bluuebunny/crossref_metadata_2025 huggingface dataset:
Inborn errors of metabolism and pregnancy
Authors: Walter J. H.
Published: December 2002

An increasing number of women with inborn errors of metabolism are now reaching child‐bearing age. For certain disorders there are maternal risks associated with pregnancy. These may be related to an increased likelihood of metabolic decompensation (e.g. disorders of the urea cycle) or to increased stress to systems already compromised by disease (e.g. cardiomyopathy in GSD III). Detrimental effects upon the fetus may also be caused by maternal disease, as occurs with phenylketonuria, or from medication used to treat the mother's condition. Less commonly, fetal inborn errors may adversely effect the mother's health – e.g. fetal long‐chain acyl‐CoA dehydrogenase deficiency and the maternal HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and AFLP (acute fatty liver of pregnancy). Because of the rarity of individual disorders, our knowledge of risks associated with pregnancy is limited. Even for more common inborn errors such as phenylketonuria, there remain a number of questions that have not been fully answered.
Microphotometric analysis of NADH‐tetrazolium reductase deficiency in fibroblasts of patients with Leber hereditary optic neuropathy
Authors: Malik S. , Sudoyo H. , Marzuki S.
Published: December 2002

We employed a microphotometric approach to examine whether a defect in the mitochondrial respiratory complex I expected in Leber hereditary optic neuropathy (LHON) as the consequence of a mtDNA (11778G>A) mutation in the ND4 gene coding for a subunit of the respiratory complex I can be detected at the single‐cell level. Genetically stable fibroblast cell lines were established from skin biopsies of two members of a Chinese Indonesian family with LHON. The fibroblasts were homoplasmic for the 11778G>A mutation. The activity of the respiratory complex I was examined histochemically by staining for NADH‐tetrazolium reductase. The histochemical staining showed a typical pattern with an apparent concentration of the activity around the nucleus, suggested as the reflection of the gradient in the thickness of the unsectioned fibroblast cells. Microphotometric quantification of the staining intensity showed that the activity is linear for at least 60min. The activity shows a discontinuity in its Arrhenius kinetics with a break point at 13.0–13.5°C (activation energy at 50–58 J/mol and 209–238 J/mol above and below the break temperature, respectively), indicating the membrane association of the NADH‐tetrazolium reductase activity. Both patients showed lower fibroblast NADH‐tetrazolium reductase activity, with a reduction of ∼30%. Our results demonstrate the utility of microphotometric analysis in the study of biochemical defects associated with mutations in the mtDNA.
Normative Influences on Aggression in Urban Elementary School Classrooms
Authors: Henry David , Guerra Nancy , Huesmann Rowell , Tolan Patrick , VanAcker Richard , Eron Leonard
Published: December 2002

We report a study aimed at understanding the effects of classroom normative influences on individual aggressive behavior, using samples of 614 and 427 urban elementary school children. Participants were assessed with measures of aggressive behavior and normative beliefs about aggression. We tested hypotheses related to the effects of personal normative beliefs, descriptive classroom norms (the central tendency of classmates' aggressive behavior), injunctive classroom normative beliefs (classmates' beliefs about the acceptability of aggression), and norm salience (student and teacher sanctions against aggression) on longitudinal changes in aggressive behavior and beliefs. Injunctive norms affected individual normative beliefs and aggression, but descriptive norms had no effect on either. In classrooms where students and teachers made norms against aggression salient, aggressive behavior diminished over time. Implications for classroom behavior management and further research are discussed.
The Latent Structure of Substance Use Among American Indian Adolescents: An Example Using Categorical Variables
Authors: Mitchell Christina M. , Plunkett Mark
Published: December 2002

Researchers frequently have only categorical data to analyze and cannot, for theoretical or methodological reasons, assume that the observed variables are discrete representations of an underlying continuous variable. We present latent class analysis as an alternative method of measuring latent variables in these circumstances. Latent class analysis does not require the assumptions of factor analyses about the nature of manifest and latent variables, but does allow the use of more precise model selection than techniques such as cluster analysis. We modeled the lifetime substance use of American Indian youth. The latent class model of American Indian teenagers' substance use had four classes: Abstaining, Predominantly Alcohol, Predominantly Alcohol and Marijuana, and Plural Substance. We then demonstrated the usefulness of this latent variable by using it to differentiate levels of several variables in a manner consistent with Social Cognitive Theory.
Subverting Culture: Promoting HIV/AIDS Prevention Among Puerto Rican and Dominican Women
Authors: Ortiz-Torres Blanca , Serrano-García Irma , Torres-Burgos Nélida
Published: December 2002

This article discusses the challenges faced by researchers and interventionists when attempting to promote change in social norms and normative beliefs that promote HIV/AIDS risk‐related behaviors among Puerto Rican and Dominican women. The article focuses on the role of culture in HIV/AIDS prevention with women by analyzing the sociohistorical context of some cultural beliefs and by illustrating the tension between risk‐related and protective cultural beliefs in research conducted by the authors with women in both New York and Puerto Rico. The authors propose that promoting changes in sex‐related social norms and normative beliefs might be constructed as a subversive act and present the challenge this analysis poses for community psychology. They conclude that this conceptualization might be construed as subversive because rather than idealizing culture, it promotes changes that respect diversity within the culture and foster participation in the development of new cultural values, beliefs and norms.
A Cost Analysis of Self‐Management Programs for People with Chronic Illness
Authors: Groessl Erik J. , Cronan Terry A.
Published: December 2002

