DOCSLIB.ORG

Letter to the Editor: Lysine Intolerance in Methylmalonic Acidemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Letter to the Editor: Lysine Intolerance in Methylmalonic Acidemia Pediat. Res. 14: 779 (1980) Letter to the Editor: Lysine Intolerance in Methylmalonic Acidemia ICHIRO MATSUDA,"" NORlYUKl NAGATA. ITSUKO UEHARA, AND TAKENORI TERASHIMA Department of Pediarrics. Kumamoto Universi!,' Hospiral, 860 Kumamoto. Japan There are two different metabolic pathways to synthesize urea; If lysine-urea cycle is intact in our patient, urinary homocitrul- (a) Krebs-Henselite urea cycle; and (b) lysine-homocitrulline- line and homoarginine might be elevated as blood ammonia homoarigine-urea cycle, although the latter is a minor pathway increased, like in citrullinemia (6, 8) and other Krebs-Henselite and supported by a few reports (5,7. 8, 10). The first two steps of urea cycle disorders (4). Observed results may suggest that elevated Krebs-Henselite cycle-carbamylphosphate synthesis and conver- blood methylmalonic acid or methymalonyl CoA has a toxic effect sion from ornithine to citrulline are located at mitochondria in on lysine and ammonia metabolism, possibly on the stage of the liver, where a step of lysine to homocitrulline is also thought mitochondrial function. to be located (2).. The connections of hyperlysinemia and hyperammonemia in urea cvcle disorders was re~ortedin ornithine carbamvltransferase deficiency (4). citrullinemia (5, 8), hyperlysinemia (I), and hy- REFERENCES AND NOTES perornithinemia (2). In methylmalonic acidemia, hyperlysinemia and hyperammonemia were also noted (6, 9). In earlier report, we I. Colombo. J. P.. Pldrter~ch.R.. Donath. A,. Spahr. A,. and Rossi. E: Congenital lyslne intolerance with periodic ammonia ~ntoxicalion.Lancet. 1: 1014 (1964). used the lysine loading test in two patients with variant form of 2. Fell. V.. Pollitt. R. J.. Sampson. G. A,. and Wright. T.: Ornlthinemia. hyperam- citrullinemia, in whom a higher elevation was found in blood monemla and homocitmllinurla. Am. J. Dis. Child.. 127: 752 (1974). lysine, ammonia, and urinary lysine as well as in urinary homo- 3. Gruskay. J. A. and Rosenberg. L. E.: lnhibit~on of hepat~cmitochondrial citrulline and homoarginine (5). These observations prompt us to carbamyl phosphatase synthetase (CPS') by acyl CoA esterase: poss~ble mechanism of hyperammonemia in the organic acidemias. Pediatr. Res. (Ab- perform the same loading test in a patient with methylmalonic stract). 13: 475 (1979). acidemia. A patient diagnosed as having methylmalonyl CoA 4. Krieger. I.. Bachman. C.. Gronemeyer. W.. and Cejku. J.: Propion~cac~demia mutase deficiency in cultured lymphocytes and skin fibroblasts (5) and hyperlysinemla In a case with orn~thlnetranscarbarnylase (OCT) defi- was receiving lysine (100 mg/dl per 0s) at attack of the episode ciency. J. Clin. Endocrinol. Metab.. 43: 796 (1976). 5. Matsuda. I.. Arashima. S.. Iman~sh~.Y.. Yamamoto. J.. Akaboshi. I.. Shinoruka. and under dietary control, where blood methylmalonic acid was S.. and Nagata. N.: Lysine Intolerance In a variant form of citmllinemia. 250 and below 10 pg/ml, respectively. In the former condition, Pediatr. Res.. 1.1: 1134 (1979). serum lysine was elevated from 3.5 to 38.8 pmol/dl, blood am- 6. Matsuda. 1.. Terashlma, T., Yamamoto. J., Akaboshi. I.. Shinozuka. S., Hattori. monia was elevated from 184 to 290 pg/dl, and urine lysine was S.. Nagata. N.. and Oka, Y.: Methylmalonic acidemla. Eur. J. Pediatr.. 128: 1x1 (1978). elevated from 1 13 to 986 mole/g creatinine [these increments were 7. Ryan, W. L.. Bark. A. J., and Johnson. R. J.: Lysine, homocltmll~ne and higher than those in control in our laboratory (6)], but no elevation homoarginine metabolism by the isolated perfused rat lrver. Arch. Blochem. was found in urinary homocitrulline and homoarginine. On the Biophys.. 