower risk of victimization for African‐American children and did not affect the risk of victimization for Hispanic children. In addition, African‐American children were less likely than Hispanic and White children to be repeatedly victimized by peers over time. The importance of considering ethnicity and context in explaining peer victimization is discussed and suggestions for preventive interventions and future research are provided.
Natural Disaster and Depression: A Prospective Investigation of Reactions to the 1993 Midwest Floods
Authors: Ginexi Elizabeth M. , Weihs Karen , Simmens Samuel J. , Hoyt Danny R.
Published: December 2002

A statewide sample of 1735 Iowa residents, approximately half of whom were victims of the 1993 Midwest Floods, participated in interviews 1 year prior to, and 30 to 90 days after, the disaster. Employing a rigorous methodology including both control‐group comparisons and predisaster assessments, we performed a systematic evaluation of the disaster's impact. Overall, the disaster led to true but small rises in depressive symptoms and diagnoses 60–90 days postflood. The disaster–psychopathology effect was not moderated by predisaster depressive symptoms or diagnostically defined depression; rather, predisaster symptoms and diagnoses uniquely contributed to increases in postdisaster distress. However, increases in symptoms as a function of flood impact were slightly greater among respondents with the lowest incomes and among residents living in small rural communities, as opposed to on farms or in cities. Implications for individual‐ and community‐level disaster response are discussed.
Partner Violence, Social Support, and Distress Among Inner‐City African American Women
Authors: Thompson Martie P. , Kaslow Nadine J. , Kingree J. B. , Rashid Akil , Puett Robin , Jacobs Diana , Matthews Alex
Published: December 2002

This study examined the role of social support in the partner violence–psychological distress relation in a sample of African American women seeking medical care at a large, urban hospital (n = 138). Results from bivariate correlational analyses revealed that partner violence was related to lower perceived social support and greater psychological distress, and lower social support was related to more distress. Furthermore, findings based on path analysis indicated that low levels of social support helped account for battered women's increased distress. Findings point to the need for service providers to screen for partner violence in nontraditional sites, such as hospital emergency rooms, and to address the role of social support resources in preventive interventions with African American battered women.
Expression of human phenylalanine hydroxylase activity in T lymphocytes of classical phenylketonuria children by retroviral‐mediated gene transfer
Authors: Lin C.M. , Tan Y. , Lee Y.M. , Chang C.C. , Hsiao K.J.
Published: December 2002

Classical phenylketonuria (PKU) is a metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. At present, T lymphocyte‐directed gene therapy is the only means for which a safety record has been established. Thus, we investigated the applicability of this strategy to PKU gene therapy. We first looked for tetrahydrobiopterin (BH4) and dihydropteridine reductase (DHPR) activity, which are required for the phenylalanine hydroxylation reaction and BH4 regeneration, respectively, in T cells isolated from PKU children. We found that T cells contained a small amount of biopterin, but significant DHPR activity, and that the intracellular biopterin content could be increased by exogenous BH4 supplementation. Moreover, PKU T cells were capable of taking up phenylalanine efficiently and effluxing acquired tyrosine. Finally, a recombinant retrovirus containing the human PAH cDNA was constructed and used to transduce isolated PKU T cells. Viral‐transduced T cells produced high levels of PAH activity as compared to control mock‐infected T cells. These results indicate that T lymphocytes express all that is required for synthesizing/replenishing constituents of the phenylalanine hydroxylation reaction and expressing transduced phenylalanine hydroxylase cDNA.
Severe lactic acidosis and neonatal death in Pearson syndrome
Authors: Muraki K. , Goto Y. , Nishino I. , Hayashidani M. , Takeuchi S. , Horai S. , Sakura N. , Ueda K.
Published: December 2002

Pearson marrow‐pancreas syndrome, a fatal disease associated with mitochondrial DNA rearrangements, is characterized by refractory sideroblastic anaemia during infancy. Only a few neonates with Pearson syndrome have been reported with metabolic acidosis. A female neonate who exhibited severe metabolic acidosis and anaemia at birth is described here. Her condition progressively worsened, with pancytopenia and uncontrollable metabolic acidosis resulting in death at the age of 14 days. A 4988‐base pair deletion of mtDNA was detected in the patient's leukocytes, liver and muscle. When a neonate exhibits severe metabolic acidosis of unknown cause, the possibility of Pearson syndrome should be considered.