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1.
Clin Chim Acta ; 481: 156-160, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29534959

ABSTRACT

Single large-scale mitochondrial DNA deletions disorders are classified into three main phenotypes with frequent clinical overlap: Pearson marrow-pancreas syndrome (PMS), Kearns-Sayre syndrome (KSS) and chronic progressive external ophtalmoplegia (PEO). So far, only few anecdotal studies have reported on the urinary organic acids profile in this disease class. In this single-center retrospective study, we performed quantitative evaluation of urinary organic acids in a series of 15 pediatric patients, 7 with PMS and 8 with KSS. PMS patients showed an organic acids profile almost constantly altered, whereas KSS patients frequently presented with normal profiles. Lactate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, fumarate, pyruvate, 2-hydroxybutyrate, 2-ethyl-3-hydroxypropionate, and 3-methylglutaconate represented the most frequent metabolites observed in PMS urine. We also found novel metabolites, 3-methylglutarate, tiglylglycine and 2-methyl-2,3-dihydroxybutyrate, so far never reported in this disease. Interestingly, patients with a disease onset as PMS evolving overtime into KSS phenotype, presented persistent and more pronounced alterations of organic acid signature than in patients with a pure KSS phenotype. Our study shows that the quantitative analysis of urinary organic acid profile represents a helpful tool for the diagnosis of PMS and for the differential diagnosis with other inherited diseases causing abnormal organic acidurias.


Subject(s)
Acyl-CoA Dehydrogenase, Long-Chain/deficiency , DNA, Mitochondrial/genetics , Kearns-Sayre Syndrome/urine , Lipid Metabolism, Inborn Errors/urine , Mitochondrial Diseases/urine , Muscular Diseases/urine , 3-Hydroxybutyric Acid/urine , Acyl-CoA Dehydrogenase, Long-Chain/genetics , Acyl-CoA Dehydrogenase, Long-Chain/urine , Adolescent , Child , Child, Preschool , Congenital Bone Marrow Failure Syndromes , Fumarates/urine , Glutarates/urine , Humans , Hydroxybutyrates/urine , Infant , Kearns-Sayre Syndrome/diagnosis , Kearns-Sayre Syndrome/genetics , Lactic Acid/urine , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Muscular Diseases/diagnosis , Muscular Diseases/genetics , Pyruvic Acid/urine , Retrospective Studies , Valerates/urine
2.
J Int Med Res ; 46(4): 1339-1348, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29350094

ABSTRACT

Objective The aim of this study was to determine whether an expanded newborn screening programme, which is not yet available in Slovenia, would have detected the first two patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the country. Two novel ACADM mutations are also described. Methods Both patients were diagnosed clinically; follow-up involved analysis of organic acids in urine, acylcarnitines in dried blood spots, and genetic analysis of ACADM. Cut-off values of acylcarnitines in newborns were established using analysis of 10,000 newborns in a pilot screening study. Results In both patients, analysis of the organic acids in urine showed a possible ß-oxidation defect, while the specific elevation of acylcarnitines confirmed MCAD deficiency. Subsequent genetic analysis confirmed the diagnosis; both patients were compound heterozygotes, each with one novel mutation (c.861 + 2T > C and c.527_533del). The results from a retrospective analysis of newborn screening cards clearly showed major elevations of MCAD-specific acylcarnitines in the patients. Conclusions An expanded newborn screening programme would be beneficial because it would have detected MCAD deficiency in both patients before the development of clinical signs. Our study also provides one of the first descriptions of ACADM mutations in Southeast Europe.


Subject(s)
Acyl-CoA Dehydrogenase/deficiency , Acyl-CoA Dehydrogenase/genetics , Lipid Metabolism, Inborn Errors/enzymology , Lipid Metabolism, Inborn Errors/genetics , Mutation/genetics , Neonatal Screening , Acyl-CoA Dehydrogenase/blood , Acyl-CoA Dehydrogenase/urine , Carboxylic Acids/urine , Carnitine/analogs & derivatives , Carnitine/blood , Dried Blood Spot Testing , Female , Humans , Infant , Infant, Newborn , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/urine , Male , Retrospective Studies
3.
Mol Genet Metab ; 116(4): 231-41, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26458767