123: 294 (1968). contrary, in the latter condition, serum lysine (5.1 pmole/dl) and X. Scott-Emuakpor. A,. Hlggis. J. V.. and Kohrrnan. A. F.: Citmlllnemia; a new case. with lmplicatlons concerning adaptallon to defective urea synthesis. blood ammonia (1 I1 &dl) were essentially unchanged, and an Pediatr. Res.. 0: 626 ( 1972). increase in urine lysine from 120 to 540 mole/g creatine was 9. Shapiro. L. J.. Bocan. M. E.. Paoman. L., Cedemaurn. S. D.. and Shaw. K. N. F.: within control rangk. Methylmalonyl Co-A mutase deficiency assoc~atedwith severe neonatal hy- Loading test was repeated using a double amount of lysine at perammonemia: activity of urea cycle enzymes. J. Ped~atr..93: 986 (1978). 10. Sogawa. H.. Oyanag~,K.. and Nakao. T.: Period~chyperarnmonem~a. hyperly- another attack of episode; urinary homocitrulline and homoargine sinemla and homocitrull~nem~aassociated with decreased arg~minosuccinate were again not elevated. synthetase and argin~anseact~vit~es. Pediatr. Res.. 11. 949 (1979). Shapiro et al. (9) found decreased activities of all 5 enzymes in I I. This research was supported by a grant for sc~entiticresearch from the Mln~stry Krebs-Henselite urea cycle in an autopsied liver sample of meth- of Education. Sc~ence,and Culture of Japan. 12. Requests for reprints should be addressed to: lchlro Matsuda. Department of ylmalonic acidemia. In rat and human liver homogenate, meth- Pediatrics. Kumamoto University Hosp~tal.860 Kumamoto. Japan. ylmalonyl CoA but not methylmalonic acid inhibited carbamyl- 13. Recelved for publication January 3. 1980. phosphate synthetase 1 (3). 14. Accepted for publ~cat~onJanuary 7. 1980. Copyr~ght0 1980 International Ped~atricResearch Foundation. Inc. Prinrrd in U.S. A 003 1-39YX/XO/ 1405-0779$02.00/0 .
Load more

Recommended publications
  • Hyperammonemia in Review: Pathophysiology, Diagnosis, and Treatment
    Pediatr Nephrol DOI 10.1007/s00467-011-1838-5 EDUCATIONAL REVIEW Hyperammonemia in review: pathophysiology, diagnosis, and treatment Ari Auron & Patrick D. Brophy Received: 23 September 2010 /Revised: 9 January 2011 /Accepted: 12 January 2011 # IPNA 2011 Abstract Ammonia is an important source of nitrogen and is the breakdown and catabolism of dietary and bodily proteins, required for amino acid synthesis. It is also necessary for respectively. In healthy individuals, amino acids that are not normal acid-base balance. When present in high concentra- needed for protein synthesis are metabolized in various tions, ammonia is toxic. Endogenous ammonia intoxication chemical pathways, with the rest of the nitrogen waste being can occur when there is impaired capacity of the body to converted to urea. Ammonia is important for normal animal excrete nitrogenous waste, as seen with congenital enzymatic acid-base balance. During exercise, ammonia is produced in deficiencies. A variety of environmental causes and medica- skeletal muscle from deamination of adenosine monophos- tions may also lead to ammonia toxicity. Hyperammonemia phate and amino acid catabolism. In the brain, the latter refers to a clinical condition associated with elevated processes plus the activity of glutamate dehydrogenase ammonia levels manifested by a variety of symptoms and mediate ammonia production. After formation of ammonium signs, including significant central nervous system (CNS) from glutamine, α-ketoglutarate, a byproduct, may be abnormalities. Appropriate and timely management requires a degraded to produce two molecules of bicarbonate, which solid understanding of the fundamental pathophysiology, are then available to buffer acids produced by dietary sources. differential diagnosis, and treatment approaches available.
