A species is a group of creatures that share similar features and interbreed to generate viable offspring. 1. A genus is the highest level of taxonomic categorisation, ranking below family and above species. 2. They are the most basic level of biological categorisation.

1. APPROACH TO
INBORN ERRORS OF MET
ABOLISM
Prof. Faisal

2. METABOLISM
 Metabolism Catabolism (Breakingdown)
Anabolism (Buildingup)
 Enzymesplay an important role in facilitating
the process by serving ascatalysts in the
conversion of one chemical (metabolite) to
another.

3. Dr.Padmesh.V
 Catabolism :
 Catabolism is the set of metabolic pathways that
break down molecules into smaller units and
releaseenergy.

4. Dr.Padmesh.V
 Catabolism :
 Catabolism is the set of metabolic pathways that
break down molecules into smaller units and
releaseenergy.

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 Anabolism :
 Anabolism is the set of metabolic pathways that
construct molecules from smaller units. These
reactions requireenergy.

6. Dr.Padmesh.V
 Anabolism :
 Anabolism is the set of metabolic pathways that
construct molecules from smaller units. These
reactions requireenergy.

7. Dr.Padmesh.V
 Anabolism :
 Anabolism is the set of metabolic pathways that
construct molecules from smaller units. These
reactions requireenergy.

8. Dr.Padmesh.V
 Inborn errorsof metabolism (IEM)
- Inborn errors of metabolism (IEM) aredisorders
in which there is ablock at some point in the
normal metabolicpathway
- IEMsoccurdue to mutations in DNA.
DNA
which code fora
Specificprotein
Enzyme
Receptor
Transport vehicle
Membranepump
Structural element

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 Exampleof mechanismsin IEM:
Precursor
A
Substrate
B
End-Product
C

10. Dr.Padmesh.V
 Exampleof mechanismsin IEM:
Precursor
A
Substrate
B
End-Product
C
Abnormal metabolic
pathway
Toxic Metabolite D

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 Thenumber of diseasesdue to inherited point
defects in metabolism now exceeds500.
 While the diseasesindividually are rare, they
collectively account for asignificant proportion of
neonatal and childhood morbidity and mortality.
 Diagnosisis important not only for treatment but
also for genetic counselling and antenatal
diagnosis in subsequentpregnancies.

12. Dr.Padmesh.V
 CLASSIFICATION OF IEM:
1. Amino acid metabolism
2. Carbohydrate metabolism
3. Lipid metabolism
4. Protein metabolism
5. Pigment metabolism
6. Unknown biochemical defects

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 CLASSIFICATION OF IEM:
1.Amino acid metabolism
-Phenylketonuria
-Tyrosinosis
-Albinism
-Alkaptonuria
-Cystinosis
-Cystinuria
-Homocysteinuria
-Hartnup disease
-Maple syrupdisease

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 CLASSIFICATION OF IEM:
2.Carbohydrate synthesis:
-Congenital lactose intolerance
-Galatosemia
-Glycogen storagedisease
-Diabetes mellitus
-Scurvy

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 CLASSIFICATION OF IEM:
3.Lipidmetabolism:
-Abetalipoproteinemia
-Progressive lipodystrophy
-Lipid storagedisorders
* Gaucher
* Neimann-Pick
* Tay-sachs
* Hyperlipoproteinemia

16. Dr.Padmesh.V
 CLASSIFICATION OF IEM:
4. Protein Metabolism:
-Immunoglobulin deficiencies
-Absent clotting factors
(Hemophilia, Christmasdis,
Hypoprothrombinemia)
-Metal binding proteindeficiency
(Wilson hepatolenticulardegeneration)
-Alpha-1 anti trypsindeficiency

17. Dr.Padmesh.V
 CLASSIFICATION OF IEM:
5. Pigment metabolism:
-Porphyrias
-Methemoglobinemias
-Albinism
-Crigler-Najjar dis
-Dubin-Johnson dis
-Gilbert dis
-Rotor synd
-Primary hemochromatosis