ABSTRACT

Tandem MS "profiling" of acylcarnitines and amino acids was conceived as a first-tier screening method, and its application to expanded newborn screening has been enormously successful. However, unlike amino acid screening (which uses amino acid analysis as its second-tier validation of screening results), acylcarnitine "profiling" also assumed the role of second-tier validation, due to the lack of a generally accepted second-tier acylcarnitine determination method. In this report, we present results from the application of our validated UHPLC-MS/MS second-tier method for the quantification of total carnitine, free carnitine, butyrobetaine, and acylcarnitines to patient samples with known diagnoses: malonic acidemia, short-chain acyl-CoA dehydrogenase deficiency (SCADD) or isobutyryl-CoA dehydrogenase deficiency (IBD), 3-methyl-crotonyl carboxylase deficiency (3-MCC) or ß-ketothiolase deficiency (BKT), and methylmalonic acidemia (MMA). We demonstrate the assay's ability to separate constitutional isomers and diastereomeric acylcarnitines and generate values with a high level of accuracy and precision. These capabilities are unavailable when using tandem MS "profiles". We also show examples of research interest, where separation of acylcarnitine species and accurate and precise acylcarnitine quantification is necessary.


Subject(s)
Acetyl-CoA C-Acyltransferase/deficiency , Acyl-CoA Dehydrogenase/deficiency , Amino Acid Metabolism, Inborn Errors/diagnosis , Carbon-Carbon Ligases/deficiency , Carnitine/analogs & derivatives , Lipid Metabolism, Inborn Errors/diagnosis , Urea Cycle Disorders, Inborn/diagnosis , Acetyl-CoA C-Acyltransferase/blood , Acetyl-CoA C-Acyltransferase/cerebrospinal fluid , Acetyl-CoA C-Acyltransferase/urine , Acyl-CoA Dehydrogenase/blood , Acyl-CoA Dehydrogenase/cerebrospinal fluid , Acyl-CoA Dehydrogenase/urine , Amino Acid Metabolism, Inborn Errors/blood , Amino Acid Metabolism, Inborn Errors/cerebrospinal fluid , Amino Acid Metabolism, Inborn Errors/urine , Betaine/analogs & derivatives , Betaine/blood , Betaine/cerebrospinal fluid , Betaine/urine , Carbon-Carbon Ligases/blood , Carbon-Carbon Ligases/cerebrospinal fluid , Carbon-Carbon Ligases/urine , Carnitine/blood , Carnitine/cerebrospinal fluid , Carnitine/urine , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Female , Humans , Infant, Newborn , Isomerism , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/cerebrospinal fluid , Lipid Metabolism, Inborn Errors/urine , Male , Neonatal Screening , Reproducibility of Results , Sensitivity and Specificity , Tandem Mass Spectrometry/standards , Urea Cycle Disorders, Inborn/blood , Urea Cycle Disorders, Inborn/cerebrospinal fluid , Urea Cycle Disorders, Inborn/urine
4.
Am J Med Genet A ; 167A(3): 621-8, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25691415

ABSTRACT

Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders.


Subject(s)
Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/urine , Mitochondrial Diseases/blood , Mitochondrial Diseases/urine , Muscular Diseases/blood , Muscular Diseases/urine , Acyl-CoA Dehydrogenase, Long-Chain/blood , Acyl-CoA Dehydrogenase, Long-Chain/urine , Amino Acids/blood , Biopsy , Blood Chemical Analysis , Congenital Bone Marrow Failure Syndromes , Female , Humans , Infant , Lipid Metabolism, Inborn Errors/diagnosis , Liver/metabolism , Liver/pathology , Male , Mitochondrial Diseases/diagnosis , Muscular Diseases/diagnosis , Pancreas/metabolism , Pancreas/pathology , Phenotype
5.
Tohoku J Exp Med ; 221(3): 191-5, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20543534