The soaring cost of health care is a national problem that needs response at multiple levels, including that of the community. Reducing or limiting health care costs through interventions that emphasize the self‐management of health may promote broader health care coverage, better quality of health care, and a sense of control over one's health. Therefore, it behooves community psychologists to perform cost analyses when testing interventions for people in a community. The present study investigated the effects of social support and education interventions on psychosocial variables, health status, and health care costs in older people with osteoarthritis. Participants were 363 members of a health maintenance organization (HMO), 60 years of age and older, with osteoarthritis. Participants were randomly assigned to one of three intervention groups (social support, education, or a combination of both) or to a control group. The results indicated that feelings of helplessness decreased in the intervention groups but not in the control group. All groups showed increases in self‐efficacy and overall health status. In addition, health care costs increased less in the intervention groups than in the control group. Cost analysis was used to demonstrate that the monetary savings of the intervention greatly outweighed the cost of conducting the intervention. It appears that interventions can limit health care costs while improving health and increasing feelings of control for older people with osteoarthritis. Further, this paper demonstrates how a cost‐benefit focus can benefit community studies.
Help‐Seeking Comfort and Receiving Social Support: The Role of Ethnicity and Context of Need
Authors: Kaniasty Krzysztof , Norris Fran H.
Published: December 2002

Examined help‐seeking comfort and receiving social support among Latinos, African Americans, and European Americans across two contexts: in a communitywide emergency (Hurricane Andrew) and 2 years later in a nonemergency situation. In general, help‐seeking comfort was a strong predictor of received support. Notwithstanding many similarities between the groups, the effects of ethnicity differed according to the context. In emergency, all groups reported similarly high levels of help‐seeking comfort and received support. In nonemergency, help‐seeking comfort declined for blacks and whites but not for Latinos. Although all ethnic groups reported receiving less social support in nonemergency, the decline in received support across contexts was most dramatic for Latinos. Situational, cultural, and differential resource loss explanations are offered to account for the findings.
The Coming‐Out Process and Its Adaptational and Health‐Related Associations Among Gay, Lesbian, and Bisexual Youths: Stipulation and Exploration of a Model
Authors: Rosario Margaret , Hunter Joyce , Maguen Shira , Gwadz Marya , Smith Raymond
Published: December 2002

A model is proposed and explored that links the coming‐out process to the psychological functioning (i.e., self‐esteem and distress) and sexual behaviors of gay, lesbian, and bisexual youths recruited from gay‐focused community‐based and college organizations in New York City. The coming‐out process is multidimensional, consisting, as defined here, of involvement in gay/lesbian activities, attitudes toward homosexuality, comfort with homosexuality, self‐disclosure of sexual identity to others, and sexual identity. The coming‐out dimensions were related to self‐esteem, distress, and unprotected sexual behaviors. In addition, the relations between the coming‐out dimensions and unprotected sexual behaviors were explained by psychological functioning. In particular, limited involvement in gay/lesbian activities was associated with more unprotected sex. Negative attitudes toward homosexuality were related directly to more unprotected sex, and they were related indirectly to more unprotected sex by means of increasing emotional distress. These and other findings have implications for designing preventive interventions to increase the youths' psychological functioning and reduce their unprotected sexual behaviors.
The Benefits of Mutual Support Groups for Parents of Children With Disabilities
Authors: Solomon Michael , Pistrang Nancy , Barker Chris
Published: December 2002

This study examined what parents of children with disabilities and special needs found helpful about belonging to mutual support groups. Quantitative data (based on 56 parents from 6 groups) indicated that members found the groups very helpful and were very satisfied with the support they received from their groups; they also described the groups as high in cohesion, expressiveness, task orientation, and self‐discovery. A grounded theory analysis of focus group data (based on 43 parents from 5 of the groups) indicated that such support was helpful in three broad domains: (1) the sociopolitical, which involved developing a sense of control and agency in the outside world; (2) the interpersonal, which involved asense of belonging to a community; and (3) the intraindividual, which involved self change. A central theme of identity change emerged as superordinate to these three categories.
Identification of ‘private’ mutations in patients with ornithine transcarbamylase deficiency
Authors: Tuchman M. , Morizono H. , Rajagopal B. S. , Plante R. J. , Allewell N. M.
Published: December 2002

The majority of cases of ornithine transcarbamylase deficiency are due to novel mutations making it impossible to develop common methods for genetic analysis. However, identification of causative mutations has important implications for diagnosis (particularly prenatal diagnosis), prediction of likely course and outcome and the eventual possibility of gene therapy. As part of a continuing study of ornithine transcarbamylase deficiency, we now report an additional thirty novel mutations in the ornithine transcarbamylase gene, together with a brief summary of their clinical presentations.
A new case of multiple mitochondrial enzyme deficiencies with decreased amount of heat shock protein 60
Authors: Briones P. , Vilaseca M. A. , Ribes A. , Vernet A. , Lluch M. , Cusi V. , Huckriede A. , Agsteribbe E.
Published: December 2002

