bluuebunny/crossref_metadata_2025 huggingface dataset:
X‐linked pyruvate dehydrogenase E1α subunit deficiency in heterozygous females: Variable manifestation of the same mutation
Authors: Dahl H‐H. M. , Hansen L. L. , Brown R. M. , Danks D. M. , Rogers J. G. , Brown G. K.
Published: June 2005

Three female patients are described with pyruvate dehydrogenase (PDH) deficiency as a result of mutation in the X‐linked gene for the E1α subunit of the complex. Two of these patients illustrate typical presentations of PDH E1α deficiency, with severe neurological dysfunction, degenerative changes and developmental anomalies in the brain, together with variable lactic acidosis. The third patient extends the known spectrum of the condition to include mild to moderate mental retardation and seizures in an adult. All three patients have the same mutation in the PDH E1α gene. This mutation, a C‐to‐T substitution in a CpG dinucleotide in amino acid codon 302 (designated R302C), results in the replacement of arginine by cysteine at this position. The mildly affected adult was the mother of one of the other patients, making this the first described instance of mother‐to‐daughter transmission of a mutation causing PDH E1α deficiency. The genetic basis of the variable expression of X‐linked PDH E1α deficiency in heterozygous females is discussed.
Mutation of E1α gene in a female patient with pyruvate dehydrogenase deficiency due to rapid degradation of E1 protein
Authors: Ito M. , Huq A. H. M. M. , Naito E. , Saijo T. , Takeda E. , Kuroda Y.
Published: June 2005

A mutation of an insertion of 4 bp in the gene for the α subunit of pyruvate dehydrogenase (E1α) was found in a female with pyruvate dehydrogenase deficiency due to the rapid degradation of α and β subunit proteins of pyruvate dehydrogenase. This mutation caused a frameshift that altered the amino acid sequence and created a premature stop codon. This 4‐bp insertion has been found in an unrelated female patient with E1α deficiency. It is rare that the same mutation is found in unrelated patients with this rare inborn error of metabolism. Furthermore, short deletions or duplications in the E1α gene of patients with E1α deficiency have been found only in exons 10 and 11. These exons may be hot spots for the mutations by the recombinational processes. This patient was heterozygous for the normal and a mutant allele. However, in most of the cultured skin fibroblasts from this patient, the mutant allele was expressed. These observations suggest that the X chromosome containing the normal allele was predominantly inactivated so that she developed lactic acidaemia and neurological abnormalities despite being heterozygous. The mutant α subunit protein failed to form a stable structure of pyruvate dehydrogenase, so that both α and β subunit proteins were degraded rapidly.
Hypertrophic obstructive cardiomyopathy in a neonate with the carbohydrate‐deficient glycoprotein syndrome
Authors: Clayton P. T. , Winchester B. G. , Keir G.
Published: June 2005

The carbohydrate‐deficient glycoprotein (CDG) syndrome in its most severe form (neonatal olivopontocerebellar atrophy) is a life‐threatening multisystem disease. We report a neonate who was referred for cardiological assessment because of respiratory distress, a murmur and episodes of desaturation. After initial spontaneous improvement he presented at 9 weeks with evidence of a severe hypertrophic obstructive cardiomyopathy (HOCM). The diagnosis of CDG syndrome was suggested by the characteristic dysmorphic features, hypotonia, visual inattention and severe failure to thrive; it was confirmed by electrophoresis of serum transferrin. HOCM can be a feature of the CDG syndrome, in addition to the (previously reported) pericardial effusions.
Isolated biotin‐resistant deficiency of 3‐methylcrotonyl‐CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome
Authors: Bannwart C. , Wermuth B. , Baumgartner R. , Suormala T. , Wiesmann U. N.
Published: June 2005

The son of Kurdish, consanguineous parents (cousin marriage) presented from the first day of life with inititally focal and later generalized attacks of epileptic seizures and a severe generalized muscular hypotonia. Urinary excretion of 3‐hydroxyisovalerate and of 3‐methylcrotonylglycine was persistently increased. Diagnosis of isolated biotin‐resistant 3‐methylcrotonyl‐CoA carboxylase deficiency was confirmed in cultured fibroblasts. Psychomotor retardation was progressive, seizures and marked EEG abnormalities persisted. Treatment with leucine and protein‐resistricted diet under hospital control did not significantly improve these conditions. The patient died from a cardiac and circulatory failure after a prolonged epileptic attack, with bronchial aspiration. The non‐responsiveness of our patient to therapy and the fatal outcome indicate the existence of a severe neonatal variant of this otherwise rather benign genetic enzyme deficiency.
Differential diagnosis of hydroxydicarboxylic aciduria based on release of3H2O from [9,10‐3H]myristic and [9,10‐3H]palmitic acids by intact cultured fibroblasts
Authors: Olpin S. E. , Manning N. J. , Carpenter K. , Middleton B. , Pollitt R. J.
Published: June 2005

Intact cultured fibroblasts from patients with deficiency of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase release3H2O from [9,10‐3H]myristic acid and [9,10‐3H]palmitic acid more slowly than normal. The ratio of activity (palmitate/myristate) is also low and the expression (rate with palmitate)2/(rate with myristate) gives good differentiation between affected and unaffected cells. In some patients who have shown hydroxydicarboxylic aciduria when unwell there is reduced3H2O production from [9,10‐3H]myristic and [9,10‐3H]palmitic acids by intact cultured fibroblasts but normal 3‐hydroxyacyl‐CoA dehydrogenase activities in disrupted cells. The palmitate/myristate ratio is higher than in long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency. The basic defect in these patients is still unknown but it is suggested that caution be used over the administration of medium‐chain triglyceride.
Bone marrow transplantation for Niemann‐Pick Type IA disease
Authors: Bayever E. , Kamani N. , Ferreira P. , Machin G. A. , Yudkoff M. , Conard K. , Palmieri M. , Radcliffe J. , Wenger D. A. , August C. S.
Published: June 2005