ABSTRACT

Carnitine palmitoyltransferase 2 (CPT2) deficiency is one of the most common mitochondrial beta-oxidation defects. A female patient with an infantile form of CPT2 deficiency first presented as having a Reye-like syndrome with hypoglycemic convulsions. Oral L-carnitine supplementation was administered since serum free carnitine level was very low (less than 10 micromol/L), indicating secondary carnitine deficiency. Her serum and urinary acylcarnitine profiles were analyzed successively to evaluate time-course effects of L-carnitine supplementation. After the first two days of L-carnitine supplementation, the serum level of free carnitine was elevated; however, the serum levels of acylcarnitines and the urinary excretion of both free carnitine and acylcarnitines remained low. A peak of the serum free carnitine level was detected on day 5, followed by a peak of acetylcarnitine on day 7, and peaks of long-chain acylcarnitines, such as C16, C18, C18:1 and C18:2 carnitines, on day 9. Thereafter free carnitine became predominant again. These peaks of the serum levels corresponded to urinary excretion peaks of free carnitine, acetylcarnitine, and medium-chain dicarboxylic carnitines, respectively. It took several days for oral L-carnitine administration to increase the serum carnitine levels, probably because the intracellular stores were depleted. Thereafter, the administration increased the excretion of abnormal acylcarnitines, some of which had accumulated within the tissues. The excretion of medium-chain dicarboxylic carnitines dramatically decreased on day 13, suggesting improvement of tissue acylcarnitine accumulation. These time-course changes in blood and urinary acylcarnitine levels after L-carnitine supplementation support the effectiveness of L-carnitine supplementation to CPT2-deficient patients.


Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Carnitine/deficiency , Carnitine/urine , Acetylcarnitine/blood , Acetylcarnitine/deficiency , Acetylcarnitine/urine , Amino Acid Metabolism, Inborn Errors/blood , Amino Acid Metabolism, Inborn Errors/urine , Amino Acids/blood , Amino Acids/deficiency , Amino Acids/urine , Blood Chemical Analysis , Carnitine/analogs & derivatives , Carnitine/blood , Carnitine O-Palmitoyltransferase/blood , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/urine , Reye Syndrome/blood , Reye Syndrome/urine , Time Factors , Treatment Outcome , Vitamin B Complex/blood , Vitamin B Complex/urine
6.
Mol Genet Metab ; 100(3): 241-50, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20434380

ABSTRACT

Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or "variant of unknown significance (VUS)," presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.


Subject(s)
Acyl-CoA Dehydrogenase/deficiency , Acyl-CoA Dehydrogenase/genetics , Genetic Variation , Lipid Metabolism, Inborn Errors/enzymology , Lipid Metabolism, Inborn Errors/genetics , Mutation , Adolescent , Adult , Alleles , Carnitine/analogs & derivatives , Carnitine/blood , Child , Child, Preschool , DNA Mutational Analysis , Exons , Genetic Association Studies , Genetic Carrier Screening , Genotype , Glycine/analogs & derivatives , Glycine/urine , Humans , Infant, Newborn , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/urine , Middle Aged , Mutation, Missense , Neonatal Screening , Polymorphism, Single Nucleotide , Young Adult
7.
Pediatr Res ; 67(3): 304-8, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19952864

ABSTRACT

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an inborn error, biochemically characterized by increased plasma butyrylcarnitine (C4-C) concentration and increased ethylmalonic acid (EMA) excretion and caused by rare mutations and/or common gene variants in the SCAD encoding gene. Although its clinical relevance is not clear, SCADD is included in most US newborn screening programs. Riboflavin, the precursor of flavin adenine dinucleotide (FAD, cofactor), might be effective for treating SCADD. We assessed the FAD status and evaluated the effects of riboflavin treatment in a prospective open-label cohort study involving 16 patients with SCADD, subdivided into mutation/mutation (mut/mut), mutation/variant (mut/var), and variant/variant (var/var) genotype groups. Blood FAD levels were normal in all patients before therapy, but significantly lower in the mut/var and var/var groups compared with the mut/mut group. Riboflavin treatment resulted in a decrease in EMA excretion in the mut/var group and in a subjective clinical improvement in four patients from this group. However, this improvement persisted after stopping treatment. These results indicate that high-dose riboflavin treatment may improve the biochemical features of SCADD, at least in patients with a mut/var genotype and low FAD levels. As our study could not demonstrate a clinically relevant effect of riboflavin, general use of riboflavin cannot be recommended.