Heat shock protein 60 (hsp60) is a mitochondrial matrix protein involved in the folding and correct assembly of polypeptides into complex mitochondrial enzymes. Its deficiency has recently been described as the most likely primary cause of congenital lactic acidaemia with multiple mitochondrial enzyme deficiencies in a female patient. We describe a new case of a girl with a substantially decreased amount of hsp60 in cultured fibroblasts. She presented from birth with hypotonia, unusual facial features, feeding difficulties and failure to thrive. Death occurred at age 4.5 years. Biochemical findings included metabolic acidosis with lactic acidaemia, hyperammonaemia and intermittent ketosis. In contrast to the previously reported case, organic acid analysis showed an altered profile throughout her life. In agreement with this profile, various mitochondrial enzyme activities were deficient in cultured fibroblasts, including enzymes of the respiratory chain and the Krebs cycle, the pyruvate dehydrogenase complex and the mitochondrial biotin‐dependent carboxylases. Fibroblast mitochondria showed ultrastructural abnormalities, were swollen, and were mainly localized around the nucleus.

The description of a second case of multiple mitochondrial enzyme deficiencies with reduced amount of hsp60 supports the idea that hsp60 deficiency might be a more common cause of mitochondrial disease. This opens new possibilities for the diagnosis and understanding of congenital lactic acidaemia.
Inborn errors of the purine nucleotide cycle: Adenylosuccinase deficiency
Authors: Van den Berghe G. , Vincent M. F. , Jaeken J.
Published: December 2002

Adenylosuccinase catalyses two reactions in purine metabolism: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) into amino‐imidazole carboxamide ribotide (AICAR) along the de novo synthesis of purine nucleotides, and the conversion of adenylosuccinate (S‐AMP) into AMP in the conversion of IMP into AMP. The hallmarks of adenylosuccinase deficiency are the presence of succinylaminoimidazole carboxamide riboside (SAICAriboside) and succinyladenosine (S‐Ado) in body fluids. These normally undetectable succinyl‐purines are the products of the dephosphorylation, by cytosolic 5′‐nucleotidase, of the two substrates of adenylosuccinase. The clinical picture of the enzyme deficiency is markedly heterogeneous with, as a rule, a profound, but nevertheless variable degree of psychomotor delay, often convulsions and/or autistic features, sometimes growth retardation and muscular dystrophy. The diagnostic tests that can be used for diagnosis, the enzyme and gene defects that have been identified, and the hypotheses that have been put forward to explain the pathophysiology of the disorder are reviewed.
mtDNA depletion and impairment of mitochondrial function in a case of a multisystem disorder including severe myopathy
Authors: Kirches E. J. F. , Winkler K. , Warich‐Kirches M. , Szibor R. , Wien F. , Kunz W. S. , von Bossanyi P. , Bajaj P. K. , Dietzmann K.
Published: December 2002

The ratio of mtDNA and a nuclear reference gene was estimated by Southern blotting in the skeletal muscle DNA of a 3‐year‐old girl who suffered from congenital brain damage, focal epilepsy, hepatomegaly, malabsorption syndrome and severe myopathy. The signal ratio of mtDNA versus 18S rDNA was 22% of the mean value obtained from controls. No major deletions or insertions were found and the MERRF, MELAS and NARP mutations were ruled out. Mitochondrial DNA‐encoded enzyme activities and mitochondrial respiration were reduced. The analysis of the NAD(P)H and flavoprotein redox states of intact fibres revealed the presence of mitochondrial dysfunction. In tissue sections a moderate elevation of type I and type II fibre diameter variation was detected, aberrant NADH‐ and succinate dehydrogenase staining and some ragged red fibres. This suggested that a mitochondrial disorder caused by a decrease in the amount of intact wild‐type mtDNA was responsible for the severe myopathy.
Neuropsychological outcome of experimental manipulation of phenylalanine intake in treated phenylketonuria
Authors: Griffiths P. , Ward N. , Harvie A. , Cockburn F.
Published: December 2002

Blood phenylalanine concentrations were experimentally increased for 3 months by means of a phenylalanine‐complemented amino acid supplement in a group of 16 children aged 10‐16 years with classical phenylketonuria who had been treated early and who had remained on the restricted diet. Average concentrations achieved during challenge were between 1000 and 1300 µmol/L. Psychological outcome was measured by a neuropsychological battery consisting of tests of verbal and spatial memory, attention and fine motor coordination. A triple‐blind, repeated measures, randomized, crossover design was adopted to control for practice and expectancy effects. Subjects were assessed at baseline and at the end of the first and second phenylalanine manipulation periods. Significant interactions (ANOVA) emerged as predicted for phenylalanine concentrations, but similar crossover effects were not found for any of the neuropsychological tests. The results suggested that medium‐term hyperphenylalaninaemia in treated PKU is not harmful to psychological functioning in older children and adolescents who have been continuously treated up to and beyond age 10 years, though the susceptibility of executive functions needs to be further researched. The findings add some weight to the idea that by late childhood the vulnerability of the nervous system to the neurotoxic influence of phenylalanine may be much reduced.
Treatment with low‐dose diazoxide in two growth‐retarded prepubertal girls with glycogen storage disease type Ia resulted in catch‐up growth
Authors: Nuoffer J. M. , Mullis P. E. , Wiesmann U. N.
Published: December 2002