Bone marrow transplantation has been undertaken with encouraging results as therapy for a wide variety of lysosomal storage diseases. We report a case of Niemann‐Pick disease Type IA in which, despite the presence of only mild hypotonia with depressed reflexes, the clinical course of the disease appeared to be only slightly modified by this procedure, which was performed at the earliest practical opportunity. The patient was diagnosed early when asymptomatic, because of a family history of an affected sibling who died at 14 months. He received a bone marrow transplant from an HLA‐identical, MLC non‐reactive sibling donor, whose leukocyte sphingomyelinase activity was in the homozygote normal range. There was adequate engraftment as evidenced by persistently normal leukocyte sphingomyelinase activities, and there was no evidence of graft‐versus‐host disease. Visceral storage and neurological impairment were less rapidly progressive than in his untreated sibling but he eventually died at 30 months. Autopsy confirmed that this was essentially due to the effects of the underlying Niemann‐Pick disease. We conclude that despite some success in other neurovisceral lysosomal storage disorders, bone marrow transplantation is not likely to be an adequate treatment for Niemann‐Pick disease Type IA.
3β‐hydroxy‐Δ5‐C27‐steroid dehydrogenase deficiency; effect of chenodeoxycholic acid therapy on liver histology
Authors: Horslen S. P. , Lawson A. M. , Malone M. , Clayton P. T.
Published: June 2005

The second step in the pathway for synthesis of bile acids from cholesterol is catalysed by the enzyme 3β‐hydroxy‐Δ5‐C27‐steroid dehydrogenase. Deficiency of this enzyme has been reported to produce cholestatic liver disease with progressive cirrhosis. Treatment with chenodeoxycholic acid led to clinical and biochemical improvement in one patient. We report a further child with this disorder who presented with prolonged neonatal jaundice followed by symptoms of malabsorption of fat‐soluble vitamins. Bile acid replacement therapy resulted in clinical and biochemical improvement; it was also possible to demonstrate improvement in the histological appearance of the liver biopsy 4 months after commencing treatment.
Storage material from urine and tissues in the nephropathic phenotype of infantile sialic acid storage disease
Authors: Paschke E. , Gruber W. , Ring E. , Sperl W.
Published: June 2005

We analysed urine and tissue specimens from two nephrotic infantile sialic acid storage disease patients (nISSD) for free and bound sialic acids in comparison to non‐nephrotic ISSD patients (ISSD), patients with minimal change nephrosis (nControl) and normal controls (Control). No differences in the excretion of urinary free sialic acid could be detected between ISSD and nISSD urines. Sialyloligosaccharide fractions were only slightly elevated and of apparently normal composition. Owing to glomerular dysfunction, measurable quantities of protein‐bound sialic acids were present in nISSD and nControl.

In nISSD tissues, free sialic acid was elevated 18–100‐fold above control and 3–12‐fold above Niemann‐Pick A (NPA) samples. The storage of membrane‐bound sialic acid was slightly increased compared to control tissues, but equal to those from NPA, thus reflecting an unspecific increase of membranes due to lysosomal storage.

According to these results no major biochemical differences were detectable between ISSD and nISSD. The nephrotic syndrome in nISSD could not be related to a general deficit in the sialylation of glycoproteins. Nevertheless, a cell membrane‐specific alteration in sialoglycoproteins of glomerular cells might still be possible.
Prenatal diagnosis of systemic disorders of the respiratory chain in cultured amniocytes and chorionic villus fibroblasts by studying the formation of lactate and pyruvate from glucose
Authors: Wanders R. J. A. , Wijburg F. A. , Ruiter J. , Trijbels J. M. F. , Ruitenbeek W. , Sengers R. C. A. , Bakkeren J. A. J. M. , Feller N.
Published: June 2005

Formation of lactate and pyruvate from glucose was studied in cultured amniocytes and chorionic villus fibroblasts from controls, either untreated or treated with azide, an inhibitor of cytochromec oxidase, or other inhibitors of the mitochondrial respiratory chain. Amniocytes with an established cytochromec oxidase deficiency were also investigated.

Control amniocytes treated with azide as well as cytochromec oxidase deficient amniocytes displayed strongly increased lactate‐to‐pyruvate ratios after incubation with glucose, compared to control cells. Elevated lactate‐to‐pyruvate ratios were also found in chorionic villus fibroblasts in which complexes I, III or IV were inhibited by rotenone, antimycin or azide, respectively. We conclude that measurement of lactate and pyruvate production from glucose in cultured amniocytes and/or chorionic villus fibroblasts allows adequate prenatal diagnosis of systemic cytochromec oxidase deficiency and presumably of other systemic deficiencies of mitochondrial respiratory chain enzymes.
Effect of methylmalonate onin vitro lactate release and carbon dioxide production by brain of suckling rats
Authors: Wajner M. , Dutra J. C. , Cardoso S. E. , Wannmacher C. M. D. , Motta E. R.
Published: June 2005

Methylmalonate (MMA) accumulates in the tissues of patients with methylmalonic acidaemia, who present severe neurological signs soon after birth and later mental retardation. Attempting to understand the pathophysiology of the disorder, we investigated the effects of MMA on brain glucose uptake, lactate release and CO2 production. Glucose uptake and lactate release were studied by incubating 40 µm wide brain prisms from 15‐day‐old rats in Krebs‐Ringer bicarbonate buffer, pH 7.0, containing 5.0 mmol/L glucose and one of three concentrations of MMA (1.0, 2.5 and 5.0 mmol/L). Controls did not contain MMA in the incubation medium. MMA induced a significant increase of lactate production in a dose‐dependent pattern that was proportional to glucose uptake by the brain prisms. We also studied the influence of MMA on brain CO2 production from [2‐14C]glucose and [U‐14C]acetate by incubating brain prisms in the same buffer in the presence of the substrates with (experimental groups) or without (controls) 5.0 mmol/L MMA. MMA significantly reduced CO2 formation from both substrates.
Carrier detection for Sjögren‐Larsson syndrome
Authors: Kelson T. L. , Craft D. A. , Rizzo W. B.
Published: June 2005