Subject(s)
Butyryl-CoA Dehydrogenase/deficiency , Flavin-Adenine Dinucleotide/blood , Lipid Metabolism, Inborn Errors/drug therapy , Riboflavin/administration & dosage , Vitamin B Complex/administration & dosage , Adolescent , Biomarkers/blood , Biomarkers/urine , Butyryl-CoA Dehydrogenase/genetics , Carnitine/analogs & derivatives , Carnitine/blood , Child , Child, Preschool , Female , Flavin-Adenine Dinucleotide/urine , Genetic Predisposition to Disease , Humans , Infant , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/enzymology , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/urine , Male , Malonates/urine , Mutation , Phenotype , Prospective Studies , Treatment Outcome
8.
J Child Neurol ; 23(6): 703-5, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18539996

ABSTRACT

An 8-month-old girl was admitted to an outpatient clinic with significant hypotonia and weakness. Organic acid analysis in urine revealed a significant increase in ethylmalonic acid. A deoxyribonucleic analysis revealed the presence of a 625G>A (G-to-A substitution at nucleotide 625) variant short-chain acyl-coenzyme A dehydrogenase gene polymorphism. With the clinical, biochemical and molecular findings, short-chain acyl-coenzyme A dehydrogenase deficiency was suspected. Because 625G>A and 511C>T (C-to-T substitution at nucleotide 511) genetic variations are also present in 14% of the general population, these are considered to be genetic sensitivity variations rather than causing a disease themselves and to result in possible short-chain acyl-coenzyme A dehydrogenase deficiency in the presence of environmental factors such as fever and hunger as well as cellular, biochemical, and other genetic factors. It was stressed that severe infantile hypotonia could also be the only manifestation of ethylmalonic aciduria spectrum disorders.


Subject(s)
Alleles , Butyryl-CoA Dehydrogenase/deficiency , Butyryl-CoA Dehydrogenase/genetics , DNA Mutational Analysis , Lipid Metabolism, Inborn Errors/genetics , Malonates/urine , Muscle Hypotonia/genetics , Muscle Weakness/genetics , Developmental Disabilities/diagnosis , Developmental Disabilities/genetics , Developmental Disabilities/urine , Diagnosis, Differential , Female , Genotype , Humans , Infant , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/urine , Muscle Hypotonia/diagnosis , Muscle Hypotonia/urine , Muscle Weakness/diagnosis , Muscle Weakness/urine , Neurologic Examination , Phenotype , Polymorphism, Genetic/genetics
9.
J Inherit Metab Dis ; 31 Suppl 2: S293-7, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18500571

ABSTRACT

Wolcott-Rallison syndrome (WRS) (OMIM 226980) is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3. We report a female patient who developed insulin-requiring diabetes at 2.5 months of age. Multiple epiphyseal dysplasia was diagnosed at age 2 years. At age 5.5 years she developed a Reye-like syndrome with hypoketotic hypoglycaemia and renal and hepatic insufficiency and died. A partial autopsy showed fat infiltration in the liver and kidneys. Examination of urine by gas chromatography and mass spectrometry showed large amounts of C(6)-dicarboxylic acid (adipic acid), 3-hydroxy-C(8)-dicarboxylic acid, 3-hydroxy-C(10)-dicarboxylic acid, and 3-hydroxydecenedioic acid. Acetoacetate and 3-hydroxybutyrate were absent. The findings suggested a metabolic block in mitochondrial fatty acid oxidation, but lack of material precluded enzyme analyses. The clinical diagnosis of WRS was suggested in retrospect, and confirmed by sequencing of DNA extracted from stored autopsy material. The patient was compound heterozygous for the novel EIF2AK3 mutations c.1694_1695delAT (Y565X) and c.3044T > C (F1015S). Our data suggest that disruption of the EIF2AK3 gene may lead to defective mitochondrial fatty acid oxidation and hypoglycaemia, thus adding to the heterogeneous phenotype of WRS.


Subject(s)
Diabetes Mellitus, Type 1/diagnosis , Dicarboxylic Acids/urine , Hydroxy Acids/urine , Lipid Metabolism, Inborn Errors/etiology , Osteochondrodysplasias/diagnosis , Adipates/urine , Biomarkers/urine , Child, Preschool , DNA Mutational Analysis , Diabetes Mellitus/etiology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/enzymology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/urine , Disease Progression , Epiphyses/abnormalities , Epiphyses/enzymology , Fatal Outcome , Female , Gas Chromatography-Mass Spectrometry , Hepatic Insufficiency/etiology , Humans , Infant , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/urine , Mutation , Osteochondrodysplasias/complications , Osteochondrodysplasias/enzymology , Osteochondrodysplasias/etiology , Osteochondrodysplasias/genetics , Osteochondrodysplasias/urine , Renal Insufficiency/etiology , eIF-2 Kinase/genetics
10.
Int J Immunopathol Pharmacol ; 18(4): 805-8, 2005.
Article in English | MEDLINE | ID: mdl-16388731