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 CLASSIFICATION OF IEM:
6. Unknown biochemicaldefect:
-Osteogenesisimperfecta
-Marfan synd
-Achondroplasia
-Ehler danlossynd

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APPROACH TO
IEM

20. Dr.Padmesh.V
1.Suspecting
Inborn Errors:

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 Suspecting InbornErrors:
 Inborn errors should be suspectedwhen
 HISTORY:
(1) Symptoms accompany starting/changes in diet,
(2) Children with seizures,
(3) Developmental delay,
(4) Recurrent vomiting,
(5) Unusual odour ofurine,
(6) Parental consanguinity,
(7) Problems suggestive of inborn error suchasretardation or
unexplained deaths in first- and second-degree relatives.

22. Dr.Padmesh.V
Suspecting InbornErrors:
CLINICALLY:
IEMmust be also considered in the differential diagnosis of
 Critically ill newborns,
 Neurodegeneration,
 Mental retardation,
 Coarse facies /dysmorphic features,
 Parenchymal liver disease,
 Cardiomyopathy,
 Organomegaly
 Unexplained acidosis,
 Cornealopacity, cataract or dislocation of lens,
 Hyperammonemia, and
 Hypoglycemia

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 Clinical pointers towards specific IEMs:

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InbornErrorsofAminoAcidMetabolism
AssociatedwithPeculiarOdour:

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Patterns of Presentation:
1.Encephalopathywith or without metabolic
acidosis.
2.Acute liverdisease:
- Jaundicealone
- Hepatic failure
- Neonatal cholestasis
- Hypoglycemia
3.Dysmorphic features.
4. Cardiac disease.
5.Diarrhea
6. Hepatomegaly +/-Splenomegaly
7.Predominant Neurological symptoms

26. Dr.Padmesh.V
 1)Encephalopathy with orwithout
metabolicacidosis:
 Encephalopathy,seizures,and tone abnormalities are
predominant presenting featuresof
-organic acidemias,
-urea cycledefects,and
-congenital lacticacidosis.
 Intractable seizuresareprominent in
-pyridoxine dependency,
-non-ketotic hyperglycinemia,
-molybdenum co-factordefect,and
-folinic-acid responsiveseizures.

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 2) Acute liver disease: could manifest as-
 Jaundice alone: -Gilbertsyndrome,
-Criggler-Najjar syndrome
 Hepatic failure(jaundice, ascites, hypoglycemia, coagulopathy):
-Tyrosinemia,
-galactosemia,
-neonatal hemochromatosis,
-glycogenstorage diseasetype IV.
 Neonatalcholestasis:
-alpha-1 antitrypsindeficiency,
-Niemann-Pick disease typeC.
 Persistent and severehypoglycemia:
-Galactosemia,
-fattyacid oxidation defects,
-organic acidemias,
-glycogen storage disordersand
-disorders ofgluconeogenesis.

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 3)Dysmorphic features: seen in
-Peroxisomal disorders,
-Pyruvate dehydrogenasedeficiency,
-Congenital disorders of glycosylation ,and
-Lysosomal storagediseases.
Some IEMs may presentwith
non-immune hydropsfetalis
-lysosomal storagedisorders,and
-Congenital disorders ofglycosylation.

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 4) Cardiacdisease:
Cardiomyopathy is aprominent feature in some
IEM likein:
-Fatty acid oxidationdefects,
-Glycogenstorage diseasetype II , and
-Mitochondrial electron transport chain defects.

