lesson 7.1 : metabolic diseases inborn errors of metabolism (iem)

Download Lesson 7.1 : Metabolic Diseases Inborn Errors Of Metabolism (IEM)

Post on 15-Jan-2016




0 download

Embed Size (px)


  • Lesson 7.1 : Metabolic Diseases Inborn Errors Of Metabolism (IEM)

  • A primer on metabolic disease in the neonate...

  • What is a metabolic disease?Inborn errors of metabolisminborn error : an inherited (i.e. genetic) disordermetabolism : chemical or physical changes undergone by substances in a biological systemany disease originating in our chemical individuality

  • What is a metabolic disease?Garrods hypothesis

    product deficiencysubstrate excess toxic metaboliteADBC

  • What is a metabolic disease?Small molecule diseaseCarbohydrateProteinLipidNucleic AcidsOrganelle diseaseLysosomesMitochondriaPeroxisomesCytoplasm

  • How do metabolic diseases present in the neonate ??Acute life threatening illnessencephalopathy - lethargy, irritability, comavomitingrespiratory distressSeizures, HypertoniaHepatomegaly (enlarged liver)Hepatic dysfunction / jaundiceOdour, Dysmorphism, FTT (failure to thrive), Hiccoughs

  • How do you recognize a metabolic disorder ??Index of suspicioneg with any full-term infant who has no antecedent maternal fever or PROM (premature rupture of the membranes) and who is sick enough to warrant a blood culture or LP, one should proceed with a few simple lab tests.Simple laboratory testsGlucose, Electrolytes, Gas, Ketones, BUN (blood urea nitrogen), CreatinineLactate, Ammonia, Bilirubin, LFTAmino acids, Organic acids, Reducing subst.

  • Index of suspicionFamily HistoryMost IEMs are recessive - a negative family history is not reassuring!CONSANGUINITY, ethnicity, inbreedingneonatal deaths, fetal lossesmaternal family historymales - X-linked disorders all - mitochondrial DNA is maternally inheritedA positive family history may be helpful!

  • Index of suspicionHistoryCAN YOU EXPLAIN THE SYMPTOMS?Timing of onset of symptomsafter feeds were started?Response to therapies

  • Index of suspicionPhysical examinationGeneral dysmorphisms (abnormality in shape or size), ODOURH&N - cataracts, retinitis pigmentosaCNS - tone, seizures, tense fontanelleResp - Kussmauls, tachypneaCVS - myocardial dysfunctionAbdo - HEPATOMEGALYSkin - jaundice

  • Index of suspicionLaboratoryANION GAP METABOLIC ACIDOSISNormal anion gap metabolic acidosisRespiratory alkalosisLow BUN relative to creatinineHypoglycemia especially with hepatomegalynon-ketotic

  • A parting thought ...Metabolic diseases are individually rare, but as a group are not uncommon.There presentations in the neonate are often non-specific at the outset.Many are treatable.The most difficult step in diagnosis is considering the possibility!


  • Inborn Errors of MetabolismAn inherited enzyme deficiency leading to the disruption of normal bodily metabolismAccumulation of a toxic substrate (compound acted upon by an enzyme in a chemical reaction)Impaired formation of a product normally produced by the deficient enzyme

  • Three TypesType 1: Silent DisordersType 2: Acute Metabolic CrisesType 3: Neurological Deterioration

  • Type 1: Silent DisordersDo not manifest life-threatening crisesUntreated could lead to brain damage and developmental disabilitiesExample: PKU (Phenylketonuria)

  • PKUError of amino acids metabolismNo acute clinical symptomsUntreated leads to mental retardation Associated complications: behavior disorders, cataracts, skin disorders, and movement disordersFirst newborn screening test was developed in 1959Treatment: phenylalaine restricted diet (specialized formulas available)

  • Type 2: Acute Metabolic Crisis Life threatening in infancyChildren are protected in utero by maternal circulation which provide missing product or remove toxic substanceExample OTC (Urea Cycle Disorders)

  • OTCAppear to be unaffected at birthIn a few days develop vomiting, respiratory distress, lethargy, and may slip into coma.Symptoms mimic other illnessesUntreated results in deathTreated can result in severe developmental disabilities

  • Type 3: Progressive Neurological DeteriorationExamples: Tay Sachs diseaseGaucher diseaseMetachromatic leukodystrophyDNA analysis show: mutations

  • MutationsNonfunctioning enzyme results: Early Childhood - progressive loss of motor and cognitive skillsPre-School non responsive stateAdolescence - death

