bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and laboratory findings in four patients with the non‐progressive hepatic form of type IV glycogen storage disease
Authors: McConkie‐Rosell A. , Wilson C. , Piccoli D. A. , Boyle J. , De Clue T. , Kishnani P. , Shen J.‐J. , Boney A. , Brown B. , Chen Y. T.
Published: June 2005

The classic clinical presentation for type IV glycogen storage disease (branching enzyme deficiency, GSD IV) is hepatosplenomegaly with failure to thrive occurring in the first 18 months of life, followed by progressive liver failure and death by age 5 years. Although there have been two patients without apparent liver progression previously reported, no long‐term follow‐up clinical data have been available. We present here the clinical spectrum of the non‐progressive liver form of GSD IV in four patients, and long‐term follow‐up of the oldest identified patients (ages 13 and 20 years). None has developed progressive liver cirrhosis, skeletal muscle, cardiac or neurological involvement, and none has been transplanted. Branching enzyme activity was also measured in cultured skin fibroblasts from patients with the classic liver progressive, the early neonatal fatal, and the non‐progressive hepatic presentations of GSD IV. The residual branching enzyme activity in the patients without progression was not distinguishable from the other forms and could not be used to predict the clinical course. Our data indicate that GSD IV does not always necessitate hepatic transplantation and that caution should be used when counselling patients regarding the prognosis of GSD IV. Patients should be carefully monitored for evidence of progression before recommending liver transplantation.
Detection of defective 3β‐hydroxysterol Δ7‐reductase activity in cultured human fibroblasts: a method for the diagnosis of Smith‐Lemli‐Opitz syndrome
Authors: Lund E. , Starck L. , Venizelos N.
Published: June 2005

Patients with the autosomal recessive disorder Smith‐Lemli‐Opitz syndrome (SLO) have recently been shown to have markedly increased tissue levels of certain cholesterol biosynthesis intermediates, most notably 7‐dehydrocholesterol. The findings strongly suggest a block in the step that catalyses reduction of 7‐dehydrocholesterol to cholesterol. The accumulation of 7‐dehydrocholesterol can generally easily be detected in serum by gas chromatography‐mass spectrometry. However, it could not be totally ruled out that SLO patients with less severe enzyme defects could escape detection by this method. A more direct way of diagnosing a defect in 7‐dehydrocholesterol reduction would be to assay the conversion of 7‐dehydrocholesterol to cholesterol in cultured fibroblasts from patients with suspected SLO.

In the present work, an assay for the conversion of [3H]lathosterol to [3H]‐cholesterol in cultured human fibroblasts is described. Lathosterol is the immediate precursor of 7‐dehydrocholesterol in the cholesterol biosynthetic pathway and was chosen for the assay instead of 7‐dehydrocholesterol owing to the difficulty in preparation and handling of the latter compound. Fibroblasts from control subjects converted [3H]lathosterol to [3H]cholesterol efficiently, whereas in fibroblasts from SLO patients the conversion did not go beyond 7‐dehydrocholesterol. It is concluded that the present method is useful for the diagnosis of SLO.
Single base deletion in exon 7 of the glycosylasparaginase gene causes a mild form of aspartylglycosaminuria in a patient of Mauritian origin
Authors: Park H. , Rossiter M. , Fensom A. H. , Winchester B. , Aronson N. N.
Published: June 2005

Aspartylglycosaminuria (AGU) is a lysosomal storage disorder of glycoprotein degradation caused by deficiency of glycosylasparaginase (GA). A deletion mutation was found in a mildly affected AGU patient whose parents are first‐cousins of Mauritian origin. One bp deletion at position 787 or 788 (ΔT788) in exon 7 of the GA gene resulted in a frameshift and produced an immediate stop codon. The resulting truncated polypeptide was defective in its post‐translational proteolytic processing and remained as a single chain (36 kDa) with no GA activity.
Tandem mass spectrometry: A new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism
Authors: Millington D. S. , Kodo N. , Norwood D. L. , Roe C. R.
Published: June 2005

Conclusion

A method for analysis of acylcarnitines in blood at physiological concentrations has been developed. Preliminary results from umbilical cord blood and neonatal blood spotted onto Guthrie cards are encouraging. This method will detect up to at least eight inherited metabolic disorders which exhibit diagnostic acylcarnitine profiles, including medium‐chain acyl‐CoA dehydrogenase deficiency. The speed and simplicity of the method permit automation with existing technology, and could enable routine neonatal screening to be carried out in an efficient and cost‐effective manner.
Respiratory‐chain and pyruvate metabolism defects: Italian collaborative survey on 72 patients
Authors: Caruso U. , Adami A. , Bertini E. , Burlina A. B. , Carnevale F. , Cerone R. , Dionisi‐Vici C. , Giordano G. , Leuzzi E. , Parenti G. , Savasta S. , Uziel G. , Zeviani M.
Published: June 2005

Conclusions

The results of this survey show that respiratory‐chain and pyruvate metabolism defects are rather frequent diseases in Italy. The clinical presentation, as well as the age of onset, is widely heterogeneous, mainly with respect to respiratory‐chain defects; unusual and new phenotypes have been described. Even the biochemical profile is variable, including rare associations with different biochemical abnormalities. In our experience, the accurate evaluation of urine organic acid would appear compulsory in all patients in whom a respiratory‐chain or pyruvate metabolism defect is suspected.