Two originally prepubertal girls suffering from glycogen storage disease type Ia and short stature were treated with low‐dose diazoxide (3‐4.8 mg/kg per day) for 7 and 4 years, respectively. Both showed an impressive catch‐up growth following this treatment. This appeared to be due to prolongation of normoglycaemia after meals and reduction of fasting lactic acidosis by diazoxide.
Assessment of homocysteine status
Authors: Refsum H. , Fiskerstrand T. , Guttormsen A. B. , Ueland P. M.
Published: December 2002

Plasma total homocysteine (tHcy) determination is used in the diagnosis of homocystinuria, in cobalamin and folate deficiency and in cardiovascular risk assessment. However, determination of tHcy includes many pitfalls which complicate the assessment of homocysteine status. In the present article, we review basic knowledge for a rational use of plasma tHcy in diagnostic as well as scientific work. The subjects dealt with are procedures for sample handling and processing, the principles of tHcy analyses, and genetic and acquired determinants of the plasma tHcy concentration.
Treatment products and approaches for phenylketonuria: improved palatability and flexibility demonstrate safety, efficacy and acceptance in US clinical trials
Authors: Prince A. P. , McMurry M. P. , Buist N. R. M.
Published: December 2002

A new amino acid formulation and a variety of treatment products incorporating it were evaluated for long‐term safety, efficacy, and acceptance in 25 subjects with phenylketonuria over a period of 5 years. Palatability of the treatment was improved by reducing the required intake of amino acids, reformulating the mixture to have better taste, and providing vitamins and minerals as tablets. The hypotheses were that these strategies would improve compliance and metabolic control and maintain nutritional status in subjects. Compliance with treatment was determined from mean reported intakes (4‐day diet records) and from mean ‘received’ intakes using receipts of treatment products actually shipped to individuals upon request. Mean amino acid intakes prescribed were significantly reduced from study entry to end, from 1.2 g/kg to 0.7 g/kg (p < 0.001). Reported intakes were similarly reduced from 1.3 g/kg to 0.7 g/kg (p < 0.001). While actually ‘received’ intakes of amino acid formula were also significantly reduced (p < 0.001), intakes by this measure were much lower than either prescribed or reported, 0.9 g/kg at entry and 0.4 g/kg at the end of the study, suggesting that acceptance of the treatment (usage of products), even when made more palatable, is below clinical expectations. In spite of these findings, mean serum proteins and minerals, height and weight were not significantly reduced during the study, supporting the safety of lowered intakes of amino acids and of nutritionally incomplete products. While the increase in mean serum phenylalanine concentration from 0.38 to 0.48 mmol/L was significant (p < 0.03), this mean rise of 0.1 mmol/L during a corresponding mean age increase of 4.2 years (from 6.9 to 11.1 years) is lower than in other recent reports from longitudinal studies of outcomes during this age range in subjects treated with traditional products. These data support the safety and efficacy of a more palatable and flexible approach to treatment.
Huntington disease: Advances in molecular and cell biology
Authors: Jones A. L. , Wood J. D. , Harper P. S.
Published: December 2002

Huntington disease is an inherited neurodegeneration, for which the associated mutation was isolated in 1993. The mutation is an expansion of a CAG trinucleotide repeat, which translates to give a polyglutamine tract at the N‐terminus of a large protein, huntingtin. Neither the normal nor the pathogenic functions of this protein have been identified, but it is clear that pathogenesis is mediated through the expanded polyglutamine tract within the protein, and that polyglutamine is toxic to cells. A number of proteins which interact with the N‐terminal region of huntingtin have been isolated, but this has not, so far, yielded a rationale for pathogenesis. Huntingtin is found in areas of the brain that degenerate in this disease, but is also associated with pathogenic inclusions in Alzheimer disease and Pick disease. It is possible that Huntington disease has pathogenic mechanisms in common with these other neurodegenerative diseases, and that the mechanism may relate to the formation of abnormal, cytoskeletal‐associated, inclusions within cells.
Social factors and the meaning of food in adherence to medical diets: results of a maternal phenylketonuria summer camp
Authors: Waisbren S. E. , Rokni H. , Bailey I. , Rohr F. , Brown T. , Warner‐Rogers J.
Published: December 2002

A Maternal PKU camp provided education and social support for 25 young women with phenylketonuria (PKU). Questionnaires were administered and blood samples were collected on the first and last days of camp to evaluate the psychological and medical impact of the programme. Long‐term outcome was assessed through telephone interviews 7 ‐ 14 months later. Knowledge of maternal PKU and the maternal PKU diet increased significantly. There was a significant increase in campers' ratings of the degree to which others supported the use of birth control to prevent late‐treated pregnancies, although campers' comfort with contraception did not change. Mean blood phenylalanine concentrations were significantly reduced by 37% during camp and by 20% at follow‐up. Ninety‐six per cent of campers remained in contact with other campers after the summer. At follow‐up, one pregnancy was reported, in which metabolic control was achieved prior to conception. Overall, attitudes about treatment and perceptions about ability to cope with PKU did not change to a significant degree. It is suggested that camps may be most successful in changing both behaviour and attitudes if they actively involve the campers in food preparation, address the psychological meaning of food in our culture, and provide social support.
Lysosomal enzyme activities in serum and leukocytes from patients with carbohydrate‐deficient glycoprotein syndrome type IA (phosphomannomutase deficiency)
Authors: Barone R. , Carchon H. , Jansen E. , Pavone L. , Fiumara A. , Bosshard N. U. , Gitzelmann R. , Jaeken J.
Published: December 2002

