Creutzfelt-Jacob Disease (CJD) A transmissible spongiform encephalopathy or “prion disease”
Does this ill child have a metabolic disease? ► General Intro ► Disease Presentation &...
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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
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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
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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
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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
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Acute presentationsAcute presentations
► NeonatalNeonatal Apparent sepsisApparent sepsis Neurological Neurological
deteriorationdeterioration HypoglycaemiaHypoglycaemia Liver dysfunctionLiver dysfunction E coli septicaemiaE coli septicaemia
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Inborn Metabolic Inborn Metabolic ErrorsErrors
Are easy!Are easy!
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IEMsIEMs
AA BB CC D D
XX YY
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IEMsIEMs
AA BB CC D D
XX YY
EE
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►Accumulation / excess storage Accumulation / excess storage metabolitesmetabolites Antenatal or postnatalAntenatal or postnatal
►Toxicity of metabolitesToxicity of metabolites►Energy insufficiencyEnergy insufficiency►Specific deficiencySpecific deficiency
►CombinationCombination
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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
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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
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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
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Acute neonatal symptomsAcute neonatal symptoms
► Present at birthPresent at birth
► Toxic typeToxic type
► Energy deficientEnergy deficient
► HypoglycaemiaHypoglycaemia
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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
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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
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IEMsIEMs
EEAA BB CC D D
XX YY
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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
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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
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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
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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
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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+].
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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
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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
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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
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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
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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)
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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””
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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
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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
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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
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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
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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
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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
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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
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Healthy Children:
Response to fasting
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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?
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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
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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
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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
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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
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► 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
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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
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