Metabolic Disorders Metabolic Disorders

Inborn Errors Of MetabolismInborn Errors Of Metabolism

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DR. ABDULLAH ALOMAIRDR. ABDULLAH ALOMAIR

MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.)MB ChB, MRCP (Edin), FRCP (Edin.), DCH (Glas.)

Associate Professor of PediatricsAssociate Professor of PediatricsConsultant PediatricianConsultant Pediatrician

Department of PediatricsDepartment of Pediatrics

PRESIDENTPRESIDENT SAUDI PEDIATRIC ASSOCIATIONSAUDI PEDIATRIC ASSOCIATION

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Inborn Errors Of Metabolism (IEM)Inborn Errors Of Metabolism (IEM) - - A large group of hereditary biochemical A large group of hereditary biochemical

diseases diseases - Specific gene mutation cause abnormal - Specific gene mutation cause abnormal or missing proteins that lead to altered or missing proteins that lead to altered

function.function.

Metabolic Disorders Metabolic Disorders

Inborn Errors Of MetabolismInborn Errors Of Metabolism

PathophysiologyPathophysiology

SINGLE GENE DEFECTSSINGLE GENE DEFECTS in synthesis in synthesis or catabolism of proteins, or catabolism of proteins, carbohydrates, carbohydrates, or fats. or fats.

DDefect in an efect in an ENZYMEENZYME or or TRANSPORT TRANSPORT PROTEINPROTEIN , which results in a block in a , which results in a block in a metabolic pathway. metabolic pathway.

PathophysiologyPathophysiology

EFFECTS EFFECTS ::

- - toxic toxic ACCUMULATIONACCUMULATION of substrates before the block, of substrates before the block,

- - intermediates fromintermediates from ALTERNATIVEALTERNATIVE pathways pathways

- - defects indefects in ENERGY ENERGY production production and utilization caused band utilization caused by a deficiency of products beyond the BLOCK.y a deficiency of products beyond the BLOCK.

EEvery metabolic disease has very metabolic disease has several several forms that vary in forms that vary in AGEAGE OF OF ONSONSEETT , clinical , clinical severityseverity and, often, and, often, MODE OF INHERITMODE OF INHERITANCEANCE. .

Metabolic DisordersMetabolic Disorders

From history:From history:

Parental history :Parental history :

Consanguineous parentsConsanguineous parents

Previous unexplained neonatal deathsPrevious unexplained neonatal deaths

Particular ethnic group (in certain diseases)Particular ethnic group (in certain diseases)

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Features suggestive of metabolic disorder :

Features suggestive of metabolic disorder :

Metabolic DisordersMetabolic Disorders Metabolic DisordersMetabolic Disorders

Examination findings:

Organomegaly (e.g. hepatomegaly)

Cardiac disease

Ocular involvement (e.g. cherry red spot)

Skin manifestations

Unusual odour

Non-specific neurological findings

Neonatal and Post Neonatal PresentationNeonatal and Post Neonatal Presentation

Neonatal presentationNeonatal presentationNormal-appearing child at birth (Normal-appearing child at birth (somesome conditions are associated with conditions are associated with dysmorphic features)dysmorphic features)

• poor feedingpoor feeding

• lethargylethargy

• vomitingvomiting

• seizuresseizures

• comacoma

• unusual odourunusual odour

• hypoglycaemia, acidosis (in some hypoglycaemia, acidosis (in some defectsdefects) )

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Neonatal and Post Neonatal PresentationNeonatal and Post Neonatal Presentation

Post neonatal presentationPost neonatal presentation

• Encephalopathy• Developmental regression• Reye syndrome• Motor deficits• Seizures• Intermittent episodes of vomiting, acidosis,

hypoglycaemia and/or coma triggered by

stress e.g. infections, surgery.

Newborn ScreeningNewborn Screening

PKU - in NICU even if not advanced to full feedsPKU - in NICU even if not advanced to full feeds GalactosemiaGalactosemia HypothyroidismHypothyroidism HemoglobinopathiesHemoglobinopathies Biotinidase defic, CAH (21-OH’ase def), Biotinidase defic, CAH (21-OH’ase def), Maple syrup urine disease ( MSUD )Maple syrup urine disease ( MSUD )

- - GUTHRIE TESTGUTHRIE TEST

Specific Tests:Specific Tests:

• Direct biochemical Direct biochemical assays of assays of

metabolites or their metabolites or their metabolic by-metabolic by-

products, or of an products, or of an enzymeenzyme’’s function.s function.

