Does this ill child have a metabolic disease? ► General Intro ► Disease Presentation & Investigation Acute Neonatal Recurrent Encephalopathy Hyperammonaemia.

Does this ill child Does this ill child have a metabolic have a metabolic

disease?disease?►General IntroGeneral Intro

►Disease Presentation & Disease Presentation &

Investigation Investigation

Acute NeonatalAcute Neonatal

Recurrent EncephalopathyRecurrent Encephalopathy

HyperammonaemiaHyperammonaemia

HypoglycaemiaHypoglycaemia

Inherited Metabolic DiseasesInherited Metabolic Diseases

► Individually rare diseasesIndividually rare diseases collectively ‘common’ collectively ‘common’ ?1 in 800?1 in 800

► Ubiquitous presentationUbiquitous presentation Modern TBModern TB

► Likely to present in Likely to present in general paediatricgeneral paediatric neonatal neonatal speciality paediatric practicespeciality paediatric practice

Collection of diagnosesCollection of diagnoses► 66 PKUPKU► 44 Urea cycleUrea cycle► 11 MSUD MSUD ► 11 Tyrosinaemia Tyrosinaemia ► 44 Organic acidaemia Organic acidaemia ► 66 Fatty acid oxidation Fatty acid oxidation

disorders (5 MCAD) disorders (5 MCAD) ► 22 X linked & 1 neonatal X linked & 1 neonatal

adrenoleucodystrophyadrenoleucodystrophy► 33 GalactosaemiaGalactosaemia► 11 L L 22 hydroxyglutaric hydroxyglutaric

aciduriaaciduria► 22 Ketothiolase deficiencyKetothiolase deficiency► 11 Transient neonatal Transient neonatal

hyperammonaemiahyperammonaemia

► 7 7 MucopolysaccharidosesMucopolysaccharidoses► 11 GSDGSD► 1 1 MucolipidosisMucolipidosis► 2 2 Ceroid lipofuscinosisCeroid lipofuscinosis► 1 1 Gauchers diseaseGauchers disease► 1 1 Refsums diseaseRefsums disease► 2 2 Steroid sulphatase def’ySteroid sulphatase def’y► 1 1 CystinuriaCystinuria► 1 1 Orotic aciduriaOrotic aciduria► 5 5 HypercholesterolaemiaHypercholesterolaemia► 2 2 Mitochondrial cytopathyMitochondrial cytopathy► 2 2 Segawa diseaseSegawa disease

The Metabolically The Metabolically

ill Infant and Childill Infant and Child

If You Don’t Think You Won’t LookIf You Don’t Think You Won’t Look

If You Don’t Look You Won’t FindIf You Don’t Look You Won’t Find

If You Don’t Find You Can’t TreatIf You Don’t Find You Can’t Treat

Acute presentationsAcute presentations

► NeonatalNeonatal Apparent sepsisApparent sepsis Neurological Neurological

deteriorationdeterioration HypoglycaemiaHypoglycaemia Liver dysfunctionLiver dysfunction E coli septicaemiaE coli septicaemia

Inborn Metabolic Inborn Metabolic ErrorsErrors

Are easy!Are easy!

IEMsIEMs

AA BB CC D D

XX YY

IEMsIEMs

AA BB CC D D

XX YY

EE

►Accumulation / excess storage Accumulation / excess storage metabolitesmetabolites Antenatal or postnatalAntenatal or postnatal

►Toxicity of metabolitesToxicity of metabolites►Energy insufficiencyEnergy insufficiency►Specific deficiencySpecific deficiency

►CombinationCombination

GeneticsGenetics

► All types of inheritanceAll types of inheritance RecessiveRecessive X linkedX linked DominantDominant Mitochondrial DNAMitochondrial DNA

► Mutation/s + genetics define level of Mutation/s + genetics define level of enzyme activityenzyme activity

► Enzyme activity informs severity and timing Enzyme activity informs severity and timing of presentationof presentation e.g. OCT deficiency, PKUe.g. OCT deficiency, PKU

Four Basic Clinical GroupsFour Basic Clinical Groups

Acute neonatal symptomsAcute neonatal symptoms►Present at birthPresent at birth►Symptom free intervalSymptom free interval

