inborn errors or metabolism

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  • INBORN ERRORS OF METABOLISM

  • INBORN ERRORS OF METABOLISMIEM occur 1 in 5000 births collectivelyOften treatable if diagnosedMost difficult task for clinician is to know when to consider IEM and which tests to order for evaluationClues to presence of IEM may often be found in FH

  • DIAGNOSING INBORN ERRORS OF METABOLISMSigns and symptoms are often nonspecificRoutine childhood illnesses excluded 1stInborn errors considered only secondarily

  • Every child with unexplained . . . Neurological deteriorationMetabolic acidosisHypoglycemiaInappropriate ketosisHypotoniaCardiomyopathyHepatocellular dysfunctionFailure to thrive. . . should be suspected of having a metabolic disorder

  • WHEN TO SUSPECT AN IEMInfants have only a limited repertoire of symptoms--sxs non-specificVomiting, lethargy, FTT, szs, resp (tachypnea, hyperpnea, apnea), coma, cardiomyopathyOdor, abnormal hair, dysmorphologyLabs: metabolic acidosis, hypoglycemia, hyperammonemia, reducing substances in urine, ketonuria, pancytopeniaNot all infants with life threatening IEM have either acidosis or hyperammonemia (i.e. non-ketotic hyperglycinemia, mild lactate elevations).

  • Laboratory Assessment of Neonates

    Suspected of Having an

    Inborn Error of Metabolism

    Routine Studies

    Special Studies

    Blood lactate and

    pyruvate

    Complete blood count

    and differential

    Plasma amino acids

    Plasma ammonia

    Plasma carnitine

    Plasma glucose

    Urine amino acids

    Plasma electrolytes and

    blood pH

    Urine organic acids

    Urine ketones

    Urine-reducing

    substances

  • Clinical Symptomatology of Inborn Errors of Metabolism (IEM) in the Neonate or Infant

    Symptoms indicating possibility of an IEM (one or all)

    Infant becomes acutely ill after period of normal behavior and feeding;

    this may occur within hours or weeks

    Neonate or infant with seizures and/or hypotonia, especially if seizures

    are intractable

    Neonate or infant with an unusual odor

    Symptoms indicating strong possibility of an IEM, particularly when coupled

    with the above symptoms

    Persistent or recurrent vomiting

    Failure to thrive (failure to gain weight or weight loss)

    Apnea or respiratory distress (tachypnea)

    Jaundice or hepatomegaly

    Lethargy

    Coma (particularly intermittent)

    Unexplained hemorrhage

    Family history of neonatal deaths, or of similar illness, especially in

    siblings

    Parental consanguinity

    Sepsis (particularly Escherichia coli)

  • Physical Anomalies Associated With Acute-Onset Inborn Errors of Metabolism (IEM)

    Anomaly

    Possible IEM

    Ambiguous genitalia

    Congentital adrenal hyperplasia

    Hair and/or skin problems (alope-

    Multiple carboxylase deficiency, biotinidase

    cia, dermatitis)

    deficiency, argininosuccinic aciduria

    Structural brain abnormalities

    Pyruvate dehydrogenase deficiency

    (agenesis of corpus callosum,

    cortical cysts)

    Macrocephaly

    Glutaric aciduria, type I

    Renal cysts, facial dysmorphia

    Glutaric aciduria, type II; Zellweger syndrome

    Facial dysmorphia

    Peroxisomal disorders, (Zellweger syndrome)

    Cataract

    Galactosemia, Lowe syndrome

    Retinopathy

    Peroxisomal disorders

    Lens dislocation, seizures

    Sulfite oxidase deficiency

    Molybdenum cofactor deficiency

    Facial dysmorphia, congenital heart

    3-OH-isobutyric CoA deacylase deficiency

    disease, vertebral anomalies

  • Clinical Manifestations of Inborn Errors Presenting Neonatally

    Neurologic Signs

    Poor suck

    Lethargy (progressing to coma)

    Abnormalities of tone

    Loss of reflexes

    Seizures

    Gastrointestinal Signs

    Poor feeding

    Vomiting

    Diarrhea

    Respiratory Signs

    Hyperpnea

    Respiratory failure

    Organomegaly

    Liver

    Heart

  • Inborn Errors of Metabolism of Acute Onset: Nonacidotic, Nonhyperammonemic Features

    Neurologic Features Predominant (Seizures, Hypotonia, Optic Abnormality)

    Glycine encephalopathy (nonketotic hyperglycinemia)

    Pyridoxine-responsive seizures

    Sulfite oxidase/santhine oxidase deficiency

    Peroxisomal disorders (Zellweger syndrome, neonatal adrenoleuko-

    dystrophy, infantile refsum disease)

    Jaundice Prominent

    Galactosemia

    Hereditary fructose intolerance

    Menkes kinky hair syndrome

    1-antitrypsin deficiency

    Hypoglycemia (Nonketotic): Fatty acid oxidation defects (MCAD, LCAD,

    carnitine palmityl transferase, infantile form)