• DNA studiesDNA studies

• Neuro-radiology Neuro-radiology

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PROCEDURES FOR DIAGNOSIC CONFIRMATION

Non – Specific Tests:

• Blood glucose, ammonia, bicarbonate and PH

• Peripheral Blood smear – WBC or bone marrow vacuolization , foam cells or granules.

• C.S.F. glycine , other amino acids , lactate.

Inborn Error of Inborn Error of MetabolismMetabolism

Urine OdorUrine Odor

Gultaric AcidemiaGultaric Acidemia Sweaty feetSweaty feet

Maple Syrup urine diseaseMaple Syrup urine disease Maple syrupMaple syrup

HypermethioninemiaHypermethioninemia Boiled cabbageBoiled cabbage

PhenylketonuriaPhenylketonuria Mousy or mustyMousy or musty

TrimethylaminuriaTrimethylaminuria Rotten fishRotten fish

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INBORN ERRORS OF AMINO ACID METABOLISM ASSOSIATED WITH ABNORMAL ODOR

Genetic:Genetic:

Establish diagnosis.Establish diagnosis.

Carrier testing.Carrier testing.

Pedigree analysis, risk counseling.Pedigree analysis, risk counseling.

Consideration of Consideration of Prenatal diagnosis Prenatal diagnosis for for pregnancies at risk.pregnancies at risk.

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MANAGEMENT OF IEMMANAGEMENT OF IEM

Family counseling and support.Family counseling and support.

Education to promote increased Education to promote increased compliance with special form of therapy compliance with special form of therapy such as Protein – restricted diet.such as Protein – restricted diet.

Assessment of community resources Assessment of community resources and support groups. and support groups.

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PSYCHOSOCIAL , EDUCATIONAL , FAMILIALPSYCHOSOCIAL , EDUCATIONAL , FAMILIAL

MANAGEMENT OF IEMMANAGEMENT OF IEM

TREATMENT OF GENETIC DISEASESTREATMENT OF GENETIC DISEASES

Modify environment, e.g., diet, drugsModify environment, e.g., diet, drugs

Avoid known environmental triggersAvoid known environmental triggers

BMTBMT Surgical, correct or repair defect or organ Surgical, correct or repair defect or organ

transplantationtransplantation

Modify or replace defective gene product, Modify or replace defective gene product, megadose vitamin therapy or enzyme megadose vitamin therapy or enzyme replacement replacement

Replace defective geneReplace defective gene

Correct altered DNA in defective geneCorrect altered DNA in defective gene

GalactosemiaGalactosemia

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:: CarbohydratesCarbohydrates

GalactosemiaGalactosemiaEnzyme deficiency:Enzyme deficiency: Galactose-1-phosphate uridyl transferase deficiency.Galactose-1-phosphate uridyl transferase deficiency.

Rare . Autosomal recessiveRare . Autosomal recessive

● Follows feeding with Follows feeding with lactose containing (breastmilk / formula) lactose containing (breastmilk / formula) ● Patient feeds poorly , have vomiting, jaundice, hepatomegaly Patient feeds poorly , have vomiting, jaundice, hepatomegaly

and hepatic failureand hepatic failure● Chronic liver diseaseChronic liver disease● CataractsCataracts● Developmental delay develop if condition is untreated.Developmental delay develop if condition is untreated.

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CYSTIC FIBROSISCYSTIC FIBROSIS

Cause : Cause : Loss of 3 DNA bases in a gene for the Loss of 3 DNA bases in a gene for the protein that transports Cl ions so salt balance is protein that transports Cl ions so salt balance is upset. Causes a build up of thick mucus in lungs upset. Causes a build up of thick mucus in lungs

and digestive organsand digestive organs..

AMINO ACID AMINO ACID DISORDERSDISORDERS

Phenyl Ketonuria (PKU)Phenyl Ketonuria (PKU)

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Phenylalanine TyrosineHydroxylase

Phenylalanine

Phenyl ethylamine Phenyl pyruvic acid

Phenylketonuria PKUPhenylketonuria PKU

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Hyperactivity, athetosis, vomiting.Hyperactivity, athetosis, vomiting.

Blond.Blond.

Seborric dermatitis or eczema skin.Seborric dermatitis or eczema skin.

Hypertonia.Hypertonia.

Seizures.Seizures.

Severe mental retardation.Severe mental retardation.

Unpleasant odor of phenyl acetic acid.Unpleasant odor of phenyl acetic acid.

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PKU PKU

DIAGNOSISDIAGNOSIS

• Screening : Guthrie Test.