From 10 patients with carbohydrate‐deficient glycoprotein (CDG) syndrome due to phosphomannomutase (PMM) deficiency, out of 10 lysosomal enzymes, 7 enzyme activities were measured in serum and 9 in leukocytes. In serum there was a 2‐fold to 4‐fold increase in activity of β‐glucuronidase, β‐hexosaminidase, β‐galactosidase, and arylsulphatase A. In leukocytes, however, several enzymes had reduced activity, particularly α‐fucosidase, β‐glucuronidase and α‐mannosidase. These abnormalities could result from missorting, defective reuptake and/or reduced stability of the enzymes due to the defective glycosylation.
Succinic semialdehyde dehydrogenase deficiency: low excretion of metabolites in a neonate
Authors: Pitt J. J. , Hawkins R. , Cleary M. , Eggington M. , Thorburn D. R. , Warwick L.
Published: December 2002

A neonate at risk for succinic semialdehyde dehydrogenase deficiency was investigated on day 1. The urine level of 4‐hydroxybutyrate was only slightly elevated (23 µmol/mmol of creatinine; controls 1.6‐14, n=18). This value was considerably less than those found for older children with succinic semialdehyde dehydrogenase deficiency and made interpretation of the result uncertain. The diagnosis of succinic semialdehyde dehydrogenase deficiency was confirmed by enzyme assay, and repeat urine testing showed a steady increase in the level of 4‐hydroxybutrate to 359 µmol/mmol at 6 months.
Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC)
Authors: Rosenblatt D. S. , Aspler A. L. , Shevell M. I. , Pletcher B. A. , Fenton W. A. , Seashore M. R.
Published: December 2002

The clbC form of methylmalonic acidaemia is a rare and poorly understood condition which results from impaired biosynthesis of methylcobalamin and adenosylcobalamin. The consequent functional deficiencies of methylmalonyl‐CoA mutase and methionine synthase produce both methylmalonic aciduria and homocystinuria. Systemic symptoms and neurological decompensation comprise the clinical phenotype. In an effort to clarify the phenotype and prognosis, we obtained clinical information on 50 patients with methylmalonic acidaemia whose cells had been assigned to the cblC complementation group. We identified two distinct phenotypes; they differed in age of onset, presence of systemic symptoms, type of neurological symptoms, and outcome after diagnosis and treatment. Forty‐four patients presented in the first year of life. Feeding difficulties, neurological dysfunction (hypotonia, seizures, developmental delay), and ophthalmological and haematological abnormalities characterized their clinical picture. About one‐quarter of those patients died. Survival was associated with neurological impairment; only one infant was neurologically intact at follow‐up. Onset in childhood, in contrast, was associated with less severe haematological abnormalities, largely involving the red cell series. Extrapyramidal signs, dementia, delirium or psychosis characterized the neurological findings. Survival, with mild to moderate disability in some, was typical in patients with later onset. Treatment in both groups included hydroxycobalamin, betaine and carnitine; complete normalization of biochemical parameters was rare.
A longitudinal study of cognitive functioning in patients with classical galactosaemia, including a cohort treated with oral uridine
Authors: Manis F. R. , Cohn L. B. , McBride‐Chang C. , Wolff J. A. , Kaufman F. R.
Published: December 2002

Existing longitudinal data on patients with classical galactosaemia suggests that neurocognitive functioning is impaired and, in isolated case reports, may show a decline in performance over time. The present study explored whether there are long‐term changes in cognitive abilities in patients with galactosaemia and whether oral uridine can improve neurocognitive performance. Thirty‐five patients (18 males, 17 females), 29 of whom received oral uridine powder at 150 mg/kg per day (divided dose, three times daily), were evaluated over a 2‐5‐year period with the Woodcock‐Johnson Revised Cognitive Abilities Test, three academic achievement tests, and the Beery Test of Visual Motor Integration. Results showed that the uridine cohort and a comparison group that received only dietary restriction made small gains in cognitive performance over the treatment period and the size of the gains did not differ significantly. Seven subjects who started uridine prior to the age of 14 months did not differ significantly in their cognitive test scores at an average age of 3.5 years from a group of older children who had begun treatment at 4.5 years of age. These results provide no support for any developmental or uridine‐treatment‐related change in cognitive functioning for this sample of galactosaemic subjects.
Identification of a common mutation (R245H) in Sanfilippo A patients from the Netherlands
Authors: Weber B. , van de Kamp J. J. P. , Kleijer W. J. , Guo X.‐H. , Blanch L. , van Diggelen O. P. , Wevers R. , Poorthuis B. J. H. M. , Hopwood J. J.
Published: December 2002

We have identified a common mutation (R245H) in the sulphamidase gene of Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA, MPS IIIA) patients from The Netherlands. Allele‐specific oligonucleotide hybridization was used to determine the incidence of this mutation in 45 unrelated MPS IIIA patients from different regions of The Netherlands. R245H was present in 51 alleles, representing 56.7% of the total allelic population. Of 39 patients, for whom we have uniform clinical details, 13 MPS IIIA patients who were homozygous for this common mutation had a more uniform but severe clinical phenotype than the remaining 21 or 5 patients, containing respectively one or no R245H alleles. The R245H allele had a higher prevalence in western rather than eastern regions of The Netherlands.
Human α‐galactosidase A: High plasma activity expressed by the ‐30G→A allele
Authors: Fitzmaurice T.F. , Desnick R.J. , Bishop D.F.
Published: December 2002