    [Show full text]
  • Effect of Propionic Acid on Fatty Acid Oxidation and U Reagenesis
    Pediat. Res. 10: 683- 686 (1976) Fatty degeneration propionic acid hyperammonemia propionic acidemia liver ureagenesls Effect of Propionic Acid on Fatty Acid Oxidation and U reagenesis ALLEN M. GLASGOW(23) AND H. PET ER C HASE UniversilY of Colorado Medical Celller, B. F. SlOlillsky LaboralOries , Denver, Colorado, USA Extract phosphate-buffered salin e, harvested with a brief treatment wi th tryps in- EDTA, washed twice with ph os ph ate-buffered saline, and Propionic acid significantly inhibited "CO z production from then suspended in ph os ph ate-buffe red saline (145 m M N a, 4.15 [I-"ejpalmitate at a concentration of 10 11 M in control fibroblasts m M K, 140 m M c/, 9.36 m M PO" pH 7.4) . I n mos t cases the cells and 100 11M in methyl malonic fibroblasts. This inhibition was we re incubated in 3 ml phosph ate-bu ffered sa lin e cont aining 0.5 similar to that produced by 4-pentenoic acid. Methylmalonic acid I1Ci ll-I4Cj palm it ate (19), final concentration approximately 3 11M also inhibited ' 'C0 2 production from [V 'ejpalmitate, but only at a added in 10 II I hexane. Increasing the amount of hexane to 100 II I concentration of I mM in control cells and 5 mM in methyl malonic did not impair palmit ate ox id ation. In two experiments (Fig. 3) the cells. fibroblasts were in cub ated in 3 ml calcium-free Krebs-Ringer Propionic acid (5 mM) also inhibited ureagenesis in rat liver phosphate buffer (2) co nt ain in g 5 g/ 100 ml essent iall y fatty ac id slices when ammonia was the substrate but not with aspartate and free bovine se rum albumin (20), I mM pa lm itate, and the same citrulline as substrates.
    [Show full text]
  • Propionic Acidemia Information for Health Professionals
    Propionic Acidemia Information for Health Professionals Propionic acidemia is an organic acid disorder in which individuals are lacking or have reduced activity of the enzyme propionyl-CoA carboxylase, leading to propionic acidemia. Clinical Symptoms Symptoms generally begin in the first few days following birth. Metabolic crisis can occur, particularly after fasting, periods of illness/infection, high protein intake, or during periods of stress on the body. Symptoms of a metabolic crisis include lethargy, behavior changes, feeding problems, hypotonia, and vomiting. If untreated, metabolic crises can lead to tachypnea, brain swelling, cardiomyopathy, seizures, coma, basal ganglia stroke, and death. Many babies die within the first year of life. Lab findings during a metabolic crisis commonly include urine ketones, hyperammonemia, metabolic acidosis, low platelets, low white blood cells, and high blood ammonia and glycine levels. Long term effects may occur despite treatment and include developmental delay, brain damage, dystonia, failure to thrive, short stature, spasticity, pancreatitis, osteoporosis, and skin lesions. Incidence Propionic acidemia occurs in greater than 1 in 75,000 live births and is more common in Saudi Arabians and the Inuit population of Greenland. Genetics of propionic acidemia Mutations in the PCCA and PCCB genes cause propionic acidemia. Mutations prevent the production of or reduce the activity of propionyl-CoA carboxylase, which converts propionyl-CoA to methylmalonyl-CoA. This causes the body to be unable to correctly process isoleucine, valine, methionine, and threonine, resulting in an accumulation of glycine and propionic acid, which causes the symptoms seen in this condition. How do people inherit propionic acidemia? Propionic acidemia is inherited in an autosomal recessive manner.