• High Phenylalanine > 20 mg/dl.

• High Phenyl pyruvic acid.

TREATMENTTREATMENT

• DIET.

• BH4 (Tetrahydrobiopterin).

• L – dopa and 5- hydroxytryptophan.

CLINICAL CLINICAL FEATURES FEATURES

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PKU

AlbinismAlbinism

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HomocystinuriaHomocystinuria

Elevated homocystine levels affect collagen , result in a Elevated homocystine levels affect collagen , result in a Marfanoid Marfanoid habitus, habitus, ectopia lentisectopia lentis, mental retardation and strokes, mental retardation and strokes

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METHIONINEMETHIONINE CYSTATHIONINECYSTATHIONINE

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Homocystinuria

Cysathionine

Synthatase

DIAGNOSIS:

High methionine and homocystine.

TREATMENT:

•High dose of B6 and Folic Acid.•Low methionine and high cystine diet,•Betain (trimethylglycine)

HomocystinuriaHomocystinuria

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Amino acid disorders :Amino acid disorders :

Urea cycle defects and hyperammonemiaUrea cycle defects and hyperammonemia

All present with lethargy, seizures, ketoacidosis, neutropenia, and All present with lethargy, seizures, ketoacidosis, neutropenia, and

hyperammonemiahyperammonemia

Ornithine carbamyl transferase (OTC) deficiencyOrnithine carbamyl transferase (OTC) deficiency

Carbamyl phosphate synthetase deficiencyCarbamyl phosphate synthetase deficiency

CitrullinemiaCitrullinemia

Arginosuccinic AciduriaArginosuccinic Aciduria

ArgininemiaArgininemia

Transient tyrosinemia of prematurityTransient tyrosinemia of prematurity

First Steps in Metabolic Therapy for First Steps in Metabolic Therapy for IEMIEM

Reduce Reduce precursorprecursor substrate load substrate load

Provide Provide caloriccaloric support support

Provide Provide fluidfluid support support

Remove metabolites via Remove metabolites via dialysisdialysis

Divert Divert metabolitesmetabolites

Supplement with Supplement with cofactor(s)cofactor(s)

An essential nutrient found in highest An essential nutrient found in highest concentration in red meat.concentration in red meat.

Primary function : Primary function : Transport long-chain Transport long-chain fatty acids into mitochondria for oxidation.fatty acids into mitochondria for oxidation.

Carnitine supplementation in Carnitine supplementation in fatty acid fatty acid oxidation disorders and organic acidosis oxidation disorders and organic acidosis may augment excretion of accumulated may augment excretion of accumulated metabolites metabolites , but may not prevent metabolic , but may not prevent metabolic crises in such patients .crises in such patients .

CARNITINE METABOLISMCARNITINE METABOLISM

Important IEM Treatment supplementsImportant IEM Treatment supplements::

Carnitine for elimination of Organic Acid through Carnitine for elimination of Organic Acid through creation of carnitine creation of carnitine esters.esters.

Sodium Benzoate, phenylacetate and Sodium Benzoate, phenylacetate and

phenylbutyrate for Hyperammonemia phenylbutyrate for Hyperammonemia eliminationelimination. .

Therapeutic Measures for IEMTherapeutic Measures for IEM

• D/CD/C oral intake temporarily oral intake temporarily• Usually IVF’s with Usually IVF’s with glucoseglucose to give 12-15 to give 12-15

mg/kg/min glu and at least 60 kcal/kg to mg/kg/min glu and at least 60 kcal/kg to prevent catabolism (may worsen PDH)prevent catabolism (may worsen PDH)

• Bicarb/citrateBicarb/citrate Carnitine/glycineCarnitine/glycine• Na Na Benzoate/arginine/citrullineBenzoate/arginine/citrulline• Dialysis-Dialysis--not exchange transfusion-not exchange transfusion• Vitamins-Vitamins--often given in cocktails after labs -often given in cocktails after labs

drawn before dx is knowndrawn before dx is known• Biotin, B6, B12, riboflavin, thiamine, folateBiotin, B6, B12, riboflavin, thiamine, folate

ORGANIC ACIDEMIAORGANIC ACIDEMIA

DisorderDisorder

• Methyl malonic Methyl malonic Acidemia.Acidemia.

• Propionic Acidemia.Propionic Acidemia.

• Multiple carboxylase Multiple carboxylase deficiency.deficiency.

• Ketothiolase deficiency .Ketothiolase deficiency .

