INBORN ERRORS OF METABOLISM (IEM) A GENERAL OVERVIEW

Transcription

1 INBORN ERRORS OF METABOLISM (IEM) A GENERAL OVERVIEW Backgrund 1. General Infrmatin Classificatin Traditinaly IEM have been classified accrding t the type f metablism invlved. (nte Purine & Pyrimidine disrders, Prphyrias, and Metal metablism disrders are classified as IEM by nly sme surces. They are included here in my attempts t be thrugh.) Amin Acid Dissrders Organic Acidemias (acidurias) Urea Cycle Defects Dissrders f Carbhydrate Metablism Fatty Acid Oxidatin Defects Mitchndrial Disrders Perxismal Dissrders Lyssmal Strage Disseases Purine and Pyrimidine Disrders Prphyrias Metal Metablism Dissrders Screening Tandem Mass Spectrmetry has been mandated in multiple states. Infrmatin n current natinal & state-by-state screening can be fund thrugh the nline resurce: (Natinal Newbrn Screening and Genetics Resurce Center). Pathphysilgy 1. Pathlgy f Disease: IEM ccur when an enzyme r its cfactr(s) are either absent r abnrmal and as a result, leads t an accumulatin f substrate r deficiency f metablic prducts. The physilgic manifestatins f an IEM are dependent n the specific metablite(s) invlved. 2. Incidence There is n cnsensus n the incidence f IEM Mst estimates are reginally specific, and exhibit significant variatin between different racial and ethnic grups. One estimate f the cllective incidence f IEM was arund 1:1500 persns 3. Risk Factrs Psitive Familial Histry (mdes f inheritance f cmmn IEM): Autsmal dminant: Marfan syndrme Acute intermittent prphyria Familial hyperchlesterlemia Autsmal recessive: PKU (Phenylketnuria) Inbrn Errrs f Metablism Page 1 f

2 MSUD (Maple syrup urine disease) Glycgen strage disease Galactsemia Organic acidurias MCAD(medium chain acylca dehydrgenase deficiency) Zellewerger syndrme X-linked recessive: Ornithine carbamylase deficiency Fabry disease Pyruvate dehydrgenase deficiency Mitchndrial: Kearns-Sayre syndrme Leigh syndrme Diagnstics 1. Presentatin Onset & Severity may vary with: individual disease prcesses/severity f disease age f individual changes in: diet/fasting hydratin/dehydratin exercise/exertin/stress cncurrent illness/infectin/trauma medicatins/supplements Symptmatic Infants: The clinical picture varies between different metablic disrders. Hwever, there are general characteristics that are cmmn. Afflicted individuals are usually asymptmatic in the early stages f mst inbrn metablic disrders. Early signs f an IEM include (Acute presentatin): Lethargy Decreased appetite / feeding Vmiting Tachypnea (assciated with acidsis) Decreased perfusin seizures As the metablic derangement prgresses, s des its manifestatins Increasing stupr r cma Prgressive neurmuscular abnrmalities tne (increased r decreased) spasticity psturing (pisthtnus, fisting) mvements (lip smacking, tngue thrusting, myclnic jerks) Symptmatic Older Infants & Children (Chrnic presentatin) Parxysmal stupr / lethargy Emesis Inbrn Errrs f Metablism Page 2 f

3 Failure t thrive Organmegaly (classically hepatsplenmegally) Neurmetablic findings Macr/micrcephaly Hyptnia Hypertnia +/- spasticity seizures Skeletal abnrmalities Carse facial features Macular r retinal changes Crneal cluding Skin changes Regressin f previusly achieves develpmental milestnes. Lss f cgnitive milestnes Lss f expressive/receptive language abilities Prgressive decline/deficits in attentin, fcus, and/r cncentratin. Maladaptive behaviral changes/decline 2. Diagnstic testing: Initial Labratry Investigatins Bld CBC (cmplete bld cunt) CMP (cmplete metablic panel/chem12) Hepatic & Renal Functin Electrlytes Uric Acid Serum Ammnia Obtain withut turniquet Transprt n ice fr immediate analysis ABG (arterial bld gas) Urine Urinalysis ph clr dr specific gravity ketnes Urine-reducing substances Additinal Labratry Investigatins Bld/Plasma quantitative amin acids lactate Obtain withut turniquet Transprt n ice fr immediate analysis pyruvate Obtain withut turniquet Transprt n ice fr immediate analysis Cllect in perchlrate t prevent degredatin aldlase, creatine kinase acyl carnitine kinase Inbrn Errrs f Metablism Page 3 f

4 Urine lipid Prfile Imaging MRI brain echcardigram Bipsy muscle skin quantitative amin acids rganic acids myglbin Genetic as indicated Labratry findings & likely metablism invlved Metablic Acidsis with: Anin gap Organic Acidemias Respiratry Alkalsis Urea Cycle Dissrders Hyperammnemia Urea Cycle Dissrders Organic Acidemias Lactic acidsis Mitchndrial disrders Glycgen strage diseases Dissrders f Glycnegenesis Dissrders f Pyruvate metablism Organic acidemias Dissrders f fatty acid xidatin Aminacidurias High lactate/pyruvate rati (nrmal: 10/1 t 20/1) Mitchndrial dissrders Pyruvate carbxylase deficiency Acylcarnitine prfile (abnrmal) Dissrders f fatty acid xidatin Organic acidemias Hypglycemia with ketsis Glycgen strage diseases Organic acidemias withut ketsis Glycgen strage diseases Maple syrup urine disease Dissrders f fatty acid xidatin Dissrders f ketgenesis Quantitative amin acid prfiles Pattens are specific fr individual dissrders Urine rganic acids Pattens are specific fr individual dissrders Inbrn Errrs f Metablism Page 4 f

5 Management 1. Specific t individual disrders and is utside the scpe f this general verview. References 1. Raghuveer TS, Garg U, Graf WD. Inbrn Errrs f Metablism in Infancy and early Childhd: An Update. AFP 2006;73: Weiner, DL. Metablic Emergencies. In: Textbk f Pediatric Emergency Medicine, 5th ed, Fleisher, GR, Ludwig, S, Henretig, FM (Eds), Lippinctt, Williams & Wilkins, Philadelphia p Kambj M. Clinical apprach t the diagnses f inbrn errrs f metablism. Pediatric Clinics f Nrth America. 55(5): , viii, 2008 Oct. Authr: Michel Ritenuti, MD, Penn State Hershey Medical Center, PA Editr: Dngsheng Jiang, MD, Penn State Hershey Medical Center, PA Inbrn Errrs f Metablism Page 5 f