Sjögren‐Larsson syndrome (SLS) is an autosomal recessive disorder associated with reduced activity of the fatty alcohol: NAD+ oxidoreductase complex (FAO). Recent studies indicate that SLS patients are specifically deficient in the fatty aldehyde dehydrogenase (FALDH) component of FAO. To investigate the possibility of carrier detection for SLS, FAO and FALDH activities were measured in cultured skin fibroblasts from normal controls, obligate SLS heterozygotes, and SLS homozygotes using the 18‐carbon substrates octadecanol and octadecanal. Three of 11 heterozygotes for SLS had FAO activities that were within the normal range; the other 8 SLS heterozygotes had FAO activities below normal. In contrast, fibroblast FALDH activity was more effective than FAO in discriminating SLS heterozygotes from normal controls. FALDH activity (nmol min−1 (mg protein)−1) in normal controls was 8.54 ± 1.16 (mean ± SD; range 6.95–10.77;n=12) and in SLS heterozygotes was 5.12 ± 1.31 (range 3.28–6.96;n=11), or 60 ± 15% of mean normal activity. One SLS heterozygote had an FALDH activity within the lower range of normal; this heterozygote had an FAO activity below normal. None of the SLS heterozygotes had an FAO or FALDH activity that was in the range of that measured in SLS homozygotes. These results indicate that measurement of FAO and FALDH activities in cultured skin fibroblasts using 18‐carbon substrates is useful for SLS carrier detection.
Comparison of total cellular DNA, mRNA, and rRNA levels between normals and down syndrome patients
Authors: McQuillan C. I. , Choo K. H.
Published: June 2005

Two recent studies have suggested that the absolute cellular RNA and/or DNA levels in Down syndrome (DS) may be unusual compared to normals and may be linked to phenotypic expression (Pashet al., 1990; Dahlet al. 1988). We have extended these two studies by directly quantitating and comparing the total cellular mRNA, rRNA, and DNA levels in fibroblasts and lymphocytes derived from normal and DS individuals. The assay methods used, which allowed us to present the various nucleic acids levels in picograms per cell, did not reveal any significant difference between the two groups.
Leucine and tissue distribution of bulky and small neutral amino acids in rats: Dissociation between transport and insulin‐mediated effects
Authors: de Céspedes C. , Thoene J. G. , Lowler K. , Christensen H. N.
Published: June 2005

The mechanism of the observed decrease in the plasma concentration of several amino acids in the presence of high levels of Leu has remained unexplained. In the present study a decrease in the plasma concentration of Ile, Val, Phe, Tyr, Met, Ala, Pro and Gly was observed after the intraperitoneal injection of Leu to weanling rats. Decreases in net intracellular concentrations in muscle accompanied the decrease in plasma of all of these amino acids except Pro and Gly. An increase in the distribution ratio muscle/plasma was observed exclusively for Gly after administration of Leu or of a non‐insulinogenic transport system L analogue. Diazoxide suppressed the Leu‐induced decreases in plasma and muscle intracellular concentrations of Ile and Val as well as of Pro in plasma. An increase in the distribution ratio liver/plasma was observed for Pro and Gly in the absence but not in the presence of diazoxide. All the above changes were statistically significant. Hence insulin probably mediates Leu effects, promoting an increased utilization of Ile and Val in muscle and of Pro in liver. A more direct effect of Leu appears to be involved in the apparent increased utilization of Phe, Tyr and Ala in the same tissue. Gly depletion in plasma can be explained by its trapping by inhibitory action of Leu on the exodus of Gly through transport system L.
Alterations of NAD and adenylyl dinucleotide metabolism in Chediak‐Higashi Syndrome fibroblasts
Authors: Baker J. C. , Ames B. N.
Published: June 2005

Chediak‐Higashi syndrome (CHS) cells have been previously observed to exhibit several of the same characteristics as those of xeroderma pigmentosum (XP) and xeroderma pigmentosum variants. Cultured CHS fibroblasts have been examined for altered responses in both depletion of NAD and elevation of diadenosine‐5′,5‴‐tetraphosphate (Ap4A) following DNA damage since both responses have been reported as altered in XP cells and since Ap4A has been reported as absent from the platelets of CHS patients. Lowering of NAD following UV irradiation occurred in CHS cells in a manner similar to that of control and XP variant cells, but different from that of XP cells. CHS fibroblasts were not found to be deficient in Ap4A and exhibit basal levels very similar to those of control fibroblasts. No change in Ap4A pools were observed which correlated with cell growth, in contrast to previously published reports. Furthermore, while Ap4A levels are not elevated in XP cells, we observe an elevation of Ap4A pools in CHS cells which mimics the elevations observed in control and XP variant cells. We conclude that:

CHS cells more closely resemble control or XP variant cells than XP cells with regard to NAD lowering and Ap4A elevation following UV irradiation;

the photosensitivity exhibited by CHS cells is not due to general defects in the synthesis of poly(ADP‐ribose) from NAD or in Ap4A metabolism; and

alteration of Ap4A pool size in CHS fibroblasts is inappropriate as a biochemical marker for CHS.
Homocitrullinuria and homoargininuria in hyperargininaemia
Authors: Kato T. , Sano M. , Mizutani N. , Hayakawa C.
Published: June 2005