30. Dr.Padmesh.V
 6. Diarrhea:
a. Severe waterydiarrhea:
- Congenital chloridediarrhea
- Galactosemia
- Primary lactase,sucrase,isomaltasedeficiency.
b. Chronicdiarrhea:
-Bile aciddisorders
-Infantile Refsumdisease
-Respiratory chain disordersassowith
steatorrhea
-Vitamin deficiencyosteopenia
-Hypocholesterolemia
c. Diarrhea,Failure to thrive,hypotonia,hepatomegaly:
-Glycogen storage dis1
- Wolmansdisease

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 7.Hepatomegaly :
-Tyrosinemia
-Galactosemia
-Fructosemia
-Alpha 1antitrypsin deficiency.
 8. Hepatomegaly +Splenomegaly:
-Mucolipidosis
-Gaucher’sdis
-Niemann-Pick typeA

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9. Predominant NeurologicalSymptoms:
a.Psychomotordelay:
-Aminoacidopathies
-Organic acidemias
-CNSstoragediseases
b. Recurrent Reye:
-Urea cycledefect
-Systemic carnitinedeficiency
c.Ataxia:
-Hartnup dis
-Urea cycledisorders
-Pyruvate decarboxylasedeficiency
d. Extrapyramidal signs:
- Wilsons disease
e. Hypotonia :
- Zellweger synd
-Mitochondrial myopathies
-Muscle carnitinedeficiency

33. Dr.Padmesh.V
INVESTIGATIONS:
 Metabolic investigations should be initiated assoon
asthe possibility isconsidered.
 Theoutcome of treatment of many IEM especially
those associated withhyperammonemia is directly
related to the rapidity with which problems are
detected andtreated.

34. Dr.Padmesh.V
 First line investigations (metabolic screen):
 Thefollowing tests shouldbe obtained in all babieswith suspected
IEM.
 1)Completeblood count: (neutropenia andthrombocytopenia
seenin propionic and methylmalonic academia)
 2)Arterial blood gasesand electrolytes
 3)Bloodglucose
 4) Plasmaammonia (Normal valuesin newborn: 90-150mg/dl or
64-107mmol/L)
 5)Arterial blood lactate (Normal values:0.5-1.6mmol/L)
 6) Liver functiontests,
 7)Urineketones,
 8) Urine reducingsubstances,
 9)Serumuric acid (low in molybdenum cofactor deficiency).

35. Dr.Padmesh.V
Suspected Metabolicdisease
PlasmaAmmonia
High Normal
Blood pH,CO2 Blood pH,CO2
Normal Acidosis
No Ketosis
Normal
PKU, Non Ketotic hyper
-glycinemia,Peroxisomal
disorders
No Ketosis Ketosis with/without lacticacidosis
UreaCycle
defect
Fatty acid
oxidationdefect
Organic acidemias
Mitochondrialdisorders

36. Dr.Padmesh.V
Normal PlasmaAmmonia
No Acidosis
PKU, Non Ketotic Hyperglycinemia,
Galacosemia, Peroxisomaldisorders

37. Dr.Padmesh.V
High PlasmaAmmonia
No Acidosis
No Ketosis
UREA CYCLE DEFECT

38. Dr.Padmesh.V
Normal or High PlasmaAmmonia
Acidosis
Ketosis
Organic acidemias, Mitochondrialdisorders

39. Dr.Padmesh.V
Normal or High PlasmaAmmonia
Acidosis
No Ketosis
Fatty acid oxidationdefects

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Categorization of neonatal IEM using metabolic
screening tests:

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46. Dr.Padmesh.V
 Second lineinvestigations
(ancillary and confirmatorytests)
 Thesetests need to be performed in atargeted manner, based
on presumptive diagnosis after first lineinvestigations:
 1)Gaschromatography massspectrometry (GCMS)of urine- for
diagnosis of organic acidemias.
 2) Plasmaamino acids and acyl carnitine profile: byTandem
massspectrometry (TMS)- for diagnosis of organic
acidemias, urea cycle defects, aminoacidopathies and fatty acid
oxidation defects.
 3)High performance liquid chromatography (HPLC): for
quantitative analysis of amino acids in blood and urine; required
for diagnosis of organic acidemiasand aminoacidopathies.