ABSTRACT

We report a case of a newborn with Glutaric aciduria type II. Pregnancy was complicated by polyhidramnios and fetal bradycardia. Cardiomegaly was detected by fetal echocardiography. The baby was admitted to the Neonatal Intensive Care Unit of Chieti with respiratory distress syndrome immediately after delivery. He showed head and neck edema, micrognathia, paucity of movement, pronounced hypotonia, bilateral cryptorchidism, micropenis, small hands, skin hyperelasticity and joint hypermobility. Serum and urine analysis showed a fatty acid beta-oxidation disorder. He died at 7 days of age for cardiac arrest and autopsy showed marked hepatic and cardiac vacuolisation, lipid storage myopathy and glial cells vacuolisation. Based upon these findings, we speculate that this infant may be suffering from inborn metabolic disease.


Subject(s)
Fatty Acids/metabolism , Glutarates/urine , Lipid Metabolism, Inborn Errors/urine , Echocardiography , Electron-Transferring Flavoproteins/metabolism , Enzymes/blood , Fatal Outcome , Female , Flavoproteins/metabolism , Humans , Infant, Newborn , Iron-Sulfur Proteins/metabolism , Male , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Pregnancy , Pregnancy Complications/pathology , Respiratory Distress Syndrome, Newborn/pathology
11.
J Inherit Metab Dis ; 26(7): 711-2, 2003.
Article in English | MEDLINE | ID: mdl-14707521

ABSTRACT

Recurrent rhabdomyolysis has previously been reported in one patient with glutaric aciduria type I. We report rhabdomyolysis in a second, unrelated patient, suggesting that there may be a specific association with thismetabolic disorder.


Subject(s)
Glutarates/urine , Lipid Metabolism, Inborn Errors/complications , Lipid Metabolism, Inborn Errors/urine , Rhabdomyolysis/etiology , Child, Preschool , Electroencephalography , Fatal Outcome , Female , Humans , Recurrence , Respiratory Tract Infections/complications
12.
Clin Chim Acta ; 323(1-2): 37-58, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12135806

ABSTRACT

Mitochondrial fatty acid beta-oxidation disorders (FAOD) are a group of clinically and biochemically heterogeneous inherited metabolic defects. The spectrum of phenotypes has expanded from hepatic encephalopathy to encompass myopathy, cardiomyopathy, peripheral neuropathy, sudden death and pregnancy complicated by fetal FAOD. Pre-symptomatic diagnosis is important to prevent morbidity and this is now achievable through newborn screening using tandem mass spectrometry (MS/MS). Moreover, most of the diagnosed defects are treatable and the prognosis is generally favourable. This article reviews the features of FAOD, critically evaluates methods of investigation including metabolite analyses in body fluids, in vitro oxidation rates and acylcarnitine profiling studies, enzymatic and mutational tests, and discusses genotype-phenotype correlation, treatment and monitoring options. Based on this knowledge, strategies for the biochemical investigation and differential diagnosis of patients presenting clinically, asymptomatic neonates detected by newborn screening, infants born after complications during late pregnancy, and cases of sudden death with suspected FAOD are presented. Laboratory investigation commonly begins with a search for diagnostic metabolites in physiological fluids, followed by in vitro functional studies if the initial findings are inconclusive, and confirmation by enzymology and molecular analyses. Occasionally a stress test in vivo may be required. At other times there may be no firm diagnosis achieved.


Subject(s)
Fatty Acids/metabolism , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/metabolism , Mitochondria/metabolism , Mitochondria/pathology , Diagnosis, Differential , Humans , Infant, Newborn , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/urine , Mass Spectrometry , Neonatal Screening , Oxidation-Reduction , Phenotype
13.
J Clin Lab Anal ; 16(2): 115-20, 2002.
Article in English | MEDLINE | ID: mdl-11948802

ABSTRACT

Current diagnostic tests to detect disorders of fatty acids metabolism, such as long-chain hydroxyacyl CoA dehydrogenase deficiency (LCHAD), are hampered by insensitivity or a long delay time required for results. Children with LCHAD deficiency are known to excrete 3-hydroxydicarboxylic acids with chain lengths of 10-16 carbons, but a quantitative method to measure excretion of these potentially diagnostically important compounds has not been reported. We report synthetic schemes for synthesis of 3-hydroxydodecanedioic acid and a di-deuterated analog, suitable for use in a stable-isotope dilution mass spectrometric analytical approach. Evaluation of several common derivatization protocols to produce a volatile derivative for gas chromatography determined that trimethylsyl derivatives produced the best efficiency and stability. Positive-ion chemical ionization mass spectrometry provided the greatest yield of characteristic ions. These results indicate the basic reagents needed to develop sensitive and accurate 3-hydroxydodecanedioic acid measurements for diagnosis of LCHAD deficiency and other fatty acid oxidation disorders.


Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/deficiency , Fatty Acids/metabolism , Lauric Acids/urine , Lipid Metabolism, Inborn Errors/urine , 3-Hydroxyacyl CoA Dehydrogenases/urine , Gas Chromatography-Mass Spectrometry/methods , Gas Chromatography-Mass Spectrometry/standards , Humans , Isotopes/standards , Reference Standards
14.
Mol Genet Metab ; 74(1-2): 105-19, 2001.
Article in English | MEDLINE | ID: mdl-11592808

ABSTRACT

Over the past few years, the number of identified inborn errors of cholesterol biosynthesis has increased significantly. The first inborn error of cholesterol biosynthesis to be characterized, in the mid 1980s, was mevalonic aciduria. In 1993, Irons et al. ( 1 ) (M. Irons, E. R. Elias, G. Salen, G. S. Tint, and A. K. Batta, Lancet 341:1414, 1993) reported that Smith-Lemli-Opitz syndrome, a classic autosomal recessive malformation syndrome, was due to an inborn error of cholesterol biosynthesis. This was the first inborn error of postsqualene cholesterol biosynthesis to be identified, and subsequently additional inborn errors of postsqualene cholesterol biosynthesis have been characterized to various extent. To date, eight inborn errors of cholesterol metabolism have been described in human patients or in mutant mice. The enzymatic steps impaired in these inborn errors of metabolism include mevolonate kinase (mevalonic aciduria as well as hyperimmunoglobulinemia D and periodic fever syndrome), squalene synthase (Ss-/- mouse), 3beta-hydroxysteroid Delta14-reductase (hydrops-ectopic calcification-moth-eaten skeletal dysplasia), 3beta-hydroxysteroid dehydrogenase (CHILD syndrome, bare patches mouse, and striated mouse), 3beta-hydroxysteroid Delta8,Delta7-isomerase (X-linked dominant chondrodysplasia punctata type 2, CHILD syndrome, and tattered mouse), 3beta-hydroxysteroid Delta24-reductase (desmosterolosis) and 3beta-hydroxysteroid Delta7-reductase (RSH/Smith-Lemli-Opitz syndrome and Dhcr7-/- mouse). Identification of the genetic and biochemical defects which give rise to these syndromes has provided the first step in understanding the pathophysiological processes which underlie these malformation syndromes.


Subject(s)
Cholesterol/biosynthesis , Lipid Metabolism, Inborn Errors/genetics , Animals , Cholesterol/metabolism , Disease Models, Animal , Humans , Lipid Metabolism, Inborn Errors/enzymology , Lipid Metabolism, Inborn Errors/urine , Mevalonic Acid/urine
15.
Am J Med Genet ; 96(2): 192-5, 2000 Apr 03.
Article in English | MEDLINE | ID: mdl-10893496

ABSTRACT

Methylmalonic acidemia is an inborn error of metabolism known to be a cause of ketoacidosis and mental retardation. The less severe mut(-) form of the disorder, however, has been described with only mild to moderate cognitive deficits or, rarely, with normal neurodevelopment in asymptomatic cases. Nevertheless, there has been no detailed documentation of long-term neuropsychological function in the mut(-) form and relatively few IQ scores. We performed longitudinal developmental and neuropsychological assessments on a girl with symptomatic mut(-) methylmalonic acidemia whose biochemical abnormalities were in the moderately severe range and who had had recurrent episodes of ketoacidosis. At almost 12 years of age, her full scale IQ on the Wechsler Intelligence Scale, third edition, was 129 with very superior and superior scores on nonverbal and verbal skills, respectively. On the National Achievement Test she scored above the 99th percentile in the Basic Battery and is considered to be a gifted student. This outcome suggests that the spectrum of cognitive attainment in mut(-) methylmalonic acidemia is wide and that even a moderate degree of biochemical severity with ketoacidotic episodes may not result in cognitive deficit. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:192-195, 2000.