    [Show full text]
  • Inherited Metabolic Disease
    Inherited metabolic disease Dr Neil W Hopper SRH Areas for discussion • Introduction to IEMs • Presentation • Initial treatment and investigation of IEMs • Hypoglycaemia • Hyperammonaemia • Other presentations • Management of intercurrent illness • Chronic management Inherited Metabolic Diseases • Result from a block to an essential pathway in the body's metabolism. • Huge number of conditions • All rare – very rare (except for one – 1:500) • Presentation can be non-specific so index of suspicion important • Mostly AR inheritance – ask about consanguinity Incidence (W. Midlands) • Amino acid disorders (excluding phenylketonuria) — 18.7 per 100,000 • Phenylketonuria — 8.1 per 100,000 • Organic acidemias — 12.6 per 100,000 • Urea cycle diseases — 4.5 per 100,000 • Glycogen storage diseases — 6.8 per 100,000 • Lysosomal storage diseases — 19.3 per 100,000 • Peroxisomal disorders — 7.4 per 100,000 • Mitochondrial diseases — 20.3 per 100,000 Pathophysiological classification • Disorders that result in toxic accumulation – Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects) – Disorders of carbohydrate intolerance – Lysosomal storage disorders • Disorders of energy production, utilization – Fatty acid oxidation defects – Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) – Mitochondrial disorders – Peroxisomal disorders IMD presentations • ? IMD presentations • Screening – MCAD, PKU • Progressive unexplained neonatal
    [Show full text]
  • Arginine-Provider-Fact-Sheet.Pdf
    Arginine (Urea Cycle Disorder) Screening Fact Sheet for Health Care Providers Newborn Screening Program of the Oklahoma State Department of Health What is the differential diagnosis? Argininemia (arginase deficiency, hyperargininemia) What are the characteristics of argininemia? Disorders of arginine metabolism are included in a larger group of disorders, known as urea cycle disorders. Argininemia is an autosomal recessive inborn error of metabolism caused by a defect in the final step in the urea cycle. Most infants are born to parents who are both unknowingly asymptomatic carriers and have NO known history of a urea cycle disorder in their family. The incidence of all urea cycle disorders is estimated to be about 1:8,000 live births. The true incidence of argininemia is not known, but has been estimated between 1:350,000 and 1:1,000,000. Argininemia is usually asymptomatic in the neonatal period, although it can present with mild to moderate hyperammonemia. Untreated, argininemia usually progresses to severe spasticity, loss of ambulation, severe cognitive and intellectual disabilities and seizures Lifelong treatment includes a special diet, and special care during times of illness or stress. What is the screening methodology for argininemia? 1. An amino acid profile by Tandem Mass Spectrometry (MS/MS) is performed on each filter paper. 2. Arginine is the primary analyte. What is an in-range (normal) screen result for arginine? Arginine less than 100 mol/L is NOT consistent with argininemia. See Table 1. TABLE 1. In-range Arginine Newborn Screening Results What is an out-of-range (abnormal) screen for arginine? Arginine > 100 mol/L requires further testing.
    [Show full text]
  • Metabolomic Analysis Reveals That the Drosophila Gene Lysine Influences Diverse Aspects of Metabolism
    Genetics: Early Online, published on October 6, 2017 as 10.1534/genetics.117.300201 Metabolomic analysis reveals that the Drosophila gene lysine influences diverse aspects of metabolism Samantha L. St. Clair*‡, Hongde Li*‡, Usman Ashraf†, Jonathan A. Karty†, and Jason M. *§ Tennessen * Department of Biology, Indiana University, Bloomington, IN 47405, USA † Department of Chemistry, Indiana University, Bloomington, IN, 47405, USA. ‡ These authors contributed equally to this work. § Correspondence: [email protected] Keywords: Drosophila, metabolomics, lysine, LKRSDH, familial hyperlysinemia 1 Copyright 2017. ABSTRACT The fruit fly Drosophila melanogaster has emerged as a powerful model for investigating the molecular mechanisms that regulate animal metabolism. A major limitation of these studies, however, is that many metabolic assays are tedious, dedicated to analyzing a single molecule, and rely on indirect measurements. As a result, Drosophila geneticists commonly use candidate gene approaches, which, while important, bias studies towards known metabolic regulators. In an effort to expand the scope of Drosophila metabolic studies, we used the classic mutant lysine (lys) to demonstrate how a modern metabolomics approach can be used to conduct forward genetic studies. Using an inexpensive and well-established gas chromatography-mass spectrometry (GC-MS)-based method, we genetically mapped and molecularly characterized lys by using free lysine levels as a phenotypic readout. Our efforts revealed that lys encodes the Drosophila homolog of Lysine Ketoglutarate Reductase/Saccharopine Dehydrogenase (LKRSDH), which is required for the enzymatic degradation of lysine. Furthermore, this approach also allowed us to simultaneously survey a large swath of intermediate metabolism, thus demonstrating that Drosophila lysine catabolism is complex and capable of influencing seemingly unrelated metabolic pathways.
    [Show full text]
  • Amino Acid Disorders
    471 Review Article on Inborn Errors of Metabolism Page 1 of 10 Amino acid disorders Ermal Aliu1, Shibani Kanungo2, Georgianne L. Arnold1 1Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 2Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA Contributions: (I) Conception and design: S Kanungo, GL Arnold; (II) Administrative support: S Kanungo; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: E Aliu, GL Arnold; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Georgianne L. Arnold, MD. UPMC Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Suite 1200, Pittsburgh, PA 15224, USA. Email: [email protected]. Abstract: Amino acids serve as key building blocks and as an energy source for cell repair, survival, regeneration and growth. Each amino acid has an amino group, a carboxylic acid, and a unique carbon structure. Human utilize 21 different amino acids; most of these can be synthesized endogenously, but 9 are “essential” in that they must be ingested in the diet. In addition to their role as building blocks of protein, amino acids are key energy source (ketogenic, glucogenic or both), are building blocks of Kreb’s (aka TCA) cycle intermediates and other metabolites, and recycled as needed. A metabolic defect in the metabolism of tyrosine (homogentisic acid oxidase deficiency) historically defined Archibald Garrod as key architect in linking biochemistry, genetics and medicine and creation of the term ‘Inborn Error of Metabolism’ (IEM). The key concept of a single gene defect leading to a single enzyme dysfunction, leading to “intoxication” with a precursor in the metabolic pathway was vital to linking genetics and metabolic disorders and developing screening and treatment approaches as described in other chapters in this issue.
    [Show full text]
  • The Pharmabiotic for Phenylketonuria: Development of a Novel Therapeutic
    University of South Carolina Scholar Commons Senior Theses Honors College Spring 2019 The hP armabiotic for Phenylketonuria: Development of a Novel Therapeutic Chloé Elizabeth LeBegue University of South Carolina, [email protected] Follow this and additional works at: https://scholarcommons.sc.edu/senior_theses Part of the Alternative and Complementary Medicine Commons, Amino Acids, Peptides, and Proteins Commons, Biochemical Phenomena, Metabolism, and Nutrition Commons, Biotechnology Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Digestive, Oral, and Skin Physiology Commons, Digestive System Diseases Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Medical Biotechnology Commons, Medical Genetics Commons, Medical Nutrition Commons, Medical Pharmacology Commons, Nutritional and Metabolic Diseases Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Pharmaceutical Preparations Commons, Pharmaceutics and Drug Design Commons, and the Preventive Medicine Commons Recommended Citation LeBegue, Chloé Elizabeth, "The hP armabiotic for Phenylketonuria: Development of a Novel Therapeutic" (2019). Senior Theses. 267. https://scholarcommons.sc.edu/senior_theses/267 This Thesis is brought to you by the Honors College at Scholar Commons. It has been accepted for inclusion in Senior Theses by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. THE PHARMABIOTIC FOR PHENYLKETONURIA: DEVELOPMENT OF A NOVEL THERAPEUTIC By Chloé Elizabeth
    [Show full text]
  • Fatal Propionic Acidemia: a Challenging Diagnosis
    Issue: Ir Med J; Vol 112; No. 7; P980 Fatal Propionic Acidemia: A Challenging Diagnosis A. Fulmali, N. Goggin 1. Department of Paediatrics, NDDH, Barnstaple, UK 2. Department of Paediatrics, UHW, Waterford, Ireland Dear Sir, We present a two days old neonate with severe form of propionic acidemia with lethal outcome. Propionic acidemia is an AR disorder, presents in the early neonatal period with progressive encephalopathy and death can occur quickly. A term neonate admitted to NICU on day 2 with poor feeding, lethargy and dehydration. Parents are non- consanguineous and there was no significant family history. Prenatal care had been excellent. Delivery had been uneventful. No resuscitation required with good APGAR scores. Baby had poor suck, lethargy, hypotonia and had lost about 13% of the birth weight. Initial investigations showed hypoglycemia (2.3mmol/L), uremia (8.3mmol/L), hypernatremia (149 mmol/L), severe metabolic acidosis (pH 7.24, HCO3 9.5, BE -18.9) with high anion gap (41) and ketonuria (4+). Hematologic parameters, inflammatory markers and CSF examination were unremarkable. Baby received initial fluid resuscitation and commenced on IV antibiotics. Generalised seizures became eminent at 70 hours of age. Loading doses of phenobarbitone and phenytoin were given. Hepatomegaly of 4cm was spotted on day 4 of life. Very soon baby became encephalopathic requiring invasive ventilation. At this stage clinical features were concerning for metabolic disorder and hence was transferred to tertiary care centre where further investigations showed high ammonia level (1178 μg/dl) and urinary organic acids were suggestive of propionic acidemia. Specific treatment for hyperammonemia and propionic acidemia was started.