A four‐year‐old boy with hyperargininaemia had increased urinary excretion of homocitrulline and homoarginine. A single oral lysine load created a marked increase in these amino acids in plasma. A daily oral lysine supplementation resulted in a remarkable urinary leakage of homocitrulline and homoarginine. These findings suggest that the patient had an enhanced synthesis of these amino acids.
Prolinase activity in prolidase‐deficient fibroblasts
Authors: Miech G. , Myara I. , Mangeot M. , Voigtlander V. , Lemonnier A.
Published: June 2005

The activity of prolinase (EC 3.4.13.8) was studied in cultured skin fibroblasts derived from three patients with deficient prolidase (EC 3.4.13.9). With pro‐val as substrate and manganese in the reaction buffer, prolinase activity was higher in prolidase‐deficient cells than in control cells (mean (SEM) 917 (67) nmol min−1 mg−1,n=3, control mean (SEM) 294, (50), n=11). The Michaelis constants were not different for the pro‐val and progly substrates in control and prolidase deficient fibroblasts. However, the constants for Vmax rose for both substrates in deficient cells. These results demonstrate that prolinase activity increases in prolidase‐deficient fibroblasts as also shown in the plasma of patients with prolidase deficiency. We suggest that in prolidase‐deficient fibroblasts, this rise in prolinase activity constitutes an attempt to compensate for the prolidase deficiency by increasing the greatly reduced intracellular proline pool.
Biotin‐responsive multiple carboxylase deficiency in an 8‐year‐old boy with normal serum biotinidase and fibroblast holocarboxylase‐synthetase activities
Authors: Holme E. , Jacobson C‐E. , Kristiansson B.
Published: June 2005

An 8‐year‐old boy with late onset multiple carboxylase deficiency is described. Biotinidase deficiency and holocarboxylase‐synthetase deficiency have been excluded. A very slow biochemical response to biotin was found. The decrease in urinary organic acid excretion followed first‐order kinetics with a half‐life of about 50 days. The initially low carboxylase activities in thrombocytes were increased but not normalized after 3 months of treatment.
The effect of oral betaine on vertebral body bone density in pyridoxine‐non‐responsive homocystinuria
Authors: Gahl W. A. , Bernardini I. , Chen S. , Kurtz D. , Horvath K.
Published: June 2005

Five pyridoxine‐non‐responsive homocystinuric patients aged 5 to 32 years were treated with oral betaine, 3 g b.i.d, in a double‐blind, placebo‐controlled, two‐year crossover study of its effect on bone mineralization. Betaine therapy significantly reduced mean plasma homocystine (36±9 (SEM) µmol L−1 to 9±4 µmol L−1), with variable increases in plasma methionine and no adverse effects. Bone density, measured by computerized tomographic scanning of vertebral bodies, was below normal in all patients at the start of the study, and was not significantly altered by betaine therapy administered according to this protocol
α‐N‐acetylgalactosaminidase deficiency, a new lysosomal storage disorder
Authors: van Diggelen O. P. , Schindler D. , Willemsen R. , Boer M. , Kleijer W. J. , Huijmans J. G. M. , Blom W. , Galjaard H.
Published: June 2005

A new lysosomal storage disease with autosomal recessive inheritance is described in two male siblings of 5 1/2 and 4 years of age. Clinical manifestations started after 9 months of age with neurological symptoms, followed by progressive psychomotor deterioration. Urinary oligosaccharide excretion was abnormal and showed a characteristic pattern on chromatography. Enzyme assays showed a profound deficiency of lysosomal α‐N‐acetylgalactosaminidase in cultured fibroblasts, leukocytes and plasma from the patients and reduced activity in material from the parents. The defiiciency was demonstrated both with an artificial substrate and a natural one, the blood group A trisaccharide. Excessive intra‐lysosomal storage of α‐N‐acetylgalactosamine‐containing material was demonstrated in cultured fibroblasts from the patients, using the lectin fromHelix pomatia which is specific for terminal α‐N‐acetylgalactosamine residues.
A protocol for the successful long‐term enzyme replacement therapy of scurvy in guinea pigs
Authors: Hadley K. , Sato P.
Published: June 2005

Gulonolactone oxidase, a key enzyme in the biosynthesis of ascorbic acid, is missing from guinea pigs and certain other scurvy‐prone species. Weekly intraperitoneal injections of glutaraldehyde cross‐linked immunoprecipitates of this enzyme have been shown to provide guinea pigs with the capability of synthesizing their own ascorbic acid and of surviving without an exogenous source of this vitamin. This protocol, however, was successful in only a small percentage of the animals tested. The reasons for the limited therapeutic success were investigated. Apparently, the gulonolactone oxidase‐treated guinea pigs fed without ascorbic acid were receiving insufficient nutrition. By supplementing these enzyme‐treated animals with vitamins A, B, D and E and selenium, we successfully maintained a high proportion of guinea pigs fed without vitamin C.
Developmental profile of patients with maple syrup urine disease
Authors: Nord A. , van Doorninck W. J. , Greene C.
Published: June 2005

The progress of nine maple syrup urine disease patients (eight classical, one possible variant) was reviewed to look for similarities in developmental patterns. A consistent developmental profile of stronger Verbal than Performance IQ and lower than familially expected IQ was seen. Younger age at diagnosis was associated with a milder neonatal course. Those who were asymptomatic or suffered mild complications in the newborn period have higher IQs than children experiencing moderate or severe complications. Children with asymptomatic or mild neonatal course also required less special education services. Overall, a picture of ubiquitous motor, visual‐analytic and learning deficits is seen.
Bony changes of PKU neonates unrelated to phenylalanine levels
Authors: Fisch R. O. , Feinberg S. B. , Weisberg S. , Day D.
Published: June 2005