47. Dr.Padmesh.V
 4) Lactate/pyruvate ratio- in caseswith elevated lactate.
 5)Urinary orotic acid- in caseswith hyperammonemiafor
classification of urea cycledefect.
 6) Enzymeassay:Thisis required for definitive
diagnosis,but not available for most IEM’s.
Available enzyme assaysinclude:
-Biotinidase assay- in caseswith suspected
biotinidase deficiency (intractable seizures,seborrheic
rash, alopecia);
-GALT(galactose1-phosphate uridyl transferase )
assay- in caseswith suspected galactosemia
(hypoglycemia,cataracts, reducing sugarsin urine).

48. Dr.Padmesh.V
 7)Neuroimaging: MRI
 SomeIEMmay be associatedwith structural
malformations .Examples:
 Zellwegersyndromehasdiffuse cortical migration and
sulcation abnormalities.
 Agenesisof corpus callosum hasbeenreported in
Menke’sdisease,pyruvate decarboxylasedeficiency and
nonketotic hyperglycinemia.
 Maple syrup urine disease(MSUD):brainstem and
cerebellaredema.
 Propionic & methylmalonic acidemia: basalganglia signal
change.
 Glutaric aciduria: frontotemporal atrophy, subdural
hematomas.

49. Dr.Padmesh.V
 8) Magnetic resonance spectroscopy (MRS): may be helpful in
selected disorders
 E.g.lactate peak elevated in mitochondrial disorders, leucine peak
elevated inMSUD.
 9) Electroencephalography(EEG):
 Comb-like rhythm inMSUD,
 Burst suppression in Non Ketotic Hyperglycemia and
holocarboxylase synthetasedeficiency.
 10)Plasmavery long chain fatty acid (VLCFA)levels: elevated in
peroxisomal disorders.
 11)Mutation analysis whenavailable.
 12)CSFaminoacid analysis:CSFGlycine levels elevated in NKH.

50. Dr.Padmesh.V
TREATMENT:
 In most cases,treatment needs to be instituted empirically
without aspecificdiagnosis.
 Themetabolic screenhelps to broadly categorize the patient’s
IEM(e.g. ureacycle defect, organic academia,
congenital lactic acidosis etc), on the basis of which, empirical
treatment can beinstituted

51. Dr.Padmesh.V
 Aims oftreatment
 1.Toreduce the formation of toxic metabolites by decreasing
substrate availability (by stopping feeds and preventing endogenous
catabolism)
 2.Toprovide adequate calories.
 3.Toenhance the excretion of toxic metabolites.
 4.Toinstitute co-factor therapy for specific diseaseandalso
empirically if diagnosis not established.
 5. Supportivecare-
-Treatment of seizures(avoid sodium valproate –
may increase ammonialevels),
-Maintain euglycemia andnormothermia,
-Fluid, electrolyte &acid-base balance,
-Treatment of infection,
-Mechanical ventilation ifrequired.

52. Dr.Padmesh.V
 Management ofhyperammonemia:
 1)Discontinue all feeds.Provide adequate calories by intravenous glucose and
lipids. Maintain glucose infusion rate 8-10mg/kg/min. Start intravenous lipid
0.5g/kg/day (up to 3g/kg/day).After stabilization gradually add protein 0.25
g/kg till 1.5g/kg/day.
 2) Dialysis is the only means for rapid removal of ammonia, and hemodialysis is
more effective and faster than peritoneal dialysis. Exchange transfusion is
not useful.
 3)Alternative pathways for nitrogen excretion-:
-Sodium benzoate (IV/oral)- loading dose 250mg/kg then 250-400 mg/kg/day
in 4 divided doses.(Intravenous preparation not available in India.)
-Sodium phenylbutyrate (not available in India)-loading dose 250mg/kg
followed by 250-500mg/kg/day.
-L-arginine (oral or IV)- 300mg/kg/day (IVpreparation not available in India)
-L-carnitine (oral or IV)- 200 mg/kg/day
 4)Supportive care:Treatment of sepsis,seizures,ventilation.
Avoid sodiumvalproate.