The true number of affected patients in Italy is certainly higher than reported here: several other patients were reported with strongly suggestive clinical and biochemical features, but still without defined diagnosis, owing to work being in progress or to the known diagnostic difficulties connected with this group of diseases.

Finally, our experience emphasizes that collaborative studies on rare disorders are effective, exchanging experiences and increasing knowledge.
Disorders of the pyruvate dehydrogenase complex
Authors: Stansbie D. , Wallace S. J. , Marsac C.
Published: June 2005

Pyruvate dehydrogenase deficiency may be a non‐specific consequence of many different neurological degenerative disorders. There are also serious methodological problems in estimating the activity of this enzyme complex.
Glucose metabolism in fibroblasts from patients with erythrocyte hexokinase deficiency
Authors: Magnani M. , Chiarantini L. , Stocchi V. , Dachà M. , Fornaini G.
Published: June 2005

Four different hexokinase (HK) isoenzymes are distributed in different proportions in human tissues. Fibroblasts contain HK type I as the predominant glucose phosphorylating activity, the same isoenzyme that predominates in red blood cells (RBC). We have established cell lines from two patients homozygous for RBC HK deficiency but carrying different mutations. In one case (HK‐Melzo) the residual RBC enzyme shows a marked heat instability but possesses normal kinetic and regulatory properties; in the other (HK‐Napoli), the enzyme is characterized by an increased Ki for glucose‐1,6‐diphosphate. These properties are also retained by the fibroblasts' hexokinase. Glucose utilization by cultured fibroblasts from these patients was markedly reduced in the cell lines where HK deficiency was more pronounced. However, cells with only 30% HK activity retained their full ability to utilize glucose in the hexose monophosphate pathway. This was shown to be true not only under basal conditions but also in the presence of oxidative agents such as methylene blue. Significant reduction of the ATP level was also found in HK‐Melzo fibroblasts. Thus, HK deficiency is associated with reduced glucose utilization and normal hexose monophosphate shunt rates. Results previously obtained on RBC support similar conclusions.
Gonadal function in patients with galactosaemia
Authors: Kaufman F. R. , Donnell G. N. , Roe T. F. , Kogut M. D.
Published: June 2005

Gonadal function was followed in 26 females and 12 males with galactosaemia due to deficiency of the enzyme galactose‐1‐phosphate (Gal‐1‐P) uridyl transferase over a 4 year period. Gonadal function was normal in males, but all females except two had evidence of acquired ovarian failure. Twelve females with ovarian failure documented at the beginning of this study continued to have either primary or secondary amenorrhoea on follow‐up. Five of six patients, who previously had normal gonadal function developed either hypergonadotrophic hypogonadism or an abnormal response to gonadotrophin‐releasing hormone (LRH) indicative of acquired ovarian damage. Seven of eight female patients, 1–12 years of age, who were evaluated for the first time had an exaggerated release of gonadotrophins during LRH stimulation tests diagnostic of gonadal insufficiency. The pathogenesis of ovarian failure remains unknown, but it appears likely that galactose or Gal‐1‐P is toxic to the ovary. The source of galactose metabolites, which may begin to accumulate prenatally and continue to damage the gonad in the postnatal period, is likely to be derived from the diet and from the endogenous synthesis of Gal‐1‐P from glucose via a variety of metabolic pathways. The testis appears to be relatively resistant to the effects of abnormal galactose metabolism.
Non‐ketotic hyperglycinaemia due to a deficiency of T‐protein in the glycine cleavage system in liver and brain
Authors: Schutgens R. B. H. , Ket J. L. , Hayasaka K. , Tada K.
Published: June 2005

Non‐ketotic hyperglycinaemia was diagnosed in a girl at 3 weeks of age because of the typical clinical presentation, the elevated glycine concentration in urine, plasma and especially in cerebrospinal fluid and the normal profile of organic acids in urine. An EEG showed the typical burst suppression pattern. Therapeutic approaches with either pyridoxine (50 mg d−1) alone or in combination with N5formyltetrahydrofolate (3×3 mg d−1) or with strychnine (0.3 mg per kg body weight) did not result in improvement.

In postmortem liver and brain of the patient the overall activity of the glycine cleavage system was deficient; examination of the activity of the individual components of the glycine cleavage system in the tissues revealed that the activity of the T‐protein was undetectable, whereas that of the other components and of lipoamide dehydrogenase was normal.
Intracerebral paraventricular hyperdensities: A new CT sign in Krabbe globoid cell leukodystrophy
Authors: Feanny S. J. , Chuang S. H. , Becker L. E. , Clarke J. T. R.
Published: June 2005

Computer‐assisted tomographic (CT) scanning showed intracranial paraventricular calcification in two out of six patients with enzymatically and/or histologically confirmed Krabbe globoid cell leukodystrophy (GLD) 1–5 months after the onset of symptoms of the disease.
The effect ofd‐(+)‐glucosamine on levels of freeN‐acetylneuraminic acid and UDP‐N‐acetylhexosamines in infantile sialic acid storage disease (ISSD) fibroblasts
Authors: Paschke E. , Höfler G. , Roscher A.
Published: June 2005

An impairment in the regulation ofN‐acetylneuraminic acid (NANA) biosynthesis might potentially contribute to accumulation of free NANA in fibroblasts of patients with sialic acid storage disease (ISSD). By the use of a glucosamine loading test an increase in uridine‐diphosphate‐N‐acetyl‐hexosamines (UDP‐HexNAc) but not in free NANA was found. NANA biosynthesis therefore appears to be under normal regulatory control in ISSD.
Comparative use of glucose and fructose in cultured fibroblasts from patients with hereditary fructose intolerance
Authors: Lemonnier F. , Delhotal‐Landes B. , Couturier M. , Decimo D. , Odiévre M. , Gautier M. , Lemonnier A.
Published: June 2005

The utilization of fructose and glucose by fibroblast cultures obtained from patients with hereditary fructose intolerance (HFI) was studied in comparison with fibroblast controls. The cell growth, the time course ofd‐glucose ord‐fructose uptake and the consumption of fructose were similar for both HFI and control cells. Some results showed significant differences between these two cell types: HFI cells consumed less glucose, produced less lactate and contained less glycogen than control cells. Furthermore, significantly less [U‐14C]d‐glucose and [U‐14C]d‐fructose was incorporated into lipids in HFI cells than in control cells. The mechanisms responsible for these differences observed between the two cell types are not known.
The long‐term outcome of patients with glycogen storage diseases
Authors: Smit G. P. A. , Fernandes J. , Leonard J. V. , Matthews E. E. , Moses S. W. , Odievre M. , Ullrich K.
Published: June 2005

In this retrospective study from five centres, 139 patients over 10 years of age with glycogen storage disease types I, III, VI and IX are described. Almost half of the patients with glycogen storage disease type Ia had retarded growth and most had hyperlipidaemia. One‐third of the patients had adenomas, although none of these showed malignant transformations. With increasing age the growth, liver size and hyperlipidaemia of patients with glycogen storage disease type III improve. However, there was a high incidence of myopathy and cardiomyopathy. Patients with glycogen storage disease types VI and IX had a normal growth pattern after childhood. Hepatomegaly and hyperchole‐sterolaemia, however, were still present in half of the patients.
Muscle glycogenosis
Authors: Moses S. W.
Published: June 2005

This review describes clinical, biochemical and genetic features of the four inborn errors affecting muscle glycogen breakdown, namely deficiencies of phosphorylase, phosphorylase kinase, amylo‐1,6‐glucosidase and acid α‐glucosidase. They are characterized by a wide spectrum of clinical manifestation, affecting age of onset, clinical features, progress of disease and tissue involvement. Biochemically, variability of all four enzyme deficiencies is evident in terms of differences in residual enzyme present in tissues, and in the presence or absence of enzyme protein. Genetic heterogeneity, which has been documented in each of the enzyme deficiencies, manifests itself in terms of the presence, absence, quantity or size of mRNA. In phosphorylase deficiency heterogeneity has also been documented at the DNA level. In acid maltase deficiency nine mutant phenotypes have been described affecting various stages of lysosomal enzyme processing.
Inherited disorders of carbohydrate metabolism in children studied by13C‐labelled precursors, NMR and GC‐MS
Authors: Lapidot A.
Published: June 2005

Glucose carbon recycling, glucose production and glucose turnover in glycogen storage disease type I and type II patients and control subjects were determined by a novel approach — mass isotopomer analysis of plasma13C glucose. Changes in the isotopomer distribution of plasma13C glucose were found only in glycogen storage disease type III patients and control subjects. Glucose carbon recyling parameters were also derived from13C NMR spectra of plasma glucose C‐1 splitting pattern. Our results eliminate a mechanism for glucose production in glycogen storage disease type I children involving gluconeogenesis. However, glucose release by amylo‐1,6‐glucosidase activity is in agreement with our results.

A quantitative determination of the metabolic pathways of fructose conversion to glucose in normal children, and in children with disorders of fructose metabolism was derived from13C NMR measurement of plasma13C glucose isotopomer populations following [U‐13C]fructose administration. A direct pathway from fructose, bypassing fructose‐1‐phosphate aldolase, to fructose‐1,6‐diphosphate in controls and hereditary fructose intolerant children (47% and 27%, respectively) was identified. In children with fructose‐1,6‐diphosphatase deficiency, only the gluconeogenic substrates were13C labelled but no synthesis of glucose from [U‐13C]fructose occurred. The significantly lower (by 68%) conversion of fructose to glucose in hereditary fructose intolerance, as compared to control subjects, and non‐conversion in fructose‐1,6‐diphosphatase deficient subjects after [U‐13C]fructose (∼ 20 mg/kg) administration can serve as the basis of a safe diagnostic test for patients suspected of inborn errors of fructose metabolism and other defects involving gluconeogenesis.
Displacement bone marrow transplantation for some inborn errors
Authors: Hobbs J. R.
Published: June 2005

The initial simple bone marrow transplants for genetic immunodeficiency diseases could hardly be rejected by the host, but required matched sibling donors, only available for about 1 in 5 patients. Improved inductions enabled alternative donors from the family or unrelated volunteers to be used. Measurement of the extent of engraftment by donor cell markers or their normal enzymes showed the need for displacement, which aims to obtain 100% donor‐type marrow so that the future immune responses of the recipient become those of the donor and tolerant to donor cells or their products. Immunoprophylaxis can prevent residual host immune cells from surviving to impair the graft. The concept of DBMT with immunoprophylaxis has evolved either to replace abnormal host cells or to confer a component transferable from donor cells to deficient host tissues. Within 10 years over 40 previously fatal genetic diseases have been satisfactorily corrected and seven partially corrected, but for five there has been inadequate delivery of component to genetically defective tissues such as heart, cartilage and brain. The principles can be applied to some 40 other genetic diseases for which no suitable alternative treatments yet exist.
Transport of amino acids by the human placenta: Predicted effects thereon of maternal hyperphenylalaninaemia
Authors: Kudo Y. , Boyd C. A. R.
Published: June 2005

Brush border and basal plasma membrane vesicles prepared from normal term human placental syncytiotrophoblast have been used to study amino acid transport. Such studies are reviewed and novel results presented which confirm that saturation of placental transport by phenylalanine is unlikely to limit delivery of this amino acid to the fetus even with grossly raised maternal concentrations. Such raised maternal levels of phenylalanine are, however, likely to severely embarrass the delivery to the fetus across the placental brush border membrane ofl‐tyrosine and, to a lesser extent, ofl‐tryptophan. Reasons for thinking that this may be relevant to the fetal damage found in maternal PKU are discussed.
Transport of amino acids across the blood‐brain barrier: Implications for treatment of maternal phenylketonuria
Authors: Gardiner R. M.
Published: June 2005

Amino acid transport at the mammalian blood‐brain barrier has been extensively characterized. Transport ofl‐phenylalanine and related neutral amino acids is known to be mediated by a stereospecific, sodium independent, saturable carrier. The affinity of this carrier is much higher than that of comparable systems in other tissues. This feature renders it susceptible to inhibition. It has been suggested that inhibition of neutral amino acid influx into the brain by hyperphenylalaninaemia contributes to the pathophysiology of brain damage in this condition.

Methods for investigation of amino acid transport at the blood‐brain barrier are discussed, and current knowledge of blood‐brain barrier amino acid transport at the blood‐brain barrier is reviewed. Developmental changes are delineated, with particular reference to recent work on the ovine blood‐brain barrier.

There is insufficient information concerning blood‐brain barrier transport of amino acids in the fetal brain to allow firm conclusions to be drawn concerning implications for treatment of maternal PKU. Reasonable extrapolation from animal data suggests that transport inhibition may contribute to impaired fetal brain growth in maternal PKU, and can be minimized by attempts to maintain a normal milieu from the time of conception.
Maternal phenylketonuria — the irish experience
Authors: Naughten E. , Saul I. P.
Published: June 2005

The outcome of 48 pregnancies in 18 women with elevated phenylalanine was studied. The women were divided into two groups, diet and non‐diet. All the women on diet had severe hyperphenylalaninaemia and only six were on the amino acid mixture at conception. In the non‐diet group four women had concentrations of less than 1000 µmol/L and five had severe hyperphenylalaninaemia. Three deaths and one stillbirth occurred in the nondiet group. Microcephaly occurred in 24 children; 11 in the diet group and 13 in the non‐diet group. There were five miscarriages in the non‐diet group and one in the diet group. Diet is beneficial when started early but planned pregnancies, good motivation and compliance were difficult to achieve in this group of women despite every reasonable effort by the PKU clinic.
Cognitive development in offspring of untreated and preconceptionally treated maternal phenylketonuria
Authors: Güttler F. , Lou H. , Andresen J. , Kok K. , Mikkelsen I. , Nielsen K. B. , Nielsen J. B.
Published: June 2005

A survey is given of literature reports on the effect of performance in offspring from 26 maternal PKU pregnancies treated prior to conception. The survey includes two women who were referred to us for genetic counselling because they had both given birth to microcephalic, mentally retarded children. The women were discovered to suffer from unrecognized maternal PKU with fasting phenylalanine concentration of 1.1–1.5mmol/L. A strict diet was introduced prior to planned pregnancy and after some months on diet (phenylalanine concentrations <0.6 mmol/L) they became pregant again. Serum phenylalanine levels were monitored weekly throughout pregnancy, and adjustments in the diet were made to keep serum phenylalanine concentration within the range of 0.18–0.42 mmol/L. The outcome of the pregnancies were healthy children who have developed normally. Their IQs are 105 and 119 at ten and four years of age, respectively and their head circumferences are normal. Our data show that the effect of preconceptional dietary treatment was children with a normal performance, contrary to their older siblings born following untreated pregnancies. These results are in agreement with the survey of ten years' promising experiences with preconceptional treatment in maternal PKU. The data may help to motivate young PKU women to accept planned pregnancies and to encourage them to return to the strict diet, which has prevented them from being retarded.
Identification of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria
Authors: Picat C. , Delfau M. H. , de Rooij F. W. M. , Beukeveld G. J. J. , Wolthers B. G. , Wadman S. K. , Nordmann Y. , Grandchamp B.
Published: June 2005

The molecular abnormalities responsible for acute intermittent porphyria were investigated in both parents of a girl who was retrospectively diagnosed as having a homozygous form of the disease. The mutations in the parents are different from each other and both of them correspond to previously identified G to A changes in the coding part of the porphobilinogen deaminase mRNA. These point mutations lead to the presence of a catalytically‐defective but immunologically‐reactive enzyme. Our results support the conclusion that the propositus girl may represent the first case of compound heterozygosity for acute intermittent porphyria alleles.
Coexistent hereditary coproporphyria and congenital erythropoietic porphyria (Günther disease)
Authors: Nordmann Y. , Amram D. , Deybach J. C. , Phung L. N. , Lesbros D.
Published: June 2005

We present data on one patient with an inheritance pattern for two porphyrias. From her mother she inherited the trait of hereditary coproporphyria; from both parents she inherited the trait of congenital erythropoietic porphyria (Günther disease). Enzyme studies confirmed this new type of dual porphyria.
Identification of a single nucleotide substitution in the coding sequence ofin vitro amplified cDNA from a patient with partial HPRT deficiency (HPRTBrisbane)
Authors: Gordon R. B. , Sculley D. G. , Dawson P. A. , Beacham I. R. , Emmerson B. T.
Published: June 2005