EnzymeEnzyme

• Methyl malonyl COA Methyl malonyl COA mutase.mutase.

• Propionyl COA Propionyl COA Carboxylase.Carboxylase.

• Malfunction of all Malfunction of all carboxylase.carboxylase.

• 2 methylacetyl COA thiolase 2 methylacetyl COA thiolase def.def.

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ORGANIC ACIDEMIAORGANIC ACIDEMIA

Clinical Clinical FeaturesFeatures

Vomiting, ketosis.Vomiting, ketosis.

ThrombocytopeniThrombocytopenia , neutropenia.a , neutropenia.

Osteoporosis.Osteoporosis.

Mental Mental retardation.retardation.

TreatmentTreatment

Hydration / alkali.Hydration / alkali.

Calories to Calories to catabolic catabolic state.state.

Exchange Exchange transfusion.transfusion.

Low protein diet.Low protein diet.

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ORGANIC ACIDEMIAORGANIC ACIDEMIA

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LYSOSOMAL STORAGE LYSOSOMAL STORAGE DISORDERSDISORDERS

Glycogen Storage DiseasesGlycogen Storage Diseases

Sphingolipidoses Sphingolipidoses (Lipidoses And Mucolipidoses)(Lipidoses And Mucolipidoses)

MucopolysaccharidosesMucopolysaccharidoses

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Lysosomal Storage DiseaseLysosomal Storage DiseaseDiseaseDisease Enzyme Defiency Enzyme Defiency Major Accumulating Major Accumulating

MetaboliteMetabolite

GlycogenosisGlycogenosis

Type II (Pompe disease)Type II (Pompe disease) GlucosidaseGlucosidase GlycogenGlycogen

SphingolipidosesSphingolipidoses

GGM1M1 gangliosidoses gangliosidoses

GGM2 M2 gangliosidosesgangliosidoses

Tay-Sachs diseaseTay-Sachs disease Gaucher diseaseGaucher disease Niemann-Pick diseaseNiemann-Pick disease

ββ-galactosidase-galactosidase

Hexosaminidase AHexosaminidase AGlucocerebrosidasGlucocerebrosidaseeSphingomyelinaseSphingomyelinase

GGM1M1 gangliosides, gangliosides, galactose-containing galactose-containing oligosaccharidesoligosaccharides

GGM2 M2 gangliosideganglioside

GlucocerebrosideGlucocerebrosideSphingomyelinSphingomyelin

MucopolysaccharidosMucopolysaccharidoseses

MPS I H (Hurler)MPS I H (Hurler)

MPS II (Hunter)MPS II (Hunter)(X-linked recessive)(X-linked recessive)

αα--L-IduronidaseL-Iduronidase

L-Iduronosulfate L-Iduronosulfate sulfatasesulfatase

Heparan sulfateHeparan sulfateDermatan sulfateDermatan sulfate

Heparan sulfateHeparan sulfateDermatan sulfateDermatan sulfate

Glycogen Storage Diseases

Name Enzyme Symptoms Type O Glycogen synthetase Enlarged, fatty liver; hypoglycemia when fasting

von Gierke (Type IA)

Glucose-6-phosphatase Hepatomegaly; slowed growth; hypoglycema; hyperlipidemia

Type IB G-6-P translocase Same as in von Gierke's disease but may be less severe; neutropenia Pompe

(Type II) Acid maltase Enlarged liver and heart, muscle weakness

Forbe (Cori) (Type III)

Glycogen debrancher Enlarged liver or cirrhosis; low blood sugar levels; muscle damage and heart damage in some people

Andersen (Type IV)

Glycogen branching enzyme Cirrhosis in juvenile type; muscle damage and CHF

McArdle's (Type V)

Muscle glycogen phosphorylase

Muscle cramps or weakness during physical activity

Her (Type VI)

Liver glycogen phosphorlyase Enlarged liver; often no symptoms

Tarui (Type VII)

Muscle phosphofructokinase Muscle cramps during physical activity; hemolysis

Type VIII Unknown Hepatomegaly; ataxia, nystagmus Type IX Liver phosphorylase kinase Hepatomegaly; Often no symptoms Type X Cyclic 3-5 dependent kinase Hepatomegaly, muscle pain (1 patient) Type XI Unknown Hepatomegaly. Stunted growth, acidosis, Rickets

PPrinciple Groups of rinciple Groups of Glycogen Storage DiseasesGlycogen Storage Diseases

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Von Gierke Disease

LYSOSOMAL STORAGE LYSOSOMAL STORAGE DISORDERS DISORDERS

Lipidoses And MucolipidosesLipidoses And Mucolipidoses

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56Gauch. cell

58Sandhoff - Dense thalam

59Leucodys..

60Lipid-retina

LYSOSOMAL STORAGE LYSOSOMAL STORAGE DISORDERSDISORDERS

MucopolysaccharidosesMucopolysaccharidoses

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Clinical And Pathological Clinical And Pathological Ultra structure Of Ultra structure Of

MucopolysaccharidosesMucopolysaccharidosesDiseaseDisease Clinical ManifestationClinical Manifestation Ultrastructure of Stored Ultrastructure of Stored

MaterialMaterial

MPS type IMPS type I

HurlerHurler

Earliest, most severe Earliest, most severe developmental regressiondevelopmental regression

coarse facial featurescoarse facial features

HepatosplenomegalyHepatosplenomegaly

dystosis of bonedystosis of bone

cardiac involvementcardiac involvement

corneal cloudingcorneal clouding

Fibrillogranular Fibrillogranular mucopolysaccharides in cells of mucopolysaccharides in cells of viscera and brainviscera and brain

MPS type IIMPS type II

HunterHunterX-linkedX-linked

Later developmental regressionLater developmental regression

coarse facial featurescoarse facial features

hepatosplenomegaly hepatosplenomegaly

dystosis of bone cardiac dystosis of bone cardiac involvementinvolvement

minimal corneal cloudingminimal corneal clouding

Fibrillogranular Fibrillogranular mucopolysaccharides in cells of mucopolysaccharides in cells of viscera and brainviscera and brain

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63Hurler’s

64Hurler’s

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66 Mcopolysacch. Morquio

Due to dysfunction of a Due to dysfunction of a single or multiple single or multiple peroxisomal enzymesperoxisomal enzymes, or to failure to form or , or to failure to form or maintain a normal number of functional maintain a normal number of functional peroxisomes.peroxisomes.

PeroxisomesPeroxisomes = Subcellular = Subcellular organelles organelles involved involved in various essential in various essential anabolic or catabolic anabolic or catabolic processes, biosynthesis of Plasmalogens and bile processes, biosynthesis of Plasmalogens and bile acids. acids.

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PEROXISOMAL DISORDERSPEROXISOMAL DISORDERS

Hypotonia.Hypotonia.

Dysmorphia.Dysmorphia.

Psychomotor delay and seizures.Psychomotor delay and seizures.

Hepatomegaly.Hepatomegaly.

Abnormal eye findings such as retinitis pigmentosa Abnormal eye findings such as retinitis pigmentosa or cataract.or cataract.

Hearing impairment.Hearing impairment.

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PEROXISOMAL DISORDERSPEROXISOMAL DISORDERS Clinical Manifestations:

Peroxisomal Disorders Peroxisomal Disorders

Zellweger Syndrome (Cerebro-hepato-renal

syndrome)

Typical and easily recognized dysmorphic facies.

Progressive degeneration of Brain/Liver/Kidney, with death ~6 mo after onset.

When screening for PDs. obtain serum Very Long Chain Fatty Acids- VLCFAs

70Zellweger

71Chond punct

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THANK YOU

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Metabolic Metabolic DisordersDisorders

Due to inherited reduced activities of proteins Due to inherited reduced activities of proteins involved in the synthesis, breakdown or transport of involved in the synthesis, breakdown or transport of amino acids, organic acids, fats, carbohydrates and amino acids, organic acids, fats, carbohydrates and complex macromolecules. complex macromolecules.

Most are autosomal recessive due to mutations that Most are autosomal recessive due to mutations that result in reduced enzyme activity or reduced amount result in reduced enzyme activity or reduced amount of enzyme.of enzyme.

Pathogenesis may include: accumulation of a toxic Pathogenesis may include: accumulation of a toxic intermediate, reduced amount of a necessary end intermediate, reduced amount of a necessary end product or activation of an alternate pathwayproduct or activation of an alternate pathway..

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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

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)

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

ClassificationClassification

Transient Hyperammonemia Transient Hyperammonemia of Newbornof Newborn

Inborn Errors of Metab:Inborn Errors of Metab:• Organic Acidemias Organic Acidemias • Fatty Acid Oxidation defFatty Acid Oxidation def• Urea Cycle DefectsUrea Cycle Defects• Amino AciduriasAmino Acidurias• Non-ketotic HyperglycinemiaNon-ketotic Hyperglycinemia

Molybdenum Cofactor Molybdenum Cofactor Deficiency Deficiency • Sulfite Oxidase DeficiencySulfite Oxidase Deficiency

Metal Storage Disorders:Metal Storage Disorders: Cholesterol Disorders:Cholesterol Disorders: Leukodystrophies, other…Leukodystrophies, other…

• Krabbe diseaseKrabbe disease

Mitochondrial Disorders Mitochondrial Disorders Glycogen Storage DisordersGlycogen Storage Disorders HyperinsulinismHyperinsulinism Carbohydrate DisordersCarbohydrate Disorders Lysosomal DisordersLysosomal Disorders

• Mucopolysaccharidoses (X-Mucopolysaccharidoses (X-linked Hunter’s, Hurler’s)linked Hunter’s, Hurler’s)

• Gaucher diseaseGaucher disease• Tay-Sachs DiseaseTay-Sachs Disease

Peroxisomal DisordersPeroxisomal Disorders• Zellwegger’s (Cerebro-Zellwegger’s (Cerebro-

Hepato-renal)Hepato-renal)• X-linked X-linked

AdrenoleukodystrophyAdrenoleukodystrophy

Diagnosis:Diagnosis:

Immunochemical studies for Peroxisomes.Immunochemical studies for Peroxisomes.

V. Long Chain FA V. Long Chain FA ( VLCFA ) level.( VLCFA ) level.

Chor. Vill. Samp. or/ amniocytes culture Chor. Vill. Samp. or/ amniocytes culture Plasmalogens Plasmalogens

synthesis.synthesis.

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PEROXISOMAL DISORDERSPEROXISOMAL DISORDERS

Treatment:

Supportive, multidisciplinary interventions.

Diet: VLCFA, phytanic acid.

Organ transplantation.

Peroxisomal DisordersPeroxisomal Disorders

GROUP II : PERSOXISOMALGROUP II : PERSOXISOMAL

ENZYME DEFECTS ENZYME DEFECTS

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GROUP I : GROUP I : BIOGENSISBIOGENSIS OF PEROXISOME OF PEROXISOME

GROUP III GROUP III :: POSITIVE PEROXISOMES BUT POSITIVE PEROXISOMES BUT MULTIPLEMULTIPLE DEFECTIVE DEFECTIVE ENZYME ENZYMEZellweger syndrome

(cerebrohepatorenal syndrome).

Neonatal adrenoleukodystrophy.

Infantile Refsum disease.

Hyperpipecolic acidemia.

Refsum disease.

X - linked Adreno-Leuko-Dystrophy.

Pseudo – Zellweger syndrome.

Hyperoxaluria….etc.

Zellweger – Like.

Pseudo – infantile Refsum disease.

Rhizomelic chondro-dysplasia

punctata

Mitochondrial Syndromes Mitochondrial Syndromes Presenting in Childhood to Presenting in Childhood to

AdultAdultSyndromeSyndrome Most Common Most Common

Clinical Clinical PresentationPresentation

Other Cliical Other Cliical FeaturesFeatures

Mt DNA Mt DNA DefectDefect

MELAS: myopathy, MELAS: myopathy, encephalopathy, encephalopathy, lactic acidosis and lactic acidosis and stroke-like episodesstroke-like episodes

Stroke-like episodes Stroke-like episodes in the first and in the first and second decade of second decade of life often associated life often associated with migraine with migraine headache, blood headache, blood lactate lactate

Deafness, Deafness, myopathy, diabetes myopathy, diabetes mellitusmellitus

mtDNA mutations at mtDNA mutations at 3243, 3271 3243, 3271 tRNA mutationstRNA mutations

MERRF: Myoclonic MERRF: Myoclonic epilepsy with ragged epilepsy with ragged red fibersred fibers

Progressive Progressive myoclonic epilepsymyoclonic epilepsy

Ataxia, myopathy Ataxia, myopathy deafness, short deafness, short staturestature

MtDNA A8344G MtDNA A8344G tRNA mutationtRNA mutation

NARP: Neurogenic NARP: Neurogenic weakness, ataxia weakness, ataxia and retinitis and retinitis pigmentosapigmentosa

Peripheral Peripheral neuropathy, neuropathy, myopathy, seizuresmyopathy, seizures

Leigh syndromeLeigh syndrome MtDNA 8993 MtDNA 8993 Complex V Complex V deficiencydeficiency

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8484

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Clinical AbnormalityClinical Abnormality Abnormal Amino AcidAbnormal Amino Acid Presumptive DiagnosisPresumptive Diagnosis

Acute neonatal Acute neonatal presentation with presentation with ketoacidosisketoacidosis

Leucine, isoleucine, Leucine, isoleucine, valinevaline

Organic Acid DisordersOrganic Acid Disorders

Maple syrup urine disease Maple syrup urine disease Methylmalonic acidemia Methylmalonic acidemia

Propionic acidemiaPropionic acidemia

Isovaleric acidemiaIsovaleric acidemia

Acute neonatal Acute neonatal presentation with presentation with hyperammonemiahyperammonemia

Arginine, CitrullineArginine, Citrulline Urea cycle disordersUrea cycle disorders

Ornithine transcarbamylase Ornithine transcarbamylase deficiency Argininosuccinate deficiency Argininosuccinate synthase deficiency synthase deficiency Argininosuccinate lyase Argininosuccinate lyase deficiencydeficiency

Marfanoid, Marfanoid, strokes, ectopia strokes, ectopia lentis, lentis, mental mental retardationretardation

Homocystine & Homocystine & methioninemethionine

HomocystinuriaHomocystinuria

Severe Severe developmental developmental delaydelay

PhenylalaninePhenylalanine PhenylketonuriaPhenylketonuria

Clinical Presentation of Amino Acid DisordersClinical Presentation of Amino Acid Disorders

Mitochondrial Mitochondrial DisordersDisorders

Classically involve mutations in Classically involve mutations in mitochondrial DNAmitochondrial DNA

Follow a Follow a maternalmaternal pattern of inheritance pattern of inheritance

Highly variable with regard to penetrance and Highly variable with regard to penetrance and expressivity based on the variability in tissue expressivity based on the variability in tissue distribution of abnormal mitochondriadistribution of abnormal mitochondria

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Predominanat Predominanat Biochemical Biochemical Clinical FindingsClinical Findings

OtherOther Most Common DiagnosisMost Common Diagnosis

KetoAcidosisKetoAcidosis

LethargyLethargy

OdorOdor

Ammonia: Normal or slightly Ammonia: Normal or slightly elevated Ketones: Elevated elevated Ketones: Elevated Glucose: Normal Glucose: Normal

Maple syrup urine diseaseMaple syrup urine disease

AcidosisAcidosis

LethargyLethargy

OdorOdor

Ammonia: Elevated Ammonia: Elevated Glucose: Normal or Glucose: Normal or decreased Ketones: decreased Ketones: May be elevated May be elevated Lactate: Slightly elevatedLactate: Slightly elevated

Methylmalonic acidemia Methylmalonic acidemia Propionic acidemia Propionic acidemia Isolvaleric Isolvaleric acidemiaacidemia

Lactic AcidosisLactic Acidosis

LethargyLethargy

Acidosis: Usually present Acidosis: Usually present Ammonia: Normal or slightly Ammonia: Normal or slightly elevated elevated Ketones: May be elevated Ketones: May be elevated

Pyruvate dehydrogenase Pyruvate dehydrogenase Pyruvate carboxylase Pyruvate carboxylase deficiency Respiratory chain deficiency Respiratory chain disorderdisorder

HypoglycemiaHypoglycemia

LethargyLethargy

Ammonia: Lactate Acidosis Ammonia: Lactate Acidosis Ketones: Absent or Ketones: Absent or inappropriately lowinappropriately low

Fatty acid oxidation defectsFatty acid oxidation defects

HyperammonemHyperammonemiaia

LethargyLethargy

Acidosis: Absent Acidosis: Absent Respiratory Alkalosis Respiratory Alkalosis

Urea cycle disordersUrea cycle disorders

Metabolic Profiles Organic and Amino Acid Disorders Metabolic Profiles Organic and Amino Acid Disorders

Newborn screening is available dependent on population frequency for some

Expanded newborn screening for fatty acid defects recently offered

CHILDREN AFTER THE NEONATAL CHILDREN AFTER THE NEONATAL PERIODPERIOD

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Clinical ManifestationClinical Manifestation

Mental retardation, Macro/Microcephaly.Mental retardation, Macro/Microcephaly.

Coarse facial features/dysmorphia.Coarse facial features/dysmorphia.

Developmental regression.Developmental regression.

Convulsion.Convulsion.

Myopathy / cardiomyopathy.Myopathy / cardiomyopathy.

Recurrent emesis with coma and hepatic dysfunction.Recurrent emesis with coma and hepatic dysfunction.

Hypertonia / hypotonia.

Failure to thrive.

Ophthalmic – related problems : e.g. cataract, corneal

cloudiness, cherry red spot, optic atrophy.

Renal failure or renal tubular acidosis.

CARNITINE METABOLISMCARNITINE METABOLISM

An essential nutrient found in highest concentration in red An essential nutrient found in highest concentration in red meat.meat.

Primary function : Primary function : Transport long-chain fatty acids into Transport long-chain fatty acids into mitochondria for oxidation.mitochondria for oxidation.

Primary defects of carnitine transport manifest as Reye Primary defects of carnitine transport manifest as Reye syndrome , cardiomyopathy or skeletal myopathy with syndrome , cardiomyopathy or skeletal myopathy with hypotonia hypotonia

Secondary carnitine deficiency is due to diet Secondary carnitine deficiency is due to diet ( esp. I.V alimentation or ketogenic diet ) , renal losses , ( esp. I.V alimentation or ketogenic diet ) , renal losses , drug therapy ( esp. valproic acid) and other metabolic drug therapy ( esp. valproic acid) and other metabolic disorders ( esp. disorders of fatty acid oxidation and disorders ( esp. disorders of fatty acid oxidation and organic acidemias )organic acidemias )

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CARNITINE METABOLISMCARNITINE METABOLISM

Prognosis depends on the cause of the carnitine Prognosis depends on the cause of the carnitine abnormality.abnormality.

Free and esterified carnitine can be measured in Free and esterified carnitine can be measured in blood.blood.

Oral or I.V. L-carnitine is used in carnitine Oral or I.V. L-carnitine is used in carnitine deficiency or lnsufficiency in doses of deficiency or lnsufficiency in doses of 25-100mg/kgm/day or higher.25-100mg/kgm/day or higher.

Carnitine supplementation in Carnitine supplementation in fatty acid oxidation fatty acid oxidation disorders and organic acidosis may augment disorders and organic acidosis may augment excretion of accumulated metabolites excretion of accumulated metabolites , but may not , but may not prevent metabolic crises in such patients .prevent metabolic crises in such patients .

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Management of IEM - NICUManagement of IEM - NICU

• Stop nutrient Stop nutrient triggering triggering disorder e.g. protein, galactosedisorder e.g. protein, galactose• Give high-Give high-energyenergy intake intake• NICU care NICU care to correct tissue perfusion, dehydration, to correct tissue perfusion, dehydration,

acidosisacidosis• Hyperammonemia Rx with Na Hyperammonemia Rx with Na benzoatebenzoate, Na , Na

phenylbutyrate, argininephenylbutyrate, arginine• DialysisDialysis• Insulin Insulin to control hyperglycemia and reduce catabolismto control hyperglycemia and reduce catabolism• Vitamins e.g Biotin, B6, B12Vitamins e.g Biotin, B6, B12• Specific therapy e.g. Specific therapy e.g. carnitine, glycinecarnitine, glycine

SINGLE GENE DEFECTS in synthesis or catabolism of proteins, carbohydrates, or fats.

Defect in an ENZYME or TRANSPORT PROTEIN , which results in a block in a metabolic pathway.

EFFECTS :

- toxic ACCUMULATION of substrates before the block,

- intermediates from ALTERNATIVE pathways

- defects in ENERGY production and utilization caused by a deficiency of products beyond the BLOCK.

Every metabolic disease has several forms that vary in AGE OF ONSET , clinical severity and, often, MODE OF INHERITANCE.

Pathophysiology

Dependent on diagnosis and Dependent on diagnosis and

severity:severity:

Dietary or vitamin therapyDietary or vitamin therapy

Drug therapyDrug therapy

BMTBMT

Avoid known environmental triggersAvoid known environmental triggers

SurgerySurgery

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MEDICALMEDICAL

Transient Hyperammonemia of Transient Hyperammonemia of Newborn Newborn::

Markedly highMarkedly high NH4 NH4 in an infant less than 24 HOL, or first in an infant less than 24 HOL, or first 1-2 DOL before protein intake occurs.1-2 DOL before protein intake occurs.

Often in context of large, Often in context of large, prematurepremature infant with infant with symptomatic pulmonary disease.symptomatic pulmonary disease.

Very Very sick sick infant. infant.

Unknown precipitant, Unknown precipitant, unknownunknown etiology (possible slow etiology (possible slow delayed urea cycle initiation), with potential for severe delayed urea cycle initiation), with potential for severe sequelae (20-30% death, 30-40% abnl dev.) if not treated. sequelae (20-30% death, 30-40% abnl dev.) if not treated.

Does not recurDoes not recur after being treated. after being treated.