In 1962 bone abnormalities were described radiographically in phenylketonuria patients. Later, observations were made on PKU infants during the neonatal period, which allowed differentiation between inherited alterations in bone development from those changes due to dietary restriction. Similar changes have been described in other aminoacidurias. Wrist radiographs and serum phenylalanine levels were obtained on 73 patients first seen between 1965 and 1990. All radiographs were taken on the day of referral, when the patient was between 6 and 57 days old. Forty‐nine patients were less than 28 days old. Bone abnormalities were present in 56 of 73 (77%) of the children, as compared to 0 of 16 in a control group. The presence or absence of bone abnormality is unrelated to serum phenylalanine level, and to the age of the children at referral. This finding suggests that the cause of these mesodermal changes is not a deviation of a single amino acid in the infant, but that they are caused by an intrauterine amino acid imbalance.
Familial combined hyperlipidaemia: Use of stable isotopes to demonstrate overproduction of very low‐density lipoprotein apolipoprotein B by the liver
Authors: Cortner J. A. , Coates P. M. , Bennett M. J. , Cryer D. R. , Le Ngoc‐Anh
Published: June 2005

We have assessed very low‐density lipoprotein apolipoprotein B production, using [15N]glycine as an endogenous marker in a 9‐hour primed constant infusion protocol, in four adult male subjects with familial combined hyperlipidaemia and in four normolipidaemic adult male controls. The mean very low‐density lipoprotein apolipoprotein B absolute synthetic rate was significantly greater in the familial combined hyperlipidaemic subjects than in control subjects (26.31 ± 8.37 vs 9.36 ± 4.07 mg/kg per 24 h,p<0.05). These results confirm findings using exogenous radioisotope labelling techniques that very low‐density lipoprotein apolipoprotein B production is significantly increased in most patients with familial combined hyperlipidaemia. A modified 9‐hour protocol can be safely done repeatedly and in children and pregnant women.
Peroxisomes in infantile phytanic acid storage disease: a cytochemical study of skin fibroblasts
Authors: Beard M. E. , Moser A. B. , Sapirstein V. , Holtzman E.
Published: June 2005

Cultured skin fibroblasts from six patients demonstrating clinical signs and biochemical characteristics of infantile phytanic acid storage disease (IPSD) were examined by electron microscopy, using cytochemical procedures for the demonstration of peroxisomal catalase activity. In four of the six fibroblast cell lines peroxisomes strongly reactive for catalase were present in numbers similar to those found in normal fibroblasts. Liver biopsy tissue from one of these patients showed no typical hepatic peroxisomes, but did show small, marginally reactive bodies. In two other IPSD fibroblast cell lines peroxisomes with appreciable cytochemical reactivity were rare or absent. It seems, therefore, that infantile phytanic acid storage disease is heterogeneous with respect to the presence of cytochemically recognizable peroxisomes, at least in the cases studied here. Furthermore, peroxisomes may be markedly affected in one cell type — liver — and yet not affected in another — skin fibroblasts — within a single individual.
A new variant of sphingomyelinase deficiency (Niemann‐Pick): visceromegaly, minimal neurological lesions and lowin vivo degradation rate of sphingomyelin
Authors: Elleder M. , Nevoral J. , Špičáková V. , Hyniová H. , Kraus J. , Krásný J. , Vanier M. T.
Published: June 2005

Three males (aged 10 years, 3 years 9 months and 2 years 8 months) with profound sphingomyelinase deficiency are presented. The sphingomyelin storage in the liver biopsies attained 30‐fold, 65‐fold and 16‐fold increases against controls, respectively. Levels of bis(monoacylglyceryl) phosphate were also increased. In two cases the bone marrow contained foam cells with liquid crystals of sphingomyelin. Besides the visceral involvement dominated by hepatosplenomegaly, all three cases showed discrete, so far stationary (8 years, 42 months and 28 months) neuropathic features and retinal lesions resembling the classical cherry‐red spot. Electrophysiological examinations showed a variable reduction of peripheral nerve conduction velocity and prolongation of the latencies of somatosensory, visual and auditory evoked potentials. Ultrastructural examination of skin nerves showed a slight storage, mainly in Schwann cells. In some myelinated fibres there were pseudomyelinic ovoids. The cases therefore displayed features of both A and B types of sphingomyelinase deficiency and should be conventionally classified as intermediate. However, the very low levels ofin vivo sphingomyelin hydrolysis (not exceeding 6%, against 30±10% in type B and 77±5% in controls) were clearly within the range of type A values (5±2%). Accordingly, we suggest that the cases may be biochemically classified as variants of type A disease.
Immunological evidence for a carbamylphosphate synthetase lesion resulting in the formation of enzyme with altered sub‐unit size
Authors: Hoogenraad N. J. , Weston H. J. , Mackenzie N.
Published: June 2005

A partial carbamylphosphate synthetase (CPS: EC 6.3.4.16) deficiency (McKusick 23730) was found in a male child who presented with generalized convulsions, rickets and apnoeic attacks at six months of age. By his second year he showed serious developmental delay and a gut biopsy revealed an absence of CPS activity with an elevated ornithine transcarbamylase activity. Analysis of the gut biopsy sample on SDS‐polyacrylamide gels, followed by electrophoretic transfer to a nitrocellulose filter probed with monospecific antibodies to CPS showed that the child had normal levels of immunoreactive enzyme, but instead of one band corresponding to normal CPS with a subunit size of 165 000u, the patient had three immunoreactive bands, one larger and two smaller than that found in normal controls. The genetic defect in this child therefore results in an unusual form of CPS being made which has markedly reduced enzyme activity.
Glycerol‐3‐phosphate excretion in fructose‐1,6‐diphosphatase deficiency
Authors: Krywawych S. , Katz G. , Lawson A. M. , Wyatt S. , Brenton D. P.
Published: June 2005