    Cardiomegaly

    Glycogen storage disease (type II phosphorylase kinase b deficiency18)

    Fatty acid oxidation defects (LCAD)

    Hepatomegaly (Fatty): Fatty acid oxidation defects (MCAD, LCAD)

    Skeletal Muscle Weakness: Fatty acid oxidation defects (LCAD, SCAD,

    multiple acyl-CoA dehydrogenase

  • defective enzymeSubstrate(increased)Product(decreased)actionMetabolites(increased)Co-factor ACo-factor BotherenzymesMetabolites(decreased)EFFECT ON OTHER METABOLIC ACTIVITYe.g., activation, inhibition, competitionTheoretical consequences of an enzyme deficiency.

  • PROTEINGLYCOGENFATAMINO ACIDSFRUCTOSEGALACTOSEFREE FATTY ACIDSAMMONIAUREAUREA CYCLEORGANIC ACIDSGLUCOSEPYRUVATEACETYL CoAKREBS CYCLENADHKETONESATPLACTATEAn integrated view of the metabolic pathways

  • FIRST STEPS IN METABOLIC THERAPY FOR INBORN ERRORS OF METABOLISMReduce precursor substrate loadProvide caloric supportProvide fluid supportRemove metabolites via dialysisDivert metabolitesSupplement with cofactor(s)

  • THERAPEUTIC MEASURES FOR IEMD/C oral intake temporarilyUsually IVFs with glucose to give 12-15 mg/kg/min glu and at least 60 kcal/kg to prevent catabolism Na benzoate/arginine/citrullineDialysis--not exchange transfusionVitamins--often given in cocktails after labs drawn before dx is knownBiotin, B6, B12, riboflavin, thiamine, folate

  • TREATMENT OF THE ACUTELY SICK CHILDGeneral TherapyMaintain vital functionsOxygenationHydrationAcid/Base balanceSpecific TherapyTreat infectionHigh dose I.V. glucoseCarnitine supplementation

  • TREATMENT OF GENETIC DISEASESMODIFY ENVIRONMENT, e.g., diet, drugsSURGICAL, correct or repair defect or organ transplantationMODIFY OR REPLACE DEFECTIVE GENE PRODUCT, megadose vitamin therapy or enzyme replacementREPLACE DEFECTIVE GENECORRECT ALTERED DNA IN DEFECTIVE GENE

  • NEWBORN SCREENINGPKU - must do on all infants in NICU even if not advanced to full feedsPositive--transient HPA, tyr, liver disease, benign HPA, classical PKUGalactosemia-HypothyroidismHemoglobinopathiesBiotinidase def, CAH (21-OHase def), MSUD

  • METABOLIC DISORDERS PRESENTING AS SEVERE NEONATAL DISEASEDisorders of Carbohydrate MetabolismGalactosemia - presents with severe liver disease, gram negative sepsis, and/or cataractsEnz deficiency: Gal-1-phos uridyl transferase, UDP-gal-4-epimeraseGlycogen storage disease type 1a & 1b - presents as hypoglycemiaEnz deficiency: Glucose-6 phosphatase Lactic Acidosis - presents as lactic acidosis +/- hypoglycemiaEnz deficiency: Pyruvate carboxylase, Pyr dehydrogenase, etc.Fructose intolerance - Needs fructose exposure, hypoglycemia and acidosis

  • METABOLIC DISORDERS PRESENTING AS SEVERE NEONATAL DISEASEAmino Acid DisordersMaple syrup urine disease - presents with odor to urine and CNS problemsEnz deficiency: Branched chain ketoacid decarboxylaseNonketotic hyperglycinemia - presents with CNS problemsEnz deficiency: Glycine cleavage systemTyrosinemia - Severe liver disease, renal tubular dysfunctionEnz deficiency: Fumaryl acetateTransient tyrosinemia of prematurity - progressive coma following respiratory distress

  • METABOLIC DISORDERS PRESENTING AS SEVERE NEONATAL DISEASEUrea Cycle Defects and Hyperammonemia

    All present with lethargy, seizures, ketoacidosis, neutroenia, and hyperammonemiaOrnithine carbamyl transferase (OTC) deficiencyCarbamyl phosphate synthetase deficiencyCitrullinemiaArginosuccinic AciduriaArgininemiaTransient tyrosinemia of prematurity

  • METABOLIC DISORDERS PRESENTING AS SEVERE NEONATAL DISEASEAll present with lethargy, seizures, ketoacidosis, neutropenia, hyperammonemia, and/or hyperglycinemiaOrganic Acid DefectsMethylmalonic acidemiaProprionic acidemiaIsovaleric acidemia - odor of sweaty feetGlutaric aciduria type IIDicarboxylic aciduriaMiscellaneousPeroxisomal disordersLysosomal storage diseasePyridoxine dependent seizures

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