53. Dr.Padmesh.V
 Acute management of newborn with suspected
organic acidemia:
 1)Thepatient is kept nil per orally and intravenous glucose is provided.
 2)Supportive care:hydration, treatment of sepsis,seizures, ventilation.
 3)Carnitine:100mg/kg/day IVor oral.
 4)Treat acidosis:Sodiumbicarbonate0.35-0.5mEq/kg/hr(max 1-
2mEq/kg/hr)
 5)Start Biotin 10mg/day orally.
 6)StartVitamin B121-2mg/day I/M (usefulin B12responsiveforms of
methylmalonic acidemias)
 7)StartThiamine 300mg/day (useful inThiamine-responsivevariants of
MSUD).

54. Dr.Padmesh.V
 Management of congenital lactic acidosis:
 1)Supportive care:hydration, treatment of sepsis,seizures, ventilation.
Avoid sodiumvalproate.
 2)Treat acidosis:sodium bicarbonate 0.35-0.5mEq/kg/hr
(max1-2mEq/kg/hr)
 3)Thiamine: up to 300mg/day in 4 divided doses.
 4)Riboflavin: 100mg/day in 4 divided doses.
 5)Add co-enzymeQ: 5-15mg/kg/day
 6)L-carnitine:50-100mg/kg orally.

55. Dr.Padmesh.V
 Treatment of newborn with refractory seizures
with no obvious etiology (suspected metabolic
etiology):
 1)If patient persists to have seizures despite 2 or 3
antiepileptic drugs in adequate doses, consider trial of
pyridoxine 100mg intravenously. If intravenous preparation
not available, oral pyridoxine canbe given (15mg/kg/day).
 2) If seizures persist despite pyridoxine, give trial of biotin 10
mg/day and folinic acid 15mg/day (folinic acid responsive
seizures).
 3)Rule out glucose transporter defect: measureCSFand blood
glucose.This disorder responds to the ketogenic diet.

56. Dr.Padmesh.V
 Management of asymptomatic newborn
with a history of sibling death with
suspected IEM:
 1)After baseline metabolic screen, start oral dextrose feeds (10%
dextrose).
 2)After 24 hours, repeat screen. If normal, start breast feeds.
Monitor sugar,blood gasesand urine ketones, blood ammoniaQ6
hourly.
 3)Some recommend starting medium chain triglycerides (MCToil)
before starting breastfeeds,
 4) After 48 hours, repeat metabolic screen. Obtain samples for urine
organic acidtests.
 5) The infant will need careful observation and follow-up for the first
few months, asIEM may present in different age groups in members
of thesame family.

57. Dr.Padmesh.V
 Long term treatment of IEM
 1)Dietary treatment: This is the mainstay of treatment in
phenylketonuria, maple syrupurine
disease, homocystinuria,galactosemia, and glycogen storage
diseaseType I & III.
 Some disorders like urea cycle disorders and organic acidurias
require dietary modification (protein restriction) in addition to
other modalities.
 2) Enzyme replacement therapy (ERT): ERTis now
commercially available for some lysosomal storage disorders.
However, these disorders do not manifest in the newborn
period, except Pompe’s disease (Glycogen storage disorder
Type II) which may present in the newborn period and for
which ERTis nowavailable.

58. Dr.Padmesh.V
3) Cofactor replacement therapy:
Thecatalytic properties of manyenzymes depend on the participation
of non protein prosthetic groups, such as vitamins and minerals,as
obligatory cofactors.

59. Dr.Padmesh.V
PREVENTION

60. Dr.Padmesh.V
1.Geneticcounselling and prenatal diagnosis:
Most of the IEMare single gene defects, inherited in an autosomal recessive
manner, with a25%recurrencