Home About us Contact
|
Home About us Contact | ||
|
|
||
Inborn Errors (inborn + error)
Selected AbstractsPediatric Endocrinology and Inborn Errors of MetabolismJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 11 2009Dr Ian Hughes No abstract is available for this article. [source] Pediatric Endocrinology and Inborn Errors of MetabolismJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 7-8 2009Dr Ian Hughes No abstract is available for this article. [source] Fetal dilated cardiomyopathy: an unsuspected presentation of methylmalonic aciduria and hyperhomocystinuria, cblC type,PRENATAL DIAGNOSIS, Issue 3 2009Isabelle De Bie Abstract Objective To report the prenatal presentation with dilated cardiomyopathy of methylmalonic aciduria and homocystinuria, cblC type [cobalamin C (cblC) deficiency] (MIM 277400). Method We describe a boy with cblC deficiency who presented prenatally with fetal ultrasound findings of dilated cardiomyopathy and growth restriction. Results Dilated cardiomyopathy and growth retardation were detected in the third trimester of an initially uncomplicated pregnancy. Investigations were negative for chromosomal and other known causes. Growth restriction persisted but fetal heart function improved. Postnatal biochemical evaluation revealed combined methylmalonic acidemia and homocystinemia. Molecular investigations confirmed cblC deficiency. Initiation of treatment was followed by rapid clinical improvement. Conclusion Prenatal dilated cardiomyopathy can be the presenting sign of cblC deficiency. Inborn errors of metabolism should be considered in the investigation of prenatally diagnosed dilated cardiomyopathy in view of the possible impact on treatment and future reproductive options, in some of these conditions. Copyright © 2009 John Wiley & Sons, Ltd. [source] Aromatic l -amino acid decarboxylase deficiency associated with epilepsy mimicking non-epileptic involuntary movementsDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 11 2008Susumu Ito MD Aromatic l -amino acid decarboxylase (AADC) deficiency is a rare inborn error of neurotransmitter biosynthesis that leads to a combined deficiency of catecholamines and serotonin and is characterized by global developmental delay, involuntary movements, and autonomic dysfunction. We report the case of an 11-year-old male patient with AADC deficiency who also had epileptic spasms and generalized tonic seizures with asymmetrical features, in addition to frequent involuntary non-epileptic movements. The clinical manifestation of the epileptic attacks apparently resembled that of non-epileptic attacks. It was difficult to differentiate between both attacks without the help of an ictal electroencephalographic study. The epileptic attacks were finally controlled by appropriate antiepileptic drugs. Because an association with epileptic seizures is uncommon in AADC deficiency, some cases may have been regarded as involuntary non-epileptic movements. This indicates that the differentiation of epileptic attacks from non-epileptic ones is indispensable for the adequate treatment of patients with AADC deficiency. [source] Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene,HUMAN MUTATION, Issue 7 2007Eva Trevisson Abstract Argininosuccinic aciduria (ASAuria) is an inborn error of metabolism caused by mutations in the argininosuccinate lyase (ASL) gene, which leads to the accumulation of argininosuccinic acid (ASA) in body fluids and severe hyperammonemia. A severe neonatal form and a milder late-onset variant are described. We report a novel ASL pseudogene located in the centromeric region of chromosome 7, 14 novel mutations in the ASL gene, and a novel intronic polymorphism found in a cohort of Italian patients. Our approach relied exclusively on genomic DNA analysis. We found seven missense mutations, two nonsense, three small insertions/deletions, and two splicing mutations. Only two patients harbored previously described mutations, and among the novel variants only two were present in more than one kindred. The pathogenicity of the splicing mutations was demonstrated by a functional splicing assay that employed a hybrid minigene. We also performed molecular modeling using the reported three-dimensional structure of ASL to predict the functional consequences of the missense mutations. There was no genotype,phenotype correlation. Patients with neonatal onset display developmental delay and seizures despite adequate metabolic control. Moreover, hepatomegaly, fibrosis, and abnormal liver function tests are common complications in these patients, but not in patients with the late infancy form. We stress the importance of mutation analysis in patients with ASAuria, to confirm the clinical diagnosis, and to perform DNA-based prenatal diagnosis in future pregnancies of these families. Hum Mutat 28(7), 694,702, 2007. © 2007 Wiley-Liss, Inc. [source] Enzyme Replacement Therapy for Murine Hypophosphatasia,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2008José Luis Millán PhD Abstract Introduction: Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5,-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6 -dependent seizures. There is no established medical treatment. Materials and Methods: Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one-step purification and a deca-aspartate sequence (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP-null mice (Akp2,/,), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, ,CT, and histomorphometry. Results:Akp2,/, mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease. Conclusions: Enzyme replacement using a bone-targeted, recombinant form of human TNALP prevents infantile HPP in Akp2,/, mice. [source] Effects of long-term oral administration of polymeric microcapsules containing tyrosinase on maintaining decreased systemic tyrosine levels in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2004Binglan Yu Abstract There is no effective treatment for melanoma, a fatal skin cancer occurring with increasing frequency. Dietary tyrosine restriction lowers systemic tyrosine and suppresses the growth of melanoma in mice, but this is not tolerated by human resulting in nausea, vomiting, and weight loss. We report here the successful use of oral polymeric microcapsules containing tyrosinase to lower the systemic tyrosine level in the rats. We found that microencapsulated tyrosinase incubated with intestinal content of rats selectively lowered the tyrosine level. We then studied the daily oral administration of microencapsulated tyrosinase in rats of one dose a day, two doses a day, and three doses a day over a period of up to 22 days. With three doses a day, the tyrosine levels in the test group decreased to 68.8% of the control group by day 4 and then decreased to 52.6% after this and remained at this level throughout the 22 days test period. This is the level shown earlier by other workers using dietary restriction of tyrosine to result in suppression of growth of melanoma. However, unlike dietary tyrosine restriction, oral tyrosinase microcapsules did not result in adverse effects nor significant differences in growth (weight gain) when compared to the control group. This approach can also be used for the lowering of systemic tyrosine in hypertyrosinemia, an inborn error of metabolism. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 831,837, 2004 [source] L-2-Hydroxyglutaric Aciduria in Staffordshire Bull TerriersJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2003Carley J. Abramson L-2-Hydroxyglutaric aciduria is an inborn error of metabolism, which has been recognized in humans since 1980. The metabolic defect responsible for the disease is unknown, but the disorder can be diagnosed in humans by elevations of the organic acid, L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma, and urine of affected patients. The disorder produces a variety of clinical neurological defects in humans including psychomotor retardation, seizures, and ataxia. There have previously been no recognized animal models of the disease. However, 6 Staffordshire Bull Terriers were recently identified with the disorder. The animals presented with a variety of clinical signs, most notably seizures, ataxia, dementia, and tremors. They were all screened for organic acid abnormalities in urine, and CSF and plasma (when available). Levels of L-2-hydroxyglutaric acid were elevated in all body fluids evaluated. The clinical, clinicopathologic, and magnetic resonance imaging (MRI) characteristics associated with L-2-hydroxyglutaric acid in Stafforshire Bull Terriers is reported herein and represents the first veterinary model of this inborn error of metabolism. [source] Atypical presentation of VLCAD deficiency associated with a novel ACADVL splicing mutationMUSCLE AND NERVE, Issue 3 2009Oleg Shchelochkov MD Abstract Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive inborn error of metabolism characterized by impaired mitochondrial ,-oxidation of fatty acids with a chain length between 14 and 18 carbons. While expansion of newborn screening has improved our ability to detect VLCAD deficiency in early childhood, the late-onset form of the disease still presents a significant diagnostic challenge. We report a 20-year-old female with VLCAD deficiency who first presented in infancy with hypoketotic hypoglycemia. In childhood the patient developed complex partial seizures that were aggravated by Lamotrigine treatment. The clinical course in early adulthood was complicated by recurrent, often unprovoked, episodes of rhabdomyolysis and myoglobinuria. In addition, she suffered from chronic myalgia, muscle weakness, and diffuse abdominal tenderness. A muscle biopsy revealed accumulation of fat droplets. Her acylcarnitine profile showed significantly elevated C14, C14:1, C16, and C18-carnitines. Sequence analysis of ACADVL revealed a heterozygous recurrent mutation c.848T>C (p.V283A) and a heterozygous novel splice mutation c.879-8T>A that results in the inclusion of six nucleotides from intron 9 into the transcript sequence. The molecular characterization of this novel mutation and its correlation with the clinical phenotype are discussed. Muscle Nerve 39: 374,382, 2009 [source] Abnormal sterol metabolism in holoprosencephaly,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Dorothea Haas Abstract Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The HPE phenotype is extremely variable and the etiology is heterogeneous. Among a variety of embryological toxins that can induce HPE, inhibitors, and other pertubations of cholesterol biosynthesis have been shown to be important factors, most likely because cholesterol is required in the Sonic hedgehog signaling cascade. Decreased levels of maternal cholesterol during pregnancy increase the risk for preterm delivery, but they are not associated with congenital malformations. However, if the fetus is affected by an inborn error of endogenous cholesterol synthesis, a reduction of maternal cholesterol concentration and cholesterol transport over the placenta aggravates the phenotypic expression. Exposure to lipophilic statins in early pregnancy may be associated with a substantial risk for structural CNS defects. © 2010 Wiley-Liss, Inc. [source] Novel mutation and prenatal sonographic findings of glutaric aciduria (type I) in two Taiwanese familiesPRENATAL DIAGNOSIS, Issue 8 2002S. K. Lin Abstract Glutaric aciduria type I (GA I) is an autosomal recessively inherited inborn error with a defect of the enzyme glutaryl-CoA dehydrogenase (GCDH), which has never been diagnosed prenatally in Taiwanese patients. We present the prenatal sonographic findings and mutational analysis data of three children in two Taiwanese families. One patient from each family was diagnosed postnatally due to macrocephaly and neurological deterioration at 4,months and 10,months, respectively. The third child, sister of the first patient, was diagnosed prenatally at 11,weeks' gestation through chorionic villus sampling (CVS). Molecular analysis revealed that the fetus and child in Family 1 were homozygous for a common mutation, IVS10 -2A>C, which has not been reported in the Caucasian population. The patient in Family 2 was a compound heterozygote for IVS10 -2A>C and a novel mutation 749T>C (L238P). After genetic counseling, the couple decided to continue the second pregnancy. However, dilatation of quadrigeminal cistern (QC) and suspicious macrocephaly were noted at 30,weeks. Progressive dilatation of the QC associated with macrocephaly, fronto-temporal atrophy and wide space of perisylvian fissure were found in the follow-up scans. The affected girl was delivered at 37,weeks' gestation by cesarean section. Postnatal magnetic resonance imaging (MRI) studies confirmed the prenatal sonographic findings. With prenatal sonographic findings and mutational analysis presented in the present cases, the feasibility of prenatal diagnosis of GA I in high-risk pregnancy can not be overlooked. Copyright © 2002 John Wiley & Sons, Ltd. [source] Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine ,-synthase (CBS) deficiencyAMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2002Reza Yaghmai Abstract Cystathionine ,-synthase (CBS) deficiency, the most common form of homocystinuria, is an autosomal recessive inborn error of homocysteine metabolism. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives (tHcy) by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma tHcy. With betaine therapy, methionine levels increase over baseline, but usually remain below 1,500 ,mol/L, and these levels have not been associated with adverse affects. We report a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine levels reached 3,000 ,mol/L on betaine, and who subsequently developed massive cerebral edema without evidence of thrombosis. We investigated the etiology by determining methionine and betaine metabolites in our patient, and several possible mechanisms for her unusual response to betaine are discussed. We conclude that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism is uncertain. This case cautions physicians to monitor methionine levels in CBS-deficient patients on betaine and to consider betaine as an adjunct, not an alternative, to dietary control. © 2002 Wiley-Liss, Inc. [source] Specific congenital heart defects in RSH/Smith-Lemli-Opitz syndrome: Postulated involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly or heterotaxiaBIRTH DEFECTS RESEARCH, Issue 3 2003Maria Cristina Digilio BACKGROUND RSH/Smith-Lemli-Opitz syndrome is an autosomal recessive syndrome due to an inborn error of cholesterol metabolism and is characterized by developmental delay, facial anomalies, hypospadias, congenital heart defect (CHD), postaxial polydactyly, and 2,3 toe syndactyly. CHD is found in half of the propositi, and a specific association with atrioventricular canal defect (AVCD) and anomalous pulmonary venous return has been demonstrated. METHODS We report on an additional patient with RSH/SLOS presenting with complete AVCD and anomalous pulmonary venous return, and discuss the possible relationship of the Sonic Hedgehog (SHH) pathway as causative factor of these CHDs and those in heterotaxia patients with postaxial polydactyly syndromes. RESULTS Anatomic similarities between heterotaxia and CHDs of several syndromes with postaxial polydactyly have been noted previously, considering the frequent association of AVCD with common atrium in these conditions. It is known that both CHDs of heterotaxia and postaxial polydactyly can be related to abnormalities of the SHH pathway. Cholesterol has a critical role in the formation of normally active hedgehog proteins. It could be hypothesized that specific types of CHDs in RSH/SLOS can be caused by modifications of the SHH protein related to the defect of cholesterol biosynthesis. CONCLUSIONS The specific association of AVCD and anomalous pulmonary venous return in patients with RSH/SLOS and the finding of AVCD ± common atrium in several syndromes with polydactyly leads to the hypothesis that heterotaxia due to SHH anomalies could be involved in a large spectrum of conditions. Perturbations in different components of the SHH pathway could lead to several developmental errors presenting with partially overlapping clinical manifestations. Birth Defects Research (Part A) 67149,153, 2003. © 2003 Wiley-Liss, Inc. [source] Analysis of the VCX3A, VCX2 and VCX3B genes shows that VCX3A gene deletion is not sufficient to result in mental retardation in X-linked ichthyosisBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2008S.A. Cuevas-Covarrubias Summary Background, X-linked ichthyosis (XLI), an inborn error of metabolism, is due to steroid sulphatase (STS) deficiency. Most patients with XLI harbour complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats on either side of the STS gene seems to have a major role in the high frequency of these deletions. Some patients with XLI with terminal deletions of Xp22.3 involving marker DXS1139 and the STS gene show mental retardation (MR); VCX3A is the only gene located on this critical region. Objectives, To analyse the VCX3A, VCX, VCX2 and VCX3B genes in 80 unrelated Mexican patients with XLI with normal intelligence. Methods, STS activity was measured in the leucocytes using 7-[3H]-dehydroepiandrosterone sulphate as a substrate. Amplification of the regions from telomeric DXS89 to centromeric DXS1134 including both extremes of the STS and the VCX3A, VCX, VCX2 and VCX3B genes was performed using polymerase chain reaction. Results, No STS activity was detected in the patients with XLI (0·00 pmol mg,1 protein h,1). We observed two different deletion patterns: the first group included 62 patients with deletion of VCX3A and VCX genes. The second group included 18 patients with breakpoints at several regions on either side of the STS gene not including the VCX3A gene. Conclusions, These data indicate that more complex mechanisms, apart from possible VCX3A gene participation, are occurring in the genesis of MR in XLI, at least in the sample of Mexican patients analysed. [source] Molecular and phenotypic characteristics of patients with phenylketonuria in Serbia and MontenegroCLINICAL GENETICS, Issue 2 2006M Stojiljkovic Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Caucasians. PKU is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) enzyme. Here, we report the spectrum and the frequency of mutations in the PAH gene and discuss genotype,phenotype correlation in 34 unrelated patients with PKU from Serbia and Montenegro. Using both polymerase chain reaction,restriction fragment length polymorphism and ,broad-range' denaturing-gradient gel electrophoresis/DNA sequencing analysis, 19 disease-causing mutations were identified, corresponding to mutation detection rate of 97%. The most frequent ones were L48S (21%), R408W (18%), P281L (9%), E390G (7%) and R261Q (6%), accounting for 60% of all mutant alleles. The genotype,phenotype correlation was studied in homozygous and functionally hemizygous patients. We found that the most frequent mutation, L48S, was exclusively associated with the classical (severe) PKU phenotype. The mutation E390G gave rise to mild PKU. For the mutation R261Q, patients had been recorded in two phenotype categories. Considering allele frequencies, PKU in Serbia and Montenegro is heterogeneous, reflecting numerous migrations over the Balkan Peninsula. [source] Endothelial markers and homocysteine in patients with classic Fabry diseaseACTA PAEDIATRICA, Issue 2002K Demuth Aim: Fabry disease is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of ,-galactosidase A, a lysosomal enzyme. It is a multisystem disorder characterized by progressive renal insufficiency, with added morbidity from cardio- and cerebrovascular involvement. The recent availability of genetically engineered enzyme offers an effective targeted treatment approach, but also emphasizes the need for surrogate markers to delineate organ damage and monitor the efficacy of enzyme replacement therapy (ERT). Methods: Multiple endothelial factors and plasma homocysteine concentrations were investigated in 12 consecutive hemizygous males with classic Fabry disease and 15 controls as part of an exhaustive baseline evaluation prior to ERT. Results: Compared with the controls, plasma concentrations of homocysteine were significantly (p > 0.01) higher in patients with Fabry disease in the absence of chronic renal failure or vitamin deficiency. Plasma concentrations of vascular cell adhesion molecule-1 were also significantly (p > 0.05) higher in the patients, and there was a trend for decreased endothelin-1 levels. No difference was found in serum intercellular adhesion molecule-1, plasma P-selectin, serum E-selectin and plasma thrombomodulin between the patients and controls. Conclusions: The results do not reveal measurable evidence for endothelial and leukocyte activation that could reliably serve as surrogate markers for routine monitoring of the efficacy of ERT in patients with Fabry disease. While the exact origin and clinical significance of hyperhomocysteinaemia in Fabry disease remains to be studied in a larger cohort of patients carefully monitored for their concurrent medications, especially carbamazepine, we suggest that patients may benefit from folic acid or multivitamin therapy to treat this additional vascular risk factor, when present. [source] Epidemiology and carcinogenesis of hepatocellular carcinomaHPB, Issue 1 2005TRISHE Y.-M. Abstract The incidence of hepatocellular carcinoma (HCC) shows marked variation worldwide but the magnitude of this tumor is reflected by the occurrence of at least 1 million new cases annually and the uniformly dismal outlook with median survivals of <25 months after resection and <6 months with symptomatic treatment. The strikingly uneven distribution of this tumor parallels the prevalence of hepatitis B infection with rising incidence in western countries attributed to hepatitis C infection. Chronic hepatitis and cirrhosis constitute the major preneoplastic conditions in the majority of HCCs and may be related to other etiologic agents such as environmental chemical carcinogens including nitrites, hydrocarbons, solvents, organochlorine pesticides, and the chemicals in processed foods, cleaning agents, cosmetics and pharmaceuticals, as well as plant toxins such as aflatoxins produced by fungi that cause spoilage of grain and food in the tropics. Genetic diseases such as genetic hematochromatosis, Wilson's disease, ,-1-antitrypsin deficiency, and the inborn errors of metabolism including hereditary tyrosinemia and hepatic porphyria, are known to be associated with HCC. Numerous genetic alterations and the modulation of DNA methylation are recognized in HCC and it is likely that these genetic and epigenetic changes combine with factors involved in chronic hepatocyte destruction and regeneration to result in neoplastic growth and multiple molecular pathways may be involved in the production of subsets of hepatocellular tumors. [source] Impact of selected inborn errors of metabolism on prenatal and neonatal developmentIUBMB LIFE, Issue 6 2010Sabine Illsinger Abstract In general, data regarding maturational processes of different metabolic pathways in the very vulnerable fetal and neonatal period are rare. This review is to substantiate the impact of selected inborn errors of metabolism on this critical period of life and their clinical manifestation. Significant adaptation of mitochondrial/energy-, carbohydrate-, lysosomal-, and amino acid-metabolism occurs during early prenatal and neonatal development. In utero, metabolic environment has an impact on the development of the fetus as well as fetal organ maturation. Defects of distinct metabolic pathways could therefore already be of significant relevance in utero and for clinical manifestations in the early fetal and neonatal period. Disturbances of these pathways may influence intrauterine growth and health. Production of a toxic intrauterine milieu, energy-deficiency, modification of membrane function, or disturbance of the normal intrauterine expression of genes may be responsible for fetal compromise and developmental disorders. Three categories of metabolic disorders will be discussed: the "intoxication type" (classical galactosemia, ornithine transcarbamylase deficiency, and "maternal phenylketonuria"), the "storage type" (Morbus Niemann Pick type C), and the "energy deficient type" (including long-chain fatty acid oxidation disorders, pyruvate dehydrogenase deficiency, and respiratory chain defects). For these disorders, the pathophysiology of early manifestation, special aspects regarding the prenatal and neonatal period, and diagnostic as well as therapeutic options are presented. © 2010 IUBMB IUBMB Life, 62(6): 403,413, 2010 [source] Novel primary immunodeficiencies relevant to internal medicine: novel phenotypesJOURNAL OF INTERNAL MEDICINE, Issue 6 2009L. Maródi Abstract. Primary immunodeficiencies (PIDs) are often recognized in adults, either because of delayed diagnosis of a paediatric illness, or increasingly because of the recognition of adult onset forms of these diseases. Moreover, a growing fraction of children diagnosed with PIDs reach adulthood. It has become clear that many of these conditions affect various organs and therefore will be referred to professionals from various fields of internal medicine. It is well known that infectious diseases, allergy, auto-immunity and cancer may result from PIDs. Surprisingly, other clinical manifestations were recently found to reflect inborn errors of immunity. Ground-breaking discoveries suggest that atypical haemolytic uraemic syndrome, Crohn's disease, and alveolar proteinosis may actually be manifestations of novel PIDs. [source] Metabolic liver disease in children,LIVER TRANSPLANTATION, Issue 4 2008Keli Hansen The aim of this article is to provide essential information for hepatologists, who primarily care for adults, regarding liver-based inborn errors of metabolism with particular reference to those that may be treatable with liver transplantation and to provide adequate references for more in-depth study should one of these disease states be encountered. Liver Transpl 14:391,411, 2008. © 2008 AASLD. [source] Gene therapy as an alternative to liver transplantationLIVER TRANSPLANTATION, Issue 12 2002Betsy T. Kren Liver transplantation has become a well-recognized therapy for hepatic failure resulting from acute or chronic liver disease. It also plays a role in the treatment of certain inborn errors of metabolism that do not directly injure the liver. In fact, the liver maintains a central role in many inherited and acquired genetic disorders. There has been a considerable effort to develop new and more effective gene therapy approaches, in part, to overcome the need for transplantation as well as the shortage of donor livers. Traditional gene therapy involves the delivery of a piece of DNA to replace the faulty gene. More recently, there has been a growing interest in the use of gene repair to correct certain genetic defects. In fact, targeted gene repair has many advantages over conventional replacement strategies. In this review, we will describe a variety of viral and nonviral strategies that are now available to the liver. The ever-growing list includes viral vectors, antisense and ribozyme technology, and the Sleeping Beauty transposon system. In addition, targeted gene repair with RNA/DNA oligonucleotides, small-fragment homologous replacement, and triplex-forming and single-stranded oligonucleotides is a long-awaited and potentially exciting approach. Although each method uses different mechanisms for gene repair and therapy, they all share a basic requirement for the efficient delivery of DNA. [source] Gas chromatographic,mass spectrometric urinary metabolome analysis to study mutations of inborn errors of metabolismMASS SPECTROMETRY REVIEWS, Issue 6 2005Tomiko Kuhara Abstract Urine contains numerous metabolites, and can provide evidence for the screening or molecular diagnosis of many inborn errors of metabolism (IEMs). The metabolomic analysis of urine by the combined use of urease pretreatment, stable-isotope dilution, and capillary gas chromatography/mass spectrometry offers reliable and quantitative data for the simultaneous screening or molecular diagnosis of more than 130 IEMs. Those IEMs include hyperammonemias and lactic acidemias, and the IEMs of amino acids, pyrimidines, purines, carbohydrates, and others including primary hyperoxalurias, hereditary fructose intolerance, propionic acidemia, and methylmalonic acidemia. Metabolite analysis is comprehensive for mutant genotypes. Enzyme dysfunction,either by the abnormal structure of an enzyme/apoenzyme, the reduced quantity of a normal enzyme/apoenzyme, or the lack of a coenzyme,is involved. Enzyme dysfunction,either by an abnormal regulatory gene, abnormal sub-cellular localization, or by abnormal post-transcriptional or post-translational modification,is included. Mutations,either known or unknown, common or uncommon,are involved. If the urine metabolome approach can accurately observe quantitative abnormality for hundreds of metabolites, reflecting 100 different disease-causing reactions in a body, then it is possible to simultaneously detect different mutant genotypes of far more than tens of thousands. © 2004 Wiley Periodicals, Inc., Mass Spec Rev 24:814,827, 2005 [source] Glycosphingolipid lysosomal storage diseases: therapy and pathogenesisNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2002M. Jeyakumar Paediatric neurodegenerative diseases are frequently caused by inborn errors in glycosphingolipid (GSL) catabolism and are collectively termed the glycosphingolipidoses. GSL catabolism occurs in the lysosome and a defect in an enzyme involved in GSL degradation leads to the lysosomal storage of its substrate(s). GSLs are abundantly expressed in the central nervous system (CNS) and the disorders frequently have a progressive neurodegenerative course. Our understanding of pathogenesis in these diseases is incomplete and currently few options exist for therapy. In this review we discuss how mouse models of these disorders are providing insights into pathogenesis and also leading to progress in evaluating experimental therapies. [source] In vivo proton MR spectroscopy findings specific for adenylosuccinate lyase deficiencyNMR IN BIOMEDICINE, Issue 5 2010M. Henneke Abstract Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29,ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3,ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder. Copyright © 2010 John Wiley & Sons, Ltd. [source] Management of a cadaveric orthotopic liver transplantation in a pediatric patient with complex congenital heart diseasePEDIATRIC ANESTHESIA, Issue 6 2006DENNIS E. FEIERMAN MD PhD Summary Pediatric orthotopic liver transplantations (OLT) are commonly performed nowadays. Two primary reasons for OLT in children are complications from either extrahepatic biliary atresia (EHBA) or inborn errors of metabolism. However, congenital liver disease may be associated with significant other congenital abnormalities. We present a case of a successful OLT in a pediatric patient with a history of EHBA, situs inversus, and complex congenital heart disease. The cardiac anomalies include dextrocardia, absence of the atrial septum (single atrium), single atrioventricular valve (a-v canal), and an incomplete ventricular septum. Prior surgery include a Kasai procedure for EHBA, banding of the proximal main pulmonary artery, and Broviac catheter placement. We present the anesthesia concerns and management for this complicated case. [source] Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantationPEDIATRIC TRANSPLANTATION, Issue 2003Bruce Bostrom Abstract: We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean ± SD, 1.21 ± 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4,12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis. [source] Biochemical findings in common inborn errors of metabolism,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 2 2006Marzia Pasquali Abstract The application of tandem mass spectrometry (MS/MS) to newborn screening has led to the detection of patients with a wider spectrum of inborn errors of metabolism. A definitive diagnosis can often be established early enough to start treatment before symptoms appear. Here, we review common biochemical findings in disorders caused by deficiency of 3-methylcrotonyl-CoA carboxylase, isobutyryl-CoA dehydrogenase, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase, 3-ketothiolase, 2-methylbutyryl-CoA dehydrogenase, and medium chain acyl CoA dehydrogenase. The diagnosis of these disorders requires biochemical confirmation by measurement of plasma acylcarnitine profile, urine organic acids, and urine acylglycine profiles followed by measurement of enzyme activity or detection of causative mutations. Early treatment can improve the outcome of these disorders. © 2006 Wiley-Liss, Inc. [source] A mass spectrometric strategy for profiling glycoproteinoses, Pompe disease, and sialic acid storage diseasesPROTEOMICS - CLINICAL APPLICATIONS, Issue 4 2008Valegh Faid Abstract Glycoproteinoses, Pompe disease, and sialic acid storage diseases are characterized by a massive accumulation of unprocessed oligosaccharides and/or glycoconjugates in urine. The identification of these glycocompounds is essential for a proper diagnosis. In this study, we investigated the potential of MALDI-TOF-MS to identify glycocompounds present in urine from patients with different inborn