    [Show full text]
  • Table S1. Disease Classification and Disease-Reaction Association
    Table S1. Disease classification and disease-reaction association Disorder class Associated reactions cross Disease Ref[Goh check et al.
    [Show full text]
  • Laboratory Diagnostic Approaches in Metabolic Disorders
    470 Review Article on Inborn Errors of Metabolism Page 1 of 14 Laboratory diagnostic approaches in metabolic disorders Ruben Bonilla Guerrero1, Denise Salazar2, Pranoot Tanpaiboon2,3 1Formerly Quest Diagnostics, Inc., Ruben Bonilla Guerrero, Rancho Santa Margarita, CA, USA; 2Quest Diagnostics, Inc., Denise Salazar and Pranoot Tanpaiboon, San Juan Capistrano, CA, USA; 3Genetics and Metabolism, Children’s National Rare Disease Institute, Washington, DC, USA Contributions: (I) Conception and design: All authors; (II) Administrative support: R Bonilla Guerrero; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Ruben Bonilla Guerrero. Formerly Quest Diagnostics, Inc., Ruben Bonilla Guerrero, 508 Sable, Rancho Santa Margarita, CA 92688, USA. Email: [email protected]. Abstract: The diagnosis of inborn errors of metabolism (IEM) takes many forms. Due to the implementation and advances in newborn screening (NBS), the diagnosis of many IEM has become relatively easy utilizing laboratory biomarkers. For the majority of IEM, early diagnosis prevents the onset of severe clinical symptoms, thus reducing morbidity and mortality. However, due to molecular, biochemical, and clinical variability of IEM, not all disorders included in NBS programs will be detected and diagnosed by screening alone. This article provides a general overview and simplified guidelines for the diagnosis of IEM in patients with and without an acute metabolic decompensation, with early or late onset of clinical symptoms. The proper use of routine laboratory results in the initial patient assessment is also discussed, which can help guide efficient ordering of specialized laboratory tests to confirm a potential diagnosis and initiate treatment as soon as possible.
    [Show full text]
  • Blueprint Genetics Hyperammonemia and Urea Cycle Disorder Panel
    Hyperammonemia and Urea Cycle Disorder Panel Test code: ME1601 Is a 49 gene panel that includes assessment of non-coding variants. Is ideal for patients with hyperammonemia or a clinical suspicion of a disorder of urea cycle metabolism. The genes on this panel are included in the Comprehensive Metabolism Panel. About Hyperammonemia and Urea Cycle Disorder Congenital urea cycle disorders are the result of defects in the metabolism of nitrogen waste. Deficiency of any of the enzymes in the urea cycle results in an excess of ammonia or other precursor metabolites in the blood. Normally, urea production lowers the ammonia levels in the blood but in the case of defective enzymes, the urea cycle is disturbed. Infants with urea cycle disorders (UCDs) develop cerebral edema, lethargy, hypothermia, neurologic signs and coma, often shortly after birth. Partial, or milder, UCDs are possible if the affected enzyme is positioned in a later phase of the urea cycle. Patients with UCDs may present with hyperammonemia often triggered by stress or illness. The most common primary hyperammonemia is X-linked recessive ornithine transcarbamylase deficiency caused by mutations in the OTC gene. The estimated prevalence is 1:56,000. Prevalence estimates for the other specific urea cycle disorders are 1:200,000 for ASL- and ASS1-related deficiencies and <1:1,000,000 for ARG1, CPS1 and NAGS-related deficiencies. The diagnostic yield ranges from 50% to 80% for different primary urea cycle disorders. In addition to congenital UCDs, this panel has the ability to diagnose other diseases of early phase hyperammonemia and other inborn errors of metabolism showing similar and overlapping symptoms.
    [Show full text]