A patient aged 23 months with fructose‐1,6‐diphosphatase deficiency is reported. This infant demonstrated an increased urine excretion of glycerol‐3‐phosphate during episodes of hypoglycaemia. The excretion of this compound has not previously been described in this disease or in those disorders associated with a deficiency in one of the other three gluconeogenic enzymes associated with hypoglycaemia. Its presence in the urine from patients may be useful in diagnosis.
A new case of arginase deficiency in a Spanish male
Authors: Jordá A. , Rubio V. , Portolés M. , Vilas J. , García‐Piño J.
Published: June 2005

A new case of arginase deficiency is reported in a male newborn from Spain. In contrast with the majority of the earlier cases, this infant showed severe protein intolerance of early onset. The diagnosis was based on the assay of the urea cycle enzymes in a postmortem liver sample. Levels of erythrocyte arginase were also determined in the parents and in a sister of the patient, and were consistent with heterozygosity. From a study of the pedigree it appears that arginase deficiency in this family presents a dramatic course.
A neonatal screening approach to the detection of familial hypercholesterolaemia and family‐based coronary prevention
Authors: Wilcken D. E. L. , Blades B. L. , Dudman N. P. B.
Published: June 2005

We measured by radial immunodiffusion apolipoprotein B (ApoB) as a genetic marker for familial hypercholesterolaemia in heel prick blood spot samples on filter paper routinely collected from 5000 3‐ to 5‐day‐old neonates for current screening programmes. Dried blood spot ApoB levels were distributed continuously and were 9% higher in female neonates than in males (0.246±0.085 versus 0.225±0.079 g/L of whole blood, mean ±SD,p<0.0001). Neonates of birth weight under 2.5 kg had lower levels than the population mean in both sexes but levels did not change with birth weight within this range; in those with the birth weights greater than 2.5 kg levels increased with increasing birth weight. Sex and birth weight could account for 5.7% of the variability of ApoB. Levels had largely stabilized by day 3 of life. Of parents of neonates whose ApoB levels were among the top 2%, 45 families were available for study when the infants were aged 12.3±3.3 months. In 6 of these families there was a persisting elevation of ApoB both in the infants (levels greater than 0.7 g/L of whole blood) and in one parent who also had elevated ApoB and a lipid profile of familial hypercholesterolaemia phenotype, results indicating an ascertainment rate of between 1 in 365 and 1 in 830 of the screened population. These studies have defined the variables affecting neonatal ApoB levels and establish that neonatal screening for familial hypercholesterolaemia is feasible. Primary prevention of vascular disease in young families with the gene should be possible with this approach.
3‐Hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) lyase deficiency in Saudi Arabia
Authors: Ozand P. T. , Al Aqeel A. , Gascon G. , Brismar J. , Thomas E. , Gleispach H.
Published: June 2005

Deficiency of 3‐hydroxy‐3‐methylglutaryl‐CoA lyase has been studied in 11 Saudi infants. The diagnosis was established by the measurement of enzyme activity in lymphocytes, in fibroblasts and, in seven patients, by the gas chromatography/mass spectrometer pattern of excreted organic acids in the urine. In seven infants the disease caused a devastating acidotic attack within the first day of life, while in two the crisis occurred by the third day of life. In two infants from one family the disease appeared later in infancy. The clinical presentation of an acidotic attack is lethargy, hyperpnoea, tachypnoea and seizures, either at birth (two infants), following first feeding (in five infants), or following vomiting or refusal of food in later infancy. The acidotic attacks recurred later in life following minor illness or refusal to eat. The acidosis of this enzyme deficiency progresses rapidly, leading to cardiopulmonary arrest and death within hours of onset unless treated promptly. In four surviving infants diagnosed and treated early, development is normal. Magnetic resonance and computerized tomography brain scans in these infants, however, show white matter lesions and mild atrophy.
Phenotypic variability and abnormal type I collagen unstable at body temperature in a family with mild dominant osteogenesis imperfecta
Authors: Tenni R. , Biglino P. , Dyne K. , Rossi A. , Filocamo M. , Pendola F. , Brunelli P. , Buttitta P. , Borrone C. , Cetta G.
Published: June 2005

Autosomal dominant inheritance of a mild form of osteogenesis imperfecta (osteogenesis imperfecta type I) with different phenotypic expression was found in a family. Phenotypic expression was different for the affected mother and son, in the presence of the same biochemical results.

Dermal fibroblast cultures synthesized normal and mutant type I collagen α chains. Collagen heterotrimers containing abnormal chains were overmodified along the entire triple helical domain and showed an unusually low denaturation temperature, so far found only in lethal cases. The mild phenotype in the family is probably due to the fact that abnormal type I collagen molecules are more likely to be degraded than utilized in the extracellular matrix.
Clinical and biochemical findings in parents of children with vitamin D‐dependent rickets type II
Authors: Yokota I. , Takeda E. , Ito M. , Kobashi H. , Saijo T. , Kuroda Y.
Published: June 2005