Subject(s)
Cognition Disorders/psychology , Lipid Metabolism, Inborn Errors/psychology , Methylmalonic Acid/blood , Adolescent , Child , Cognition Disorders/blood , Cognition Disorders/genetics , Cognition Disorders/urine , Female , Humans , Intelligence Tests , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/urine , Longitudinal Studies , Methylmalonic Acid/urine , Neuropsychological Tests , Prospective Studies
16.
Tohoku J Exp Med ; 191(1): 31-8, 2000 May.
Article in English | MEDLINE | ID: mdl-10896037

ABSTRACT

We report the peculiar serial electroencephalographic (EEG) findings in a 7-year-old boy with glutaric aciduria type 1 during an episode of acute encephalopathy. The patient developed Reye-like syndrome triggered by cellulitis. Cranial magnetic resonance imaging demonstrated diffuse softening of cerebral hemisphere. The EEG on the day following onset of acute encephalopathy showed suppression burst pattern including continuous 14-15 Hz rhythmic waves at first. Then, periodic synchronous discharge appeared and lasted for about 40 minutes. Periodic synchronous discharge finally disappeared and nearly total electrocerebral silence continued. There have been no reports indicating such a change of EEG in a short period. The serial EEG changes probably reflect the process of electrical death of neurons in cerebral hemispheres.


Subject(s)
Brain Injuries/complications , Brain/physiopathology , Glutarates/urine , Lipid Metabolism, Inborn Errors/complications , Acute Disease , Brain/pathology , Brain Injuries/physiopathology , Child , Electroencephalography , Humans , Lipid Metabolism, Inborn Errors/physiopathology , Lipid Metabolism, Inborn Errors/urine , Magnetic Resonance Imaging/methods , Male
18.
Clin Chim Acta ; 295(1-2): 87-96, 2000 May.
Article in English | MEDLINE | ID: mdl-10767396

ABSTRACT

In urine of patients with propionyl-CoA carboxylase deficiency or with methylmalonic acidemia, carnitine esters of 2-methyl-branched fatty acids of all chain lengths between 4 and 9 atoms of carbon were identified during the acute phase of the diseases. The chemical structure of these compounds was obtained by gas chromatography-mass spectrometry analysis of their fatty acid moieties in their free and picolinyl ester forms. We suggest mechanisms for the biosynthesis of these branched fatty acids, and their accumulation in urine during episodes of caloric imbalance.


Subject(s)
Carnitine/analogs & derivatives , Methylmalonic Acid/blood , Propionates/blood , Adult , Carboxy-Lyases/deficiency , Carnitine/chemistry , Carnitine/urine , Case-Control Studies , Gas Chromatography-Mass Spectrometry , Humans , Infant , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/urine , Male , Methylmalonyl-CoA Decarboxylase , Spectrometry, Mass, Fast Atom Bombardment
19.
J Pharm Biomed Anal ; 21(6): 1215-24, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10708405

ABSTRACT

The analysis of acylglycines is an important biochemical tool for the diagnosis of inherited disorders of mitochondrial fatty acid beta-oxidation. A stable isotope dilution gas chromatography negative chemical ionisation mass spectrometry method for the quantitative analysis of short- and medium-chain acylglycines as their bis(trifluoromethyl)benzyl (BTFMB) ester derivatives is described. The diagnostic usefulness of the method was demonstrated in nine patients with medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency, and seven patients with multiple acyl-CoA dehydrogenation defect (MAD). The urinary acylglycine profiles in these patients were compared to those in controls (n = 19), children on a medium-chain triglyceride (MCT) supplemented diet (n = 4), and patients with various other diseases (n = 5).


Subject(s)
Gas Chromatography-Mass Spectrometry/methods , Glycine/urine , Lipid Metabolism, Inborn Errors/diagnosis , Acyl Coenzyme A/metabolism , Acyl-CoA Dehydrogenase , Child , Child, Preschool , Fatty Acid Desaturases/deficiency , Fatty Acid Desaturases/metabolism , Humans , Infant , Infant, Newborn , Lipid Metabolism, Inborn Errors/urine , Mitochondria/metabolism , Oxidation-Reduction , Reference Values , Reproducibility of Results , Sensitivity and Specificity
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