errors of glycan metabolism. Urinary glycocompounds were permethylated, and analyzed using GC-MS and MALDI-TOF-MS. In order to confirm tentative assignments, a second aliquot of urine was purified on a C18 Sep-Pak cartridge and glycocompounds were desalted on a column of nonporous graphitized carbon. The glycocompounds were then sequentially on-plate digested using an array of exoglycosidases. A range of disease-specific oligosaccharides as well as glycopeptides was identified for all oligosacchariduria models. In addition, free sialic acid accumulated in urine from a patient suffering from French-type sialuria, has been detected by a GC-MS approach, which could be applied to other sialic acid storage diseases. This procedure is simple, and can be performed in few simple steps in less than 24,h. This current method can be applied for newborn screening for other inherited metabolic diseases as well as for assessing treatments in clinical trials. [source] Precursor ion scan profiles of acylcarnitines by atmospheric pressure thermal desorption chemical ionization tandem mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 23 2008Giuseppe Paglia The fatty acyl esters of L-carnitine (acylcarnitines) are useful biomarkers for the diagnosis of some inborn errors of metabolism analyzed by liquid chromatography/tandem mass spectrometry. In this study the acylcarnitines were analyzed by atmospheric pressure thermal desorption chemical ionization using a commercial tandem mass spectrometer (APTDCI-MS/MS). The method is based on the precursor ion scan mode determination of underivatized acylcarnitines desorbed from samples by a hot desolvation gas flow and ionized by a corona pin discharge. During desorption/ionization step the temperature induces the degradation of acylcarnitines; nevertheless, the common fragment to all acylcarnitines [MH,59]+ is useful for analyzing their profile. APTDCI parameters, including angle of collection and incidence, gas flows and temperatures, were optimized for acylcarnitines. The experiments were performed drying 2,µL of an equimolar mixture of acylcarnitine standards on a glass slide. The specificity was evaluated by comparing product ion spectra and the precursor ion spectra of 85 m/z of acylcarnitines obtained by the APTDCI method and by electrospray ionization flow injection analysis (ESI-FIA). The method was also employed to analyze acylcarnitines extracted from a pathological dried blood spot and a control. The method enables analysis of biological samples and recognition of some acylcarnitines that are diagnostic markers of inherited metabolic diseases. The intrinsic high-throughput analysis of the ambient desorption ionization methods offers a new opportunity either for its potential application in clinical chemistry and for the expanded screening of some inborn errors of metabolism. Copyright © 2008 John Wiley & Sons, Ltd. [source] Rapid comprehensive amino acid analysis by liquid chromatography/tandem mass spectrometry: comparison to cation exchange with post-column ninhydrin detectionRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 22 2008Dennis J. Dietzen Ion-exchange chromatography with ninhydrin detection remains the gold standard for detecting inborn errors of amino acid catabolism and transport. Disadvantages of such analysis include long chromatography times and interference from other ninhydrin-positive compounds. The aim of this project was to develop a more rapid and specific technique using liquid chromatography/tandem mass spectrometry (LC/MS/MS). Optimal fragmentation patterns for 32 amino acids were determined on a triple quadrupole mass spectrometer following butylation. Chromatographic characteristics of each of the amino acids were determined using C8 reversed-phase chromatography with 20% acetonitrile/0.1% formic acid as isocratic mobile phase. Quantitation using eleven deuterated internal standards was compared to cation exchange and ninhydrin detection on a Beckman 7300 system. Following methanol extraction and butylation, determination of 32 amino acids required 20,min. The dynamic range of each amino acid was generally 1,1000,µmol/L. Imprecision ranged from 7 to 23% (CV) over 6 months and recovery ranged from 88,125%. Deming regression with the Beckman 7300 yielded slopes from 0.4,1.2, intercepts from ,21 to 65,µmol/L, correlation coefficients from 0.84,0.99 and Syx from 2,125,µmol/L. Isobaric amino acids were separated by chromatography (e.g. leucine, isoleucine) or by unique fragmentation (e.g., alanine, , -alanine). LC/MS/MS is comparable to traditional LC-ninhydrin detection. Mass spectral detection shortens analysis times and reduces potential for interference in detecting inborn metabolic errors. Copyright © 2008 John Wiley & Sons, Ltd. [source] | ||||||||||||||||||||||||||||||||||