Vitamin D‐dependent rickets type II is a rare disease caused by a disorder of the receptor for 1, 25‐dihydroxyvitamin D (1, 25(OH)2D). Several parameters of this receptor‐effector system were investigated to obtain biochemical information on the presumed heterozygotes of vitamin D‐dependent rickets type II in parents of five patients and in their age‐matched controls. It was found that the serum concentrations of 1,25‐(OH)2D and 24,25‐dihydroxy‐vitamin D (24, 25(OH)2D), and the ratio of 1,25‐(OH)2D/24,25‐(OH)2D differed significantly in the parents from those of the patients and the respective control groups. In the parents' cultured skin fibroblasts, the activity of 25‐hydroxyvitamin D‐24‐hydroxylase induced by 10−8 mol/L 1, 25‐(OH)2D3 ranged from 50 to 82% of that of their controls (versus 1–13% of controls for the patients). The binding capacity of the parents' [3H]1, 25‐(OH)2D3 to the nucleus was 38–54% of that of their control subjects (versus 7–27% of controls for the patients). The parents' values were thus in a range between those of the patients and the control groups. These findings suggest that, in the parents, a partial impairment of the receptor system for 1,25‐(OH)2D led to an imbalance of vitamin D metabolism, thus confirming that vitamin D‐dependent rickets type II is an autosomal recessive inherited disease. Serum concentrations of 1, 25‐(OH)2D and 24,25‐(OH)2D may provide useful parameters for detecting heterozygotes of this disease.
Neutral lipid storage disease with ichthyosis: Serum apolipoprotein levels and cholesterol metabolism in monocyte‐derived macrophages
Authors: Bergman R. , Aviram M. , Bitterman‐Deutsch O. , Oiknine Y. , Shemer A. , Srebnik A. , Brook J. G. , Friedman‐Birnbaum R.
Published: June 2005

Neutral lipid storage disease with ichthyosis (NLSDI) is an inherited metabolic disorder characterized by accumulation of neutral lipids, in a wide variety of cells, by a still unknown mechanism. Previous studies have shown normal cholesterol content in NLSDI granulocytes, fibroblasts and skin cells. Monocyte‐derived macrophages possess an additional pathway of cholesterol uptake, which is not shared by these cells and which is not regulated by intracellular cholesterol levels. This pathway is thought to play a rôle in the process of atherosclerosis. Three NLSDI patients were studied. The serum levels of triglycerides, cholesterol, high‐density lipoprotein cholesterol, and apolipoproteins A‐I and B were within normal limits in all three patients. The intracellular levels of free and esterified cholesterol were measured in the monocyte‐derived macrophages of one patient and found to be normal, while the triglyceride concentrations were twice as high as normal. The cholesterol esterification rates, which serve as a sensitive indicator of intracellular changes in cholesteryl ester levels, were normal in the monocyte‐derived macrophages of all three patients. These findings provide further evidence that cholesterol metabolism is not disturbed in NLSDI, and it may be inferred that in this respect these patients are not at increased risk for atherosclerosis.
Fruits and vegetables are a source of galactose: Implications in planning the diets of patients with Galactosaemia
Authors: Gross K. C. , Acosta P. B.
Published: June 2005

It has become apparent that removing dairy products from the diets of patients with galactosaemia does not sufficiently diminish the deleterious signs. We have determined the amount of soluble monomeric galactose in 45 fruits and vegetables using capillary gas chromatography and selective ion monitoring. Galactose contents ranged from less than 0.1 mg per 100 g of tissue in artichoke, mushroom, olive, and peanut to 35.4 mg per 100 g in persimmon. Fruits and vegetables with over 10 mg per 100 g included date, papaya, bell pepper, tomato and watermelon. These results will provide important data for planning the diets of patients with galactosaemia.
Biosynthesis of tetrahydrobiopterin in man
Authors: Curtius H. ‐Ch. , Heintel D. , Ghisla S. , Kuster Th. , Leimbacher W. , Niederwieser A.
Published: June 2005

The biosynthesis of tetrahydrobiopterin (BH4) from dihydroneopterin triphosphate (NH2P3) was studied in human liver extract. The phosphate‐eliminating enzyme (PEE) was purified ~750‐fold. The conversion of NH2P3 to BH4 was catalyzed by this enzyme in the presence of partially purified sepiapterin reductase, Mg2+ and NADPH. The PEE is heat stable when heated at 80°C for 5 min. It has a molecular weight of 63 000 daltons. One possible intermediate 6‐(1′‐hydroxy‐2′‐oxopropyl)5,6,7,8‐tetrahydropterin(2′‐oxo‐tetrahydropterin) was formed upon incubation of BH4 in the presence of sepiapterin reductase and NADP+ at pH 9.0. Reduction of this compound with NaBD4 yielded monodeutero threo and erythro‐BH4, the deuterium was incorporated at the 2′ position. This and the UV spectra were consistent with a 2′‐oxo‐tetrahydropterin structure. Dihydrofolate reductase (DHFR) catalyzed the reduction of BH2 to BH4 and was found to be specific for the pro‐R‐NADPH side. The sepiapterin reductase catalyzed the transfer of the pro‐S hydrogen of NADPH during the reduction of sepiapterin to BH2. In the presence of crude liver extracts the conversion of NH2P3 to BH4 requires NADPH. Two deuterium atoms were incorporated from (4S‐2H)NADHP in the 1′ and 2′ position of the BH4 side chain. Incorporation of one hydrogen from the solvent was found at position C(6). These results are consistent with the occurrence of an intramolecular redox exchange between the pteridine nucleus and the side chain and formation of 6‐pyruvoyl‐5,6,7,8‐tetrahydropterin(tetrahydro‐1′‐2′‐dioxopterin) as intermediate.
Biotinidase deficiency: A novel vitamin recycling defect
Authors: Wolf B. , Grier R. E. , Secor McVoy J. R. , Heard G. S.
Published: June 2005

The recent finding that biotinidase deficiency is the primary biochemical defect in late‐onset multiple carboxylase deficiency has stimulated new interest in the inherited disorders of biotin‐dependent carboxylases. The clinical and biochemical features of biotinidase deficiency are discussed. We also speculate about two exciting areas currently being investigated: the localization of action of biotinidase, and the possible role of the enzyme as a binding or carrier protein for biotin.
Biotinidase deficiency: Factors responsible for the increased biotin requirement
Authors: Baumgartner E. R. , Suormala T. , Wick H. , Bausch J. , Bonjour J. ‐P.
Published: June 2005

Inability to recycle biotin from endogenous biocytin in congenital biotinidase deficiency is associated with increased requirement of exogenous free biotin. We have observed that severe biotin depletion with clinical and biochemical consequences occurs within 12 days after birth in a newborn patient and within 15–20 days after withdrawal of biotin supplementation in four other patients. Our studies have shown that:

Urinary loss of biotin and biocytin are major causes for this rapid biotin depletion.