Later onset acute/intermittentLater onset acute/intermittent

Chronic progressive generalChronic progressive general

Specific symptoms of a disorderSpecific symptoms of a disorder

History Clues

► Age onsetAge onset► Disease progressionDisease progression► Precipitating factorsPrecipitating factors

Milk feedsMilk feeds WeaningWeaning InfectionInfection FastingFasting

► Sibling deathSibling death► Maternal HELLP and AFLP syndromesMaternal HELLP and AFLP syndromes

Acute neonatal symptomsAcute neonatal symptoms

► Present at birthPresent at birth

► Toxic typeToxic type

► Energy deficientEnergy deficient

► HypoglycaemiaHypoglycaemia

Acute neonatal symptomsAcute neonatal symptoms► From birthFrom birth

Facial dysmorphismFacial dysmorphism Profound hypotoniaProfound hypotonia SeizuresSeizures Liver disorderLiver disorder

? Peroxisomal disorder? Peroxisomal disorder ? Respiratory chain ? Respiratory chain ? Carbohydrate Deficient ? Carbohydrate Deficient

Glycoprotein disorder Glycoprotein disorder (CDG)(CDG)

Zellwegers syndromeZellwegers syndrome

ZellwegerZellweger

► Zellweger disease - antenatal onsetZellweger disease - antenatal onset Neurological - disorder neuronal migrationNeurological - disorder neuronal migration Hepatic - jaundice, bleeding, ^ ALT, mild Hepatic - jaundice, bleeding, ^ ALT, mild

cirrhosis on biopsycirrhosis on biopsy Cardiac anomaly - 32% VSD : 22% aorticCardiac anomaly - 32% VSD : 22% aortic Renal cystsRenal cysts Calcific stippling of patellaCalcific stippling of patella Eyes - ERG always abnormalEyes - ERG always abnormal Death in 1-2 yrsDeath in 1-2 yrs

► DiagnosisDiagnosis ^VLCFA^VLCFA ^pristanic, phytanic acids & some bile acids^pristanic, phytanic acids & some bile acids hypoprothrombinaemiahypoprothrombinaemia

IEMsIEMs

EEAA BB CC D D

XX YY

Acute Neonatal Symptoms Acute Neonatal Symptoms Toxic TypeToxic Type

► Symptom free intervalSymptom free interval ► Unexpected/”mysterious” deteriorationUnexpected/”mysterious” deterioration► Poor sucking / feedingPoor sucking / feeding► EncephalopathyEncephalopathy

►Hiccups, apnoeaHiccups, apnoea►Bradycardia, hypothermiaBradycardia, hypothermia►Relative hypertonia, OpisthotonusRelative hypertonia, Opisthotonus►Pedalling/boxingPedalling/boxing►Tremors / jerksTremors / jerks

True seizures rareTrue seizures rare► Odour eg MSUD/IVAOdour eg MSUD/IVA► ComaComa

Acute neonatal symptomsAcute neonatal symptoms► Energy deficientEnergy deficient

non specific symptomsnon specific symptoms

►+/- symptom free interval+/- symptom free interval

►severe generalised severe generalised hypotoniahypotonia

►then rapidly progressive neurological then rapidly progressive neurological

deteriorationdeterioration

►cardiomyopathycardiomyopathy

►lactic acidosis commonlactic acidosis common

► HypoglycaemiaHypoglycaemia►hepatomegalyhepatomegaly

►liver dysfunctionliver dysfunction

Acute neonatal symptomsAcute neonatal symptoms

Watch out forWatch out for► initial respiratory alkalosisinitial respiratory alkalosis► neutropaenianeutropaenia► thrombocytopaeniathrombocytopaenia► pancytopaeniapancytopaenia► clotting disturbanceclotting disturbance► vomitingvomiting► abdominal distentionabdominal distention

► IMD may mimic infectionIMD may mimic infection

Acute Neonatal Acute Neonatal Symptoms Initial Investigations

►BloodBlood FBC, clottingFBC, clotting U&E, (anion gap)U&E, (anion gap) GlucoseGlucose GasesGases Uric acidUric acid LFTLFT AmmoniaAmmonia LactateLactate CalciumCalcium

Anion GapAnion Gap

►= ( Na+K ) - (Cl+HCO3) = ( Na+K ) - (Cl+HCO3)

►8 to 16 mmol/L when not including 8 to 16 mmol/L when not including [K+] [K+]

►10 to 20 mmol/L when including [K+]. 10 to 20 mmol/L when including [K+].