Human α‐galactosidase A (EC 3.2.1.22; α‐Gal A) is the lysosomal exoglycosidase responsible for the hydrolysis of terminal α‐galactosyl residues from glycoconjugates and is the defective enzyme causing Fabry disease (McKusick 301500). An unsually elevated level of plasma α‐Gal A activity (>2.5 times the normal mean) was detected in two unrelated normal males and the elevated activities were inherited as X‐linked traits in their families. Sequencing of the α‐Gal A coding region, intron/exon boundaries and 5′‐flanking region from the proband identified a single mutation, a G→A transition 30 nt upstream from the initiation of translation codon in exon 1. The ‐30G→A mutation occurred in a putative NFκB/Ets consensus binding site that was recently shown to inhibit protein binding to the 5′‐untranslated region of the gene, providing a possible explanation for its high activity. To further characterize the mutation, the mRNA and protein expressed by this variant allele were studied. Purified plasma and lymphoblast α‐Gal A activity from individuals with the ‐30G→A mutation had normal physical and kinetic properites. In vitro translation of mRNAs from the cloned normal and high plasma activity alleles resulted in similar levels of α‐Gal A protein, indicating that this mutation did not enhance translation. These findings suggest that the ‐30G→A mutation in the 5′‐untranslated region of the α‐Gal A gene enhances transcription, presumably by interfering with the binding of negatively‐acting transcription factors which normally decrease α‐Gal A expression in various cells. Preliminary studies of the frequency of the ‐30G→A mutation in 395 unrelated normal males of mixed ancestry revealed two additional unrelated individuals who had high plasma enzymatic activity and the mutation, confirming the effect of this mutation on enzyme expression and suggesting that about 0.5% of normal individuals have high plasma α‐Gal A activity due to this variant allele.
The association between haematological manifestation and mtDNA deletions in Pearson syndrome
Authors: Muraki K. , Nishimura S. , Goto Y. , Nonaka I. , Sakura N. , Ueda K.
Published: December 2002

We studied the proportion of deleted mitochondrial DNA in blood cells from patients with Pearson syndrome. Patient 1 is a 17‐year‐old female with Kearns‐Sayre syndrome who survived Pearson syndrome. Patient 2 is a 5‐year‐old boy with Pearson syndrome who recovered from refractory anaemia but continues to have thrombocytopenia and neutropenia. Patient 3 is a female neonate who died with severe acidosis and pancytopenia at 14 days of age. Southern blot analysis was performed with total DNA from three patients' blood cells and two samples of bone marrow cells from one patient. In peripheral blood, patients with a higher proportion of deleted mitochondrial DNA had lower blood cell counts. In patient 2, the percentage of mutant mitochondrial DNA in bone marrow cells decreased as anaemia improved. This indicates that the proportion of deleted mitochondrial DNA in peripheral blood and in bone narrow has a tendency to correlate to the severity of haematological manifestation.
Pregnancy in a woman with maple syrup urine disease
Authors: Grÿnewald S. , Hinrichs F. , Wendel U.
Published: December 2002

We present the favourable outcome of a pregnancy in a woman with maple syrup urine disease. Keeping the maternal plasma levels of the branched‐chain amino acids between 100 and 300 µmol/L is compatible with delivery of a normal infant. Leucine tolerance increased progressively from the 22nd week of gestation from 350 to 2100 mg/day. The risk of metabolic decompensation in the postpartum period can be minimized by careful monitoring of the mother after delivery.
Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene
Authors: Dionisi‐Vici C. , Seneca S. , Zeviani M. , Fariello G. , Rimoldi M. , Bertini E. , De Meirleir L.
Published: December 2002

We report an Italian family in which the T‐to‐C point mutation at nucleotide 9176 of the mitochondrial adenosine triphosphate synthetase (mtATPase) 6 gene is associated with an early‐onset fulminant form of Leigh syndrome and with sudden unexpected death in two siblings, respectively. Polymerase chain reaction single‐strand conformation polymorphism (PCR‐SSCP) analysis and direct sequencing revealed that the mutation was homoplasmic in mitochondrial DNA of the proband. The T9176C mutation changes a highly conserved leucine to a proline in subunit 6 of the mtATPase gene and is maternally inherited, but the maternal relatives are asymptomatic. This point mutation was initially described in two brothers with bilateral striatal necrosis, a milder variant of Leigh syndrome.
The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease
Authors: Bonham J. R. , Guthrie P. , Downing M. , Allen J. C. , Tanner M. S. , Sharrard M. , Rittey C. , Land J. M. , Fensom A. , O'Neill D. , Duley J. A. , Fairbanks L. D.
Published: December 2002