The change in genomic DNA responsible for HPRT deficiency has been determined in a patient with urate overproduction and gout. In erythrocyte cell lysates, this patient had approximately 10% of normal HPRT enzyme activity and 26% of immunoidentical HPRT protein. Cultured lymphoblasts derived from this patient were used to extract mRNA. This was reverse transcribed to cDNA, which was then amplified using the polymerase chain reaction. The resulting DNA was cloned and the nucleotide sequence determined. In addition a portion of the sequence was derived from cloned double‐stranded cDNA prepared by conventional first and second strand synthesis. A single nucleotide base change (a C → T transition) was detected, which predicts an amino acid substitution of isoleucine for threonine at amino acid 168 of the HPRT protein. The nucleotide substitution creates aBamHI site, confirming a restriction fragment length polymorphism previously reported in this patient.
Pyrimidine 5′‐nucleotidase activity in normal and deficient human lymphoblastoid cells
Authors: Hopkinson D. A. , Swallow D. M. , Marinaki A. , Harley E. H.
Published: June 2005

Two distinct pyrimidine 5′‐nucleotidases (UMPH‐1 and UMPH‐2) have previously been detected in human erythrocytes; UMPH‐1 is deficient in a haemolytic anaemia, while UMPH‐2 is unaffected. Only the erythrocyte shows pathological effects in this disorder. Here we have studied lymphoblastoid cell lines from control and UMPH‐1 deficient patients to determine whether UMPH‐1 can be detected in lymphoblastoid cells and whether the deficiency of UMPH‐1 results in any measurable metabolic effects. Both UMPH‐1 and a UMPH‐2‐like activity were found to be present in control lymphoblastoid cells. UMPH‐1 was undetectable in the patients' cells; minor but significant changes were found in the pyrimidine nucleotide and nucleoside pools in the cells.
Inherited metabolic disorders in Turkey
Authors: Özalp I. , Coskun T. , Tokol S. , Demircin G. , Mönch E.
Published: June 2005

A high prevalence of inherited metabolic diseases is present in Turkey; at least in part, this is due to consanguineous marriages.
Heterogeneity of phenylketonuria at the clinical, protein and DNA levels
Authors: Cotton R. G. H.
Published: June 2005

The cloning of the phenylalanine hydroxylase gene and cDNA has potentially allowed the complete characterization of patients with phenylketonuria and already many mutations have been defined. Parents of patients now have the option of prenatal diagnosis. The 18 mutations defined so far indicate enormous heterogeneity not only within particular populations but also between populations. These mutations give little indication as to the locations of the amino acid residues important in enzyme function but one‐third of the mutations are in exon 7 which may be indicating the importance of the region coded by this exon in the protein.
Deletions of the mitochondrial genome
Authors: Harding A. E. , Hammans S. R.
Published: June 2005

Single large deletions of mitochondrial DNA are found in the muscle of about 40% of patients with mitochondrial myopathies, and are detectable in both blood and muscle in Pearson syndrome. In mitochondrial myopathies, there is a close association between the presence of deletions and involvement of extra‐ocular muscles, together with other features of the Kearns‐Sayre syndrome. Deletions appear to arise as fresh mutations in the vast majority of patients and are often flanked by direct repeats up to 13 nucleotides in length. They should affect translation of all mitochondrially encoded components of the respiratory chain, but there is evidence to suggest that intramitochondrial complementation occurs in some cases.
Duplications of mitochondrial DNA: Implications for pathogenesis
Authors: Poulton J.
Published: June 2005

This paper describes the mapping data obtained on two patients in whom there was clear evidence for a rearrangement of mitochondrial DNA, using restriction enzyme analysis of DNA from whole blood and of polymerase chain reaction products. This suggested that a direct tandem duplication was present, and this was confirmed by sequence analysis of the junction fragment between duplicated segments. In each case the gene for cytochrome oxidase subunit I (MTCOX1) was interrupted, creating reading frames which, if transcribed and translated, would result in truncated versions of this peptide.

Heteroplasmy and mosaicism for the abnormal mtDNA population were apparent. Preliminary data also suggest that high‐molecular‐weight rearrangements of the duplicated region are present in all tissues.

The hypothesis that these duplicated genomes caused the phenotype was investigated by examining the distribution of duplicated genomes in various tissues using Southern hybridization and by RNA analysis. This included Northern blotting and cDNA sequencing.

In order to investigate the origins of the duplicated mtDNAs, their distribution in different cells within a tissue was documented using the polymerase chain reaction.
The X chromosome in development in mouse and man
Authors: Monk M.
Published: June 2005

In mammals, dosage compensation for X‐linked genes between males and females is achieved by the inactivation of one of the X chromosomes in females. The inactivation event occurs early in development in all cells of the female mouse embryo and is stable and heritable in somatic cells. However, in the primordial germ cells, reactivation occurs around the time of meiosis. Owing to random inactivation in somatic cells, all female mice and humans are mosaic for X‐linked gene function. Variable mosaicism can result in expression of disease in human females heterozygous for an X‐linked gene defect.

In the extra‐embryonic lineages of female mouse embryos, and in the somatic cells of female marsupials, the paternally inherited X chromosome is preferentially inactivated. The X chromosomes in the egg and sperm must be differentially marked or imprinted, so that they are distinguished by the inactivation mechanism in these tissues.

Initiation of inactivation of an entire X chromosome appears to spread from a single X‐inactivation centre and may involve the recently discovered gene,XIST, which is expressed only from the inactive X chromosome. The maintenance of inactivation of certain household genes on the inactive X chromosome involves methylation of CpG islands in their 5' regions. Critical CpG sites are methylated at, or very close to, the time of inactivation in development.

The mouse and the human X chromosomes carry the same genes but their arrangement is different and there are some genes in the pairing segment and elsewhere on the human X chromosome which can escape inactivation. Regions of homology between the mouse and human X chromosomes allow prediction of the map positions of homologous genes and provide mouse models of genetic disease in the human.
Duchenne muscular dystrophy: Gene and gene product; mechanism of mutation in the gene
Authors: Worton R. G.
Published: June 2005

The X‐linked gene responsible for Duchenne muscular dystrophy encodes dystrophin, a high‐molecular‐weight cytoskeletal protein. Studies in several laboratories have revealed deletion of one or more exons in 60% of affected boys; quantitative analysis in our laboratory has detected duplication of exons in another 6%. The severe Duchenne phenotype is associated with deletions or duplications that shift the reading frame of the message, whereas the milder Becker muscular dytrophy is associated with deletions or duplications that maintain the reading frame. Patients who have neither deletion nor duplication may have nonsense mutations, one of which has been detected by predicting the site of the mutation from the size of the truncated protein. Rare females with the disease have a translocation that disrupts the dystrophin gene on one X chromosome and causes non‐random inactivation of the normal X, resulting in the expression of the disease.

The high frequency of new mutation provides an opportunity to study the mechanism of chromosomal rearrangement that is characteristic of the disease. Our laboratory has focused on the translocations in females and on duplications in affected males. The X‐autosome translocations of affected females are allde novo events that originated in the paternal set of chromosomes. Molecular characterization of the translocation junctions revealed reciprocal translocation with both deletion and addition of nucleotides at the junction, suggestive of a breakage and reunion mechanism. Duplications studied to date are all tandem in nature and sequence analysis of duplication junctions has revealed both homologous and non‐homologous recombination. Marker segregation analysis has revealed that five out of five duplications originated in a single X chromosome of one of the maternal grandparents, suggesting that the recombination event is unequal sister chromatid exchange.
Ornithine carbamoyl transferase deficiency: Findings, models and problems
Authors: Bachmann C.
Published: June 2005

The initial clinical symptoms of ornithine carbamoyl transferase deficiency depend on the age of onset. Respiratory distress on the first day of life does not allow exclusion of OCT deficiency in the individual patient. The acid‐base status is not useful as a discriminant between urea‐cycle disorders and organic acidurias. Beyond the neonatal age, a second period of increased risk for often lethal hyperammonaemic crises is found between 12 and 15 years of age. For definite diagnosis (pre‐ and postnatal) of heterozygotes the quantity of tissue obtained should be sufficient to obtain a representative sample for a mosaic structure. Experimental work gives some clues for the interpretation of reversible symptoms of hyperammonaemia. The increased transport of tryptophan at the blood‐brain barrier in presence of increased glutamine concentration in tissue appears to depend on intact gammaglutamyl transpeptidase in brain microvessels and involves at least in part the L‐carrier. Animal research on the mechanisms leading to irreversible damage in hyperammonaemia should be encouraged in order to define reliable predictive criteria for clinical decisions.
Pyruvate dehydrogenase E1α deficiency
Authors: Brown G. K.
Published: June 2005

Pyruvate dehydrogenase (PDH) deficiency has long been recognized as the most common defined cause of primary lactic acidosis in infancy and early childhood. More recently, it has also been described in patients with subacute/chronic neurodegenerative disease without significant metabolic acidosis. The great majority of cases of PDH deficiency result from a genetic defect in the E1α subunit of the complex. PDH E1α deficiency is an X‐linked inborn error of metabolism in which a high proportion of heterozygous females manifest the condition. In this review of 29 patients with PDH E1α deficiency, particular emphasis is given to those aspects of the disorder which are specifically related to the X chromosome location of the PDH E1α gene. These include the broad spectrum of clinical presentations and problems of diagnosis, especially antenatal diagnosis, in females.
X‐linked adrenoleukodystrophy: Biochemical diagnosis and enzyme defect
Authors: Wanders R. J. A. , van Roermund C. W. T. , Lageweg W. , Jakobs B. S. , Schutgens R. B. H. , Nijenhuis A. A. , Tager J. M.
Published: June 2005

The adrenoleukodystrophies refer to three genetically distinct disorders all characterized by the accumulation of very long‐chain fatty acids. In this paper we will review the biochemical aspects of these leukodystrophies with particular emphasis on the methods used to measure very long‐chain fatty acid levels in plasma and their reliability. Furthermore, we will concentrate on the primary defect in the X‐linked form of adrenoleukodystrophy.
Adrenoleukodystrophy: Phenotypic variability and implications for therapy
Authors: Moser H. W. , Moser A. B. , Smith K. D. , Bergin A. , Borel J. , Shankroff J. , Stine O. C. , Merette C. , Ott J. , Krivit W. , Shapiro E.
Published: June 2005

X‐linked adrenoleukodystrophy (ALD) is a relatively common disorder that shows a great deal of phenotypic variability. Approximately half of the patients have the rapidly progressive childhood cerebral form that is associated with an inflammatory response in brain and leads to total disability or death during the first decade. Twenty five per cent or more of the patients have adrenomyeloneuropathy (AMN), a form that progresses slowly, involves the spinal cord mainly, shows little or no inflammatory response, manifests in adulthood, and is compatible with a near‐normal life span. The two forms of the disease occur frequently within the same kindreds and nuclear families. Segregation analysis based on 3862 individuals in 89 kindreds points to the existence of an autosomal modifier locus with a likelihood ratio of 20:1. In addition, we present preliminary results of three types of therapy. Two hundred and four patients have received a dietary regimen that combines the administration of oils containing mono‐unsaturated fatty acids (oleic and erucic) with the restricted intake of very long‐chain fatty acids. This regimen normalizes the levels of satured very long‐chain fatty acids in plasma within 4 weeks. It appears to improve peripheral nerve function in patients with AMN, and a large‐scale trial is in progress to determine whether it can prevent the onset of neurological involvement in patients who have the biochemical abnormality of ALD but are neurologically intact. We report early results of bone marrow transplantation in 14 patients. There is encouraging but still preliminary evidence that transplantation can arrest the progression of the disease in patients with mild neurological involvement. There is urgent need to develop methods to combat the rapid progression of the cerebral forms of the disease, which so far has resisted therapeutic intervention, including immunosuppression or the administration of immunoglobulin.
The molecular basis of X‐linked immunodeficiency disease
Authors: Kinnon C. , Levinsky R.
Published: June 2005

The molecular bases of the X‐linked immunodeficiency diseases remain largely undetermined. Two of the genes involved in these diseases have been isolated, namely the genes for X‐linked chronic granulomatous disease and properdin deficiency, and substantial progress has now been made in identifying the genes which are defective in the other five diseases, Wiskott‐Aldrich syndrome, X‐linked severe combined immunodeficiency, X‐linked agammaglobulinaemia, X‐linked hyper‐IgM and X‐linked lymphoproliferative syndrome. We review here the nature of the diseases, progress made in identifying and isolating the genes involved and the prospects for improved prenatal detection, carrier status determination and treatment of these life‐threatening conditions.
Gene analysis of mennonite maple syrup urine disease kindred using primer‐specified restriction map modification
Authors: Mitsubuchi H. , Matsuda I. , Nobukuni Y. , Heidenreich R. , Indo Y. , Endo F. , Mallee J. , Segal S.
Published: June 2005

Maple syrup urine disease (MSUD) is an autosomal recessive inherited disease due to a deficiency of any of the subunits, E1α, E1β or E2, of the branched‐chain α‐ketoacid dehydrogenase complex (BCKDH). A large Mennonite kindred of MSUD has been studied in Pennsylvania, USA. In the present investigation, genomes from 70 members, including 12 patients belonging to eight different Mennonite MSUD pedigrees, were examined for possible abnormalities in the E1α gene of BCKDH, by primer‐specified restriction map modification. A T‐to‐A substitution which generates an asparagine in place of a tyrosine at amino acid 394 of the mature E1α subunit was present in both alleles in all the patients and in a single allele in all obligate carriers and several siblings. We describe a new technique for rapid and easy detection of the mutant gene in this population. These family studies provide additional evidence that Mennonite MSUD is caused by a missense mutation of the E1α gene of BCKDH.
Persistent hypermethioninaemia with dominant inheritance
Authors: Blom H. J. , Davidson A. J. , Finkelstein J. D. , Luder A. S. , Bernardini I. , Martin J. J. , Tangerman A. , Trijbels J. M. F. , Mudd S. H. , Goodman S. I. , Gahl W. A.
Published: June 2005

A clinically benign form of persistent hypermethioninaemia with probable dominant inheritance was demonstrated in three generations of one family. Plasma methionine concentrations were between 87 and 475 µmol/L (normal mean 26 µmol/L; range 10–40 µmol/L); urinary methionine and homocystine concentrations were normal. Plasma homocystine, cystathionine, cystine and tyrosine were virtually normal. The concentrations in serum and urine of metabolites formed by the methionine transamination pathway were normal or moderately elevated. Methionine loading of two affected family members revealed a diminished ability to catabolize methionine, but the activities of methionine adenosyltransferase and cystathionine β‐synthase were not decreased in fibroblasts from four affected family members. Fibroblast methylenetetrahydrofolate reductase activity and its inhibition byS‐adenosylmethionine were also normal, indicating normal regulation ofN5‐methyltetrahydrofolate‐dependent homocysteine remethylation. Serum folate concentrations were not increased.

The findings in this family differ from those previously described for known defects of methionine degradation. Since the hepatic and fibroblast isoenzymes of methionine adenosyltransferase differ in their genetic control, this family's biochemical findings appear consistent with a mutation in the structural gene for the hepatic methionine adenosyltransferase isoenzyme.
3‐Methylglutaconic aciduria: A marker for as yet unspecified disorders and the relevance of prenatal diagnosis in a ‘new’ type (‘type 4’)
Authors: Chitayat D. , Chemke J. , Gibson K. M. , Mamer O. A. , Kronick J. B. , McGill J. J. , Rosenblatt B. , Sweetman L. , Scriver C. R.
Published: June 2005

The Mendelian disorder known as 3‐methylgutaconic aciduria (McKusick 250950) gives evidence of allelic and locus heterogeneity. Type 1 has a mild clinical phenotype and confirmed 3‐methylgutaconyl‐CoA hydratase deficiency; inheritance is autosomal recessive. Other forms have major clinical manifestations and subdivide into X‐linked (type 2), a form in Iraqi Jews with optic atrophy (so‐called type 3); and untyped (putative autosomal recessive) forms without identified enzyme defects. In the latter, 3‐methylglutaconic aciduria may simply be a marker for another metabolic disorder.