Acute Neonatal Acute Neonatal Symptoms Initial Investigations

►BloodBlood FBC, clottingFBC, clotting U&E, (anion gap)U&E, (anion gap) GlucoseGlucose GasesGases Uric acidUric acid LFTLFT AmmoniaAmmonia LactateLactate CalciumCalcium

►UrineUrine OdourOdour KetonesKetones

►Ketonuria is an indicator for a metabolic disease in the newborn.

Reducing substancesReducing substances PhPh

InterpretationInterpretation

Ketones+++Ketones+++ NH3 +/- NH3 +/- ►MSUDMSUD

Acidosis++Acidosis++ NH3 +/++ lactate+/- NH3 +/++ lactate+/- cytopaeniacytopaenia►OrganicaciduriasOrganicacidurias

Increased Uric acid is indicative for organic aciduria Thrombocytopenia and Neutropenia are criteria for

severity in organic aciduria

NH3++/+++NH3++/+++ acidosis - lactate +/- acidosis - lactate +/-►Urea cycle Urea cycle ►Fatty acid oxidationFatty acid oxidation

InterpretationInterpretation

Lactate +++Lactate +++ acidosis ++ ketones ++ acidosis ++ ketones ++► Respiratory chain Respiratory chain ►““Cong lactic acidosis” Cong lactic acidosis”

Liver+++Liver+++ acidosis++ lactate ++ acidosis++ lactate ++ hypoglycemia++hypoglycemia++►GSD i, iiiGSD i, iii

LFT abnLFT abn Liver +, NH3 +/- Liver +, NH3 +/-►Galactosaemia tyrosinaemia HFIGalactosaemia tyrosinaemia HFI

Acute Neonatal Symptoms Acute Neonatal Symptoms Further Investigations

► BloodBlood Amino acidsAmino acids Carnitine T & FreeCarnitine T & Free Acyl carnitinesAcyl carnitines

► Specific testsSpecific tests Eg Gal-1-PUTEg Gal-1-PUT

► UrineUrine Amino acidsAmino acids Organic acidsOrganic acids

► CSF+/-CSF+/- LactateLactate glycineglycine

Recurrent EncephalopathyRecurrent Encephalopathy

►May be well for yearsMay be well for years►Cause not immediately obviousCause not immediately obvious►Child seems sicker than expected for Child seems sicker than expected for

apparent illnessapparent illness►Rarely of sudden onsetRarely of sudden onset►Encephalopathy preceeds hypoglycaemiaEncephalopathy preceeds hypoglycaemia►Consider in any type of coma or Consider in any type of coma or

encephalopathy ( including DKA)encephalopathy ( including DKA)

Recurrent EncephalopathyRecurrent Encephalopathy

► Well between episodes Well between episodes BUTBUT May suffer neurological damage during episodes May suffer neurological damage during episodes

(MCAD, OCT) (MCAD, OCT) Many are treatableMany are treatable Early diagnosis is importantEarly diagnosis is important

► Most metabolic encephalopathies do not Most metabolic encephalopathies do not have focal neuro signs have focal neuro signs BUT BUT Strokes, ataxia,Strokes, ataxia,

► It does not quite fitIt does not quite fit►D&V more ill than expectedD&V more ill than expected

► Unexpected “psychiatric illnessUnexpected “psychiatric illness””

Recurrent encephalopathyRecurrent encephalopathy

► ““Metabolic” Metabolic” investigationsinvestigations glucoseglucose ketonesketones ammoniaammonia lactatelactate blood gasesblood gases FBCFBC carnitinescarnitines acyl carnitinesacyl carnitines

► UrineUrine OdourOdour KetonesKetones Amino acidsAmino acids Organic acidsOrganic acids

► CSF+/-CSF+/- GlucoseGlucose LactateLactate GlycineGlycine

Recurrent EncephalopathyRecurrent Encephalopathy

Metabolic causesMetabolic causes► Fatty acid oxidation disordersFatty acid oxidation disorders

MCADMCAD► Carnitine disordersCarnitine disorders► Urea cycle disordersUrea cycle disorders► Organic acidaemiasOrganic acidaemias► Respiratory chain defectsRespiratory chain defects

Recurrent EncephalopathyRecurrent Encephalopathy

Consider alsoConsider also► Stroke like episodesStroke like episodes

MELAS MELAS HomocystinuriaHomocystinuria

►Total homocysteineTotal homocysteine organic acidaemias ornithine carbamyl transferase deficiency Carbohydrate Deficient Glycoprotein syndromes Carbohydrate Deficient Glycoprotein syndromes

(CDG)(CDG)► (sialotransferrin)(sialotransferrin)

► MacrocephalyMacrocephaly Glutaric aciduria IGlutaric aciduria I

►Frontal atrophyFrontal atrophy CDG syndromesCDG syndromes

HYPERAMMONAEMIA Differential diagnosis

► INHERITED DISORDERS

► Urea cycle disorders► Organic acidaemias► Fatty acid oxidation

disorders► Other inborn errors

(OAT,PC, HHH syndrome, etc)

► ACQUIRED DISORDERS

► Liver disease► Poisoning► ‘Reye’s syndrome’ –

acquired – aspirin + viral infection

► Sodium valproate toxicity

► Asparaginase toxicity► Urinary tract infection

with stasis

HyperammonaemiaHyperammonaemia

Mainly neurological presentationMainly neurological presentation► Inhibits neurotransmittersInhibits neurotransmitters► NH3 + glutamate = glutamineNH3 + glutamate = glutamine► Osmotic load = cerebral oedemaOsmotic load = cerebral oedema► Careful sampling is importantCareful sampling is important► Values of 100 mmol/l may be significant, but

usually >200 mmol/l ► Ammonia level not a good predictor of Ammonia level not a good predictor of

severity but >350 expect neuro sequelaeseverity but >350 expect neuro sequelae

HyperammonaemiaHyperammonaemia

► Brain stem stimulant tachypnoeatachypnoea

► Cyclical vomiting Check in all children in Check in all children in

acute episodeacute episode

► anorexia► Lethargy► Failure to thrive► Delayed development► Faddy eating

► Acute encephalopathyAcute encephalopathy► irritabilityirritability► headacheheadache► confusionconfusion► ataxia / slurring of ataxia / slurring of

speechspeech► bizarre behaviourbizarre behaviour► focal neurological signsfocal neurological signs► fluctuating level of fluctuating level of

consciousnessconsciousness► comacoma

HyperammonaemiaHyperammonaemia► TreatmentTreatment

Emergency regimenEmergency regimen► Avoid catabolismAvoid catabolism► High CHO feeds onlyHigh CHO feeds only

10% dextrose IV+/- insulin 10% dextrose IV+/- insulin IVIV

► DrugsDrugs ArginineArginine BenzoateBenzoate PhenylbutyratePhenylbutyrate

► HaemofiltrationHaemofiltration► HaemodialysisHaemodialysis► Treat cerebral oedema Treat cerebral oedema

Healthy Children:

Response to fasting

HypoglycaemiaHypoglycaemia

► May be the end May be the end result of a metabolic result of a metabolic disease - sickdisease - sick

► May be the primary May be the primary symptomsymptom

► What is the timing of What is the timing of hypohypo Fasting Fasting PostprandialPostprandial Intercurrent illnessIntercurrent illness

► Hepatomegaly?Hepatomegaly? PermanentPermanent TransientTransient

► Ketosis?Ketosis?► Lactate++?Lactate++?► Liver dysfunction?Liver dysfunction?► Short stature?Short stature?