Thirty‐three children ranging from 2 weeks to 12 years of age were selected for allopurinol loading, 16 on the basis of an increased urinary orotate excretion detected by routine organic acid analysis (group A), and 17 for clinical reasons suggesting a urea cycle defect (group B). The allopurinol load test proved positive in 13 of 16 patients from group A, mean peak orotate 64.0μmol/mmol creatinine (upper limit of reference range, 13.2) and 11 of 17 patients from group B, mean peak orotate 41.0μmol/mmol creatinine (upper limit of reference range, 13.2). Thorough investigation of these patients including urinary and plasma amino acid analysis and, in 17 cases, liver biopsy for histology and measurement of ornithine carbamyltransferase (OCT) and carbamyl‐phosphate synthetase (CPS) activity failed to identify any evidence of a urea cycle disorder. However, muscle biopsies performed in 11 patients showed some evidence of mitochondrial disease in four cases, two defined on the basis of reduced respiratory chain enzyme activity and two on the basis of mtDNA abnormalities. These findings indicate that an increased excretion of orotate in sick children may not be uncommon and that a positive allopurinol load test result may not indicate a specific inherited urea cycle defect. In addition, these results raise the interesting possibility that defective ureagenesis may be a feature of mitochondrial disease in some individuals.
Glycosphingolipid degradation and animal models of GM2‐gangliosidoses
Authors: Kolter T. , Sandhoff K.
Published: December 2002

Glycosphingolipids form cell type‐specific patterns on the surface of eukaryotic cells. Degradation of glycosphingolipids requires endocytic membrane flow of plasma membrane‐derived glycosphingolipids into the lysosomes as the digesting organelles. The inherited deficiencies of lysosomal hydrolases and of sphingolipid activator proteins both give rise to sphingolipid storage diseases. Recent research has focused on the mechanisms leading to selective membrane degradation in the lysosomes and on the mechanism and physiological function of sphingolipid activator proteins. The GM2‐degrading system is a paradigm for activator protein‐dependent lysosomal degradation. Three polypeptide chains contribute to the in vivo degradation of ganglioside GM2: the α‐ and β‐chains of the β‐hexosaminidases and the GM2 activator. Mouse models of Tay–Sachs disease (α‐chain deficiency), Sandhoff disease (β‐chain deficiency) and GM2 activator deficiency have been described. While the phenotypes of these variants of GM2‐gangliosidoses are only slightly different in humans, the animal models show drastic differences in severity and course of the diseases. The reason for this is the specificity of sialidase, which is different between mouse and human. A double‐knockout mouse lacking β‐hexosaminidases A, B and S shows a phenotype of mucopolysaccharidosis and gangliosidosis. A substrate deprivation approach to therapy is discussed with respect to animal models of the GM2‐gangliosidoses.
Diagnosis of isovaleric acidaemia by tandem mass spectrometry: False positive result due to pivaloylcarnitine in a newborn screening programme
Authors: Abdenur J. E. , Chamoles N. A. , Guinle A. E. , Schenone A. B. , Fuertes A. N. J.
Published: December 2002

Tandem mass spectrometric analysis of acylcarnitines and amino acids has been applied in newborn screening programmes for the detection of several inborn errors of metabolism. We report a false positive result for isovaleric acidaemia in a newborn screening programme using this method. The newborn screening sample showed a very prominent signal corresponding to the mass of isovalerylcarnitine. Repeat samples (age 6 days) of blood and urine showed similar results. However, urine organic acids were normal. Acylcarnitine analysis in blood, breast milk and urine of the mother also showed a prominent signal of the same mass. Gas chromatography–mass spectrometry of the methyl esters demonstrated that the signal in the patient's urine was due to the presence of pivaloylcarnitine, which is isomeric with isovalerylcarnitine. The patient's mother was receiving an antibiotic containing a derivative of pivalic acid to treat a urinary tract infection. Follow‐up samples in the patient and the mother confirmed a decrease in the levels of pivaloylcarnitine, concomitant with the discontinuation of the treatment.

We conclude that pivaloylcarnitine can give a false positive result for isovaleric acidaemia in newborns whose mothers are on treatment with pivoxilsulbactam‐containing antibiotics.
Hunter disease in the Spanish population: Molecular analysis in 31 families
Authors: Gort L. , Chabás A. , Coll M. J.
Published: December 2002

Mucopolysaccharidosis type II (Hunter disease) is an X‐linked disorder due to deficiency of the lysosomal enzyme iduronate 2‐sulphatase. Here we report an update of molecular studies in 31 Spanish families with Hunter disease. We found a total of 22 novel small mutations (7 reported previously by our group), and 4 large deletions or rearrangements. Particularly relevant are two mutations, one showing an alternatively spliced product although the normal splice site is conserved; the other mutation results in an amino acid change that most likely modifies regulation of expression of the IDS gene. Except for large gene alterations and for the G374sp mutation already described, we could not establish a clear phenotype–genotype correlation. Mutation G374sp is the point mutation most frequent in our population (10%) and is always associated with mild phenotype. Our molecular analyses carried out in a relatively large series of patients with Hunter disease contribute to the identification of new mutations and reinforce the conclusions drawn in other populations about the genotype–phenotype correlation and the gene distribution of mutations.
Severe skeletal complications in Japanese patients with type 1 Gaucher disease
Authors: Ida H. , Rennert O. M. , Kato S. , Ueda T. , Oishi K. , Maekawa K. , Eto Y.
Published: December 2002

To better characterize skeletal complications in Japanese patients with type 1 Gaucher disease (GD), we performed genotyping and clinical and radiological analysis of 35 patients, the vast majority of this population, Skeletal complications tend to be very common, severe and rapidly progressive in Japanese patients with type 1 GD. Twenty (57%) of these patients manifested end points of severe bone disease including avascular necrosis, pathological fracture and/or bone crisis. Mean time from presentation/diagnosis of GD until presentation of this involvement was 3 years 6 months±4 years 1 month. Prevalence of severe bone disease is significantly higher in splenectomized than in non‐splenectomized patients – 81% (17/21) versus 21% (3/14) (p=0.0007, Fisher's exact test). Four (29%) of 14 patients receiving enzyme replacement therapy (ERT) or bone marrow transplantation (BMT) manifested severe bone involvement for the first time during or after treatment. All cases occurred in children in whom ERT doses had been lowered after only brief administration of higher starting doses (n=3) or partial donor marrow engraftment resulted in low glucocerebrosidase (GCR) activity (n=1). These observations suggest that splenectomy may correlate with accelerated skeletal deterioration with severe skeletal disease, at least in patients with severe phenotypic expression. They also suggest that it is important that sufficient GCR is available in paediatric patients with severe phenotypic expression. Hence ERT dosages should be based on disease severity and on age, with sustained administration of full doses in patients at greater risk of important skeletal complications.
Variables influencing parental perception of inherited metabolic diseases before and after genetic counselling
Authors: Saleem R. , Gofin R. , Ben‐Neriah Z. , Boneh A.
Published: December 2002

The present study was undertaken to characterize the variables that influence parental perception of metabolic disorders and their genetic origin before and after genetic counselling, the effect of counselling on parental attitudes towards prenatal diagnosis and pregnancy termination, and the factors affecting parental coping with burden.

Parents of children with metabolic diseases from 32 Arab‐Muslim families were interviewed, answering a pre‐structured questionnaire. These interviews indicate the following. (1) Traditional belief and religious commitment are more important determinants than education in parental perception of inherited metabolic diseases. (2) The number of affected children has a greater impact on parental evaluation of the burden than the number of healthy children. The social component, i.e. the way families are viewed by society, is the most significant factor of the burden. (3) Parents use different techniques to divide responsibility regarding reproduction. Having a healthy child and the availability of prenatal diagnosis and pregnancy termination were the two most important factors in parental reproductive decision making. In the absence of a healthy child and when the burden was perceived as too heavy, parents tended ‘not to decide’. (4) Parental attitude to pregnancy termination was dependent on two factors: religious commitment (leading to objection) and severity of disease (leading to flexibility and approval). (5) In almost all families, genetic counselling altered parental perception of the disease and its hereditary origin.

We conclude that genetic counselling and population education may be helpful in the prevention of consanguineous marriages and in family planning, even in a society that values traditional beliefs very highly.
Pilot study of screening for Wilson disease using dried blood spots obtained from children seen at outpatient clinics
Authors: Ohura T. , Abukawa D. , Shiraishi H. , Yamaguchi A. , Arashima S. , Hiyamuta S. , Tada K. , Iinuma K.
Published: December 2002

Wilson disease (WD) is an autosomal recessive disorder of copper accumulation leading to liver and/or brain damage. In this paper, we describe the results of a pilot study of screening for WD using ceruloplasmin determinations in dried blood samples. Specimens were collected from children aged 1 to 6 years who were seen at local paediatric outpatient clinics in the Miyagi Prefecture. We measured ceruloplasmin (CP) concentrations in 2789 children using an enzyme‐linked immunosorbent assay. The mean value was 12.4±3.95 mg/dl blood. Among these children, we identified two (case 1, male, 2 years old; case 2, female, 3 years old) with markedly reduced CP concentrations. Apart from low serum copper concentrations, their biochemical findings were almost normal, as were growth and development. To confirm the diagnosis, we analysed the WD gene and detected A803T/2871delC mutations in case 1 and R778L/G1035V mutations in case 2. We conclude that these children were presymptomatic WD patients. The CP level in dried blood samples from children aged 1 to 6 years appears to be a reliable marker for early detection of WD.
Therapeutic trials in the murine model of hereditary tyrosinaemia type I: A progress report
Authors: Grompe M. , Overturf K. , Al‐Dhalimy M. , Finegold M.
Published: December 2002

We have studied a knockout mouse with fumarylacetoacetate hydrolase (FAH) deficiency as a model of human hereditary tyrosinaemia type I (HT1). These mice have a phenotype very similar to the human disease, which is characterized by acute hepatic failure, renal tubular disease and hepatocarcinoma. We have previously reported on the efficacy of 2‐(2‐nitro‐4‐trifluoromethylbenzyol)‐1,3‐cyclohexanedione (NTBC) in preventing acute liver disease in HT1 mice. Here we present a progress report on long‐term follow up (>1 year) of high‐dose NTBC therapy in combination with tyrosine restriction. In vivo retroviral gene therapy was also effective in abolishing the acute liver failure of HT1. Retrovirally treated mice remained completely healthy and active for 12 months after retroviral gene transfer. However, hepatocarcinoma developed in 2/3 treated animals after 1 year. Southern blot analysis showed that the tumours did not arise from retrovirally transduced hepatocytes but from non‐corrected FAH‐deficient cells. These results highlight the extreme danger for tumour formation in HT1 and indicate the need for improved gene therapy that leads to the elimination of endogenous FAH‐deficient liver cells.