  • Other MutationsPartial Dysfunctioning Enzymes-Life Threatening Metabolic Crisis-ADH-LD-MRMutations are detected by Newborn Screening and Diagnostic Testing

  • TreatmentDietary RestrictionSupplement deficient productStimulate alternate pathwaySupply vitamin co-factorOrgan transplantationEnzyme replacement therapyGene Therapy

  • Children in SchoolLife long treatmentAt risk for ADHD LD MRAwareness of diet restrictionsAccommodations

  • Inborn errors of metabolismDefinition:Inborn errors of metabolism occur from a group of rare genetic disorders in which the body cannot metabolize food components normally. These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components. Alternative Names:Galactosemia - nutritional considerations; Fructose intolerance - nutritional considerations; Maple sugar urine disease (MSUD) - nutritional considerations; Phenylketonuria (PKU) - nutritional considerations; Branched chain ketoaciduria - nutritional considerations

  • Background: Inborn errors of metabolism (IEMs) individually are rare but collectively are common. Presentation can occur at any time, even in adulthood. Diagnosis does not require extensive knowledge of biochemical pathways or individual metabolic diseases. An understanding of the broad clinical manifestations of IEMs provides the basis for knowing when to consider the diagnosis. Most important in making the diagnosis is a high index of suspicion. Successful emergency treatment depends on prompt institution of therapy aimed at metabolic stabilization.

  • A genetically determined biochemical disorder in which a specific enzyme defect produces a metabolic block that may have pathologic consequences at birth (e.g., phenylketonuria) or in later life (e.g., diabetes mellitus); called also enzymopathy and genetotrophic disease.

  • Metabolic disorders testable on Newborn Screen Congenital Hypothyroidism Phenylketonuria (PKU) Galactosemia Galactokinase deficiency Maple syrup urine disease Homocystinuria Biotinidase deficiency

  • Classification Inborn Errors of Small molecule Metabolism Example: GalactosemiaLysosomal storage diseases Example: Gaucher's Disease Disorders of Energy Metabolism Example Glycogen Storage Disease Other more rare classes of metabolism error Paroxysmal disorders Transport disorders Defects in purine and pyrimidine metabolism Receptor Defects

  • Categories of IEMs are as follows: Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, and urea cycle defects) Disorders of carbohydrate metabolism (eg, carbohydrate intolerance disorders, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) Lysosomal storage disorders Fatty acid oxidation defects Mitochondrial disorders Peroxisomal disorders

  • Pathophysiology: Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, or fats. Most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, and/or defects in energy production and utilization caused by a deficiency of products beyond the block. Nearly every metabolic disease has several forms that vary in age of onset, clinical severity and, often, mode of inheritance.

  • Frequency: In the US: The incidence, collectively, is estimated to be 1 in 5000 live births. The frequencies for each individual IEM vary, but most are very rare. Of term infants who develop symptoms of sepsis without known risk factors, as many as 20% may have an IEM. Internationally: The overall incidence is similar to that of US. The frequency for individual diseases varies based on racial and ethnic composition of the population.

  • Mortality/Morbidity: IEMs can affect any organ system and usually do affect multiple organ systems.Manifestations vary from those of acute life-threatening disease to subacute progressive degenerative disorder.Progression may be unrelenting with rapid life-threatening deterioration over hours, episodic with intermittent decompensations and asymptomatic intervals, or insidious with slow degeneration over decades.

  • Purine metabolism

  • Adenine phosphoribosyltransferase deficiency

  • The normal function of adenine phosphoribosyltransferase (APRT) is the removal of adenine derived as metabolic waste from the polyamine pathway and the alternative route of adenine metabolism to the extremely insoluble 2,8-dihydroxyadenine, which is operative when APRT is inactive. The alternative pathway is catalysed by xanthine oxidase.

  • Hypoxanthine-guanine phosphoribosyltransferase (HPRT, EC 2.4.2. 8) HGPRTcatalyses the transfer of the phosphoribosyl moiety of PP-ribose-P to the 9 position of the purine ring of the bases hypoxanthine and guanine to form inosine monophospate (IMP) and guanosine monophosphate (GMP) respectively. HGPRT is a cytoplasmic enzyme present in virtually all tissues, with highest activity in brain and testes.

  • The salvage pathway of the purine bases, hypoxanthine and guanine, to IMP and GMP, respectively, catalysed by HGPRT (1) in the presence of PP-ribose-P. The defect in HPRT is shown.

  • The importa


View more >