Hypoglycaemia Hypoglycaemia investigationsinvestigations

When hypoWhen hypo► lactatelactate► KetonesKetones► FFAFFA► urateurate► CKCK► lipidslipids► GH GH ► insulin insulin ► cortisolcortisol

OthersOthers► carnitinecarnitine► acyl carnitineacyl carnitine► LFTLFT► AminoacidsAminoacids

► Urine (first available)Urine (first available) aminoacidsaminoacids organic acidsorganic acids reducing substancesreducing substances ketonesketones

Hypoglycaemia - Permanent hepatomegalyHypoglycaemia - Permanent hepatomegaly► ““All metabolic”All metabolic”► Fasting hypo/ ketosis / lactate +Fasting hypo/ ketosis / lactate +

Glycogen storage diseaseGlycogen storage disease►Trigly > cholesterol Trigly > cholesterol II►Chol > trigly Chol > trigly IIIIII►Urate ++ Urate ++ II►Creat kinase ++ Creat kinase ++ IIIIII►Lactate ++Lactate ++ II

► Liver failure / short fastLiver failure / short fast Galactosaemia Galactosaemia TyrosinaemiaTyrosinaemia

► PostprandialPostprandial Hereditary fructose intoleranceHereditary fructose intolerance

Hypoglycaemia - No Permanent Hypoglycaemia - No Permanent HepatomegalyHepatomegaly

► KetosisKetosis Organicaciduria Organicaciduria MSUD MSUD Ketotic hypoglycaemiaKetotic hypoglycaemia Adrenal insufficienyAdrenal insufficieny

► Without ketosisWithout ketosis Fatty acid oxidation disorderFatty acid oxidation disorder HyperinsulinismHyperinsulinism Growth hormone deficiencyGrowth hormone deficiency

Diagnostic algorithm

METABOLIC ACIDOSIS

HYPERAMMONEMIA

Ketonuria Ketonuria

Hyperlactatemia

Hypoglycemia

Major hyperlactatemia Maple Syrup Urine Disease (MSUD)

Maple Syrup Urine Disease (MSUD)

HypoglycemiaOrganic aciduria

Organic aciduria Pyroglutamic

aciduria

Non-ketonic hyperglycinemia Sulfite oxydase deficiency - XO

Urea Cycle Disorders

Respiratory chain

Fatty acid oxydation Variant hyperinsulinism

(glutamate dehydrogenase)

Fatty acid oxydation Glycogen storage disease

Glyconeogenesis defects

Mitochondrial defect

no

no

no no

no

no no

no

yes

yes

yes

yes

yes

yes

yes yes

► Best Practice GuidelinesBest Practice Guidelines► ContentsContents► Guidelines for the Biochemical Investigation of Patients with FGuidelines for the Biochemical Investigation of Patients with F

oetal and Neonatal oetal and Neonatal HydropsHydrops

► Guidelines for Investigation of Fits and Seizures (Instruction Guidelines for Investigation of Fits and Seizures (Instruction Sheet for CSF sample collection ) Sheet for CSF sample collection )

► Guidelines for the Investigation of Hypoglycaemia in Infants Guidelines for the Investigation of Hypoglycaemia in Infants and Children and Children

► Guidelines for the Investigation of Hyperammonaemia for Guidelines for the Investigation of Hyperammonaemia for Inherited Metabolic Disorders Inherited Metabolic Disorders

► Appendix - Notes on the measurement of ammonia in Appendix - Notes on the measurement of ammonia in blood/plasma blood/plasma

► Skin Biopsy - Information Sheet for parents/carers Skin Biopsy - Information Sheet for parents/carers ► Skin Biopsy - Consent form Skin Biopsy - Consent form ► Neonatal Jaundice in Inherited Metabolic Disorders Neonatal Jaundice in Inherited Metabolic Disorders

Inherited Metabolic DiseasesInherited Metabolic Diseases

Practice pointsPractice points

► More common than expectedMore common than expected► Can present in unexpected waysCan present in unexpected ways► If you do not think about the possibility you will not make the diagnosisIf you do not think about the possibility you will not make the diagnosis

Lower threshold to investigateLower threshold to investigate

► Be aware significance of NHBe aware significance of NH3 3 levellevel

► Hypoglycaemia is a late eventHypoglycaemia is a late event