Intestinal absorption of biotin seems to be normal at least at the loading dose of 1.5 µg/kg.

At normal or subnormal plasma biotin concentrations biocytin is found in low concentrations (below 1 nmoll−1) in plasma of patients but at much higher concentrations in urine (100–600 nmoll−1).

An oral load of biocytin results in patients in unchanged biotin levels but in a marked rise of biocytin in plasma followed by rapid renal excretion of biocytin whereas in controls biotin levels in plasma increase rapidly and biocytin remains below detection levels.
The role of vitamin E in the treatment of the neurological features of abetalipoproteinaemia and other disorders of fat absorption
Authors: Muller D. P. R. , Lloyd J. K. , Wolff O. H.
Published: June 2005

Studies in patients with abetalipoproteinaemia and other chronic and severe fat malabsorptive states, and neuropathological studies in the vitamin E‐deficient human, monkey and rat indicate that vitamin E is important for normal neurological function. Appropriate vitamin E supplementation is, therefore, advisable for all patients with chronic fat malabsorption who have low serum vitamin E concentrations.
Mutation of the 97‐197‐197‐1subunit of the pyruvate dehydrogenase complex, in relation to heterogeneity
Authors: Kitano A. , Endo F. , Matsuda I. , Miyabayashi S. , Dahl H‐H. M.
Published: June 2005

Pyruvate dehydrogenase complex was studied using bio‐ and immunochemical methods in cultured cells derived from two patients with the severe type and one patient with the mild type of pyruvate dehydrogenase complex deficiency. In patients 1 and 2, enzyme activity was all but undetectable and associated with the absence of E1α subunit of the complex. Patient 3 had a slightly reduced level of enzyme activity, and this was associated with a larger form of E1α subunit. The amount and size of E1α mRNA in the three patients was similar to that of control samples. Thus, the severity of E1α deficiency in these three patients is likely to depend on the type of mutation in the pyruvate dehydrogenase E1α subunit and the synthesis and degradation rate of the subunit.
A therapeutic trial withN‐acetylcysteine in subjects with hereditary glutathione synthetase deficiency (5‐oxoprolinuria)
Authors: Mårtensson J. , Gustafsson J. , Larsson A.
Published: June 2005

In a therapeutic trial, the effect of short‐term low‐dosageN‐acetylcysteine supplementation on glutathione metabolism was investigated in two patients with hereditary glutathione deficiency (5‐oxoprolinuria). Clinical and neurophysiological examinations of the patients indicated progressive neurological damage.

The pretreatment concentrations of total and free glutathione in leukocytes were 15–20% of normal, whereas the corresponding γ‐glutamylcysteine levels were increased. In plasma, the glutathione concentrations were similarly decreased, but no γ‐glutamylcysteine was detected. Total glutathione in erythrocytes was markedly decreased. Low urinary excretion of cysteinylglycine, cyst(e)ine, taurine,N‐acetylcysteine, mercaptolactate and mercaptoacetate and reduced leukocyte taurine levels constituted additional evidence of decreased intracellular availability of cysteine, i.e. glutathione.

Oral supplementation withN‐acetylcysteine (5 mg/kg × 3/day) had no effect on acid‐base balance, erythrocyte glutathione levels or 5‐oxoproline concentrations in plasma and urine. In leukocytes, the glutathione concentrations were increased by 20–30%, whereas the γ‐glutamylcysteine levels were essentially unaltered. In parallel, the urinary excretion of cysteinylglycine was increased and the leukocyte levels and urinary outputs of sulphur amino acids were restored. No side‐effects of the treatment were noted. The results indicate thatN‐acetylcysteine may be of value in increasing the low intracellular glutathione concentrations and cysteine availability in patients with hereditary glutathione synthetase deficiency.
Prenatal diagnosis of infantile sialic acid storage disease in a twin pregnancy
Authors: Lake B. D. , Young E. P. , Nicolaides K.
Published: June 2005

A diagnosis of infantile sialic acid storage disease was made in an infant who died aged 17 months. In the mother's next pregnancy no morphological or biochemical abnormality was found in chorionic villi, amniotic fluid, cultured amniotic fluid cells or fetal blood and a normal boy was born. In the subsequent pregnancy an ultrasound scan revealed a twin pregnancy. Chorionic villus samples were obtained from both twins and microscopic and biochemical analysis indicated one twin to be affected with sialic acid storage disease. Selective fetocide was performed. The unaffected twin proceeded to term.
Homocitrullinuria and homoargininuria in lysinuric protein intolerance
Authors: Kato T. , Sano M. , Mizutani N.
Published: June 2005

A 14‐year‐old boy with lysinuric protein intolerance had increased plasma and urinary concentrations of homocitrulline and homoarginine. The accumulation of carbamylphosphate due to depleted supply of ornithine for the urea cycle may be responsible for the enhanced synthesis of homocitrulline and homoarginine. A renal clearance study showed that the tubular transport of homoarginine in the patient was impaired. In lysinuric protein intolerance, membrane transport system for homoarginine may be defective because it is presumed that homoarginine shares a common transport system with the dibasic amino acids.