We describe a male proband with 3‐methylglutaconic aciduria designated here as ‘type 4’ (autosomal recessive, with severe psychomotor phenotype and cerebellar dysgenesis). He is the offspring of Italian consanguineous parents. Born with congenital malformations, he has been followed for 18 years, showing profound developmental delay and cerebellar dysgenesis. Measures of hydratase activity in cultured fibroblasts from the proband and 11 additional patients (two with type 1 disease, 9 with either type 2 or an unspecified form) revealed deficient enzyme activity in type 1 cases and normal activity in the proband and the other 11 cases. Two of the untyped cases probably have 3‐methylglutaconic aciduria of the type described here.

Prenatal diagnosis in the form described here may be feasible by analysis of amniotic fluid metabolites in pregnancies at risk if the mother does not entirely remove elevated concentrations. A female sibling of the proband had normal metabolite values in amniotic fluid. Postnatal follow‐up confirmed absence of the disease. We give the normal values for amniotic fluid and results on these additional fetuses at risk (none affected).
Myelin turnover in hyperphenylalaninaemia. A re‐evaluation with the HPH‐5 mouse
Authors: Hommes F. A. , Moss L.
Published: June 2005

Myelin turnover has been studied in the 25‐day‐old HPH‐5 mouse, a phenylalanine hydroxylase‐deficient mouse mutant. The half‐life of the fast component of myelin decreased from 15 days in control mice to 4.5 days at blood phenylalanine levels of 2.5 mmol/L. The slow component of myelin seems also to be affected by the high phenylalanine level. These observations confirm similar observations obtained with chemically induced models of hyperphenylalaninaemia and are therefore due to the hyperphenylalaninaemiaper se, independently of the inhibitors of phenylalanine hydroxylase. An intermediate blood level of phenylalanine (0.7 mmol/L) likewise seems to interfere with myelin metabolism, although to a lesser degree.
Diminished concentration of the NF‐H subunit of neurofilaments in cerebral cortex of rats chronically treated with proline, methylmalonate and phenylalanine plus α‐methylphenylalanine
Authors: Rubin M. A. , Wannmacher C. M. D. , Valente G. B. , Camargo M. M. , Pureur R. P.
Published: June 2005

Wistar rats from the same litter were randomly divided into four groups and received subcutaneously from the 6th to 28th daypost partum one of the following drugs:l‐proline, methylmalonate,l‐phenylalanine plus α‐methylphenylalanine, or equivalent volumes of 0.9% (w/v) saline (controls). On day 30, the animals were killed, the brain was removed and the cerebral cortex and cerebellum was immediately dissected.

Total intermediate filament fraction (IF) was obtained from cerebral cortex and cerebellum by using a high‐salt phosphate‐buffered solution supplemented by 1% Triton X‐100. The pellet contained the bulk of the IF proteins. Following SDS‐polyacrylamide gel electrophoresis, these proteins were identified as the 200, 150 and 68 kD subunits of neurofilaments (NF‐H, NF‐M and NF‐L, respectively), the 66 kDa associated protein, the 57 kDa intermediate filament‐like protein and the 52 kDa glial fibrillary acidic protein (GFAP). They were further scanned through densitometry from enriched fractions of controls and of animals treated with the various drugs in order to determine the effects of the treatments on their concentration. Our results showed that the concentration of IF protein in cerebellum was not affected by the treatments, whereas chronic administration of all drugs significantly decreased NF‐H subunit concentration in rat cerebral cortex.
3‐Hydroxy‐3‐methylglutaryl‐coenzyme A lyase deficiency: A review
Authors: Wysocki S. J. , Hähnel R.
Published: June 2005

Children with 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency (HMG‐CoA‐LD; McKusick 24645), have inherited two areas of metabolic weakness. Firstly, they are unable to metabolize fully the carbon skeleton of leucine, and secondly, they cannot make ketone bodies in response to prolonged fasting. In the first year of life infants with HMG‐CoA‐LD run a high risk of developing severe hypoglycaemia which can lead to death if prompt intervention does not occur. The metabolic crisis develops when the infant is first introduced to dietary protein soon after birth, or later, when a reduced intake of glucose, often during a viral infection, results in a drain on the infant's circulating glucose levels. However, where diets are adequately adjusted to limit protein and fat intake, the metabolic handicaps of individuals with HMG‐CoA‐LD are not exposed and they are virtually symptomless. As children with HMG‐CoA‐LD grow older the incidence of hypoglycaemic attacks diminishes and they usually develop normally. This article reviews literature on cases of HMG‐CoA‐LD and interprets data on altered metabolism in these children.
Tetrahydrobiopterin non‐responsiveness in dihydropteridine reductase deficiency is associated with the presence of mutant protein
Authors: Cotton R. G. H. , Jennings I. , Bracco G. , Ponzone A. , Guardamagna O.
Published: June 2005

Correlation of the response to a load of tetrahydrobiopterin (BH4) in dihydropterin reductase (DHPR) deficient patients to the type of mutation in these patients has led to the conclusion that 4 patients without mutant DHPR molecules in their cells respond to the BH4 load, whereas 3 patients with mutant DHPR in their cells do not respond. Intravenous injection of BH4 in 1 of the cases not responding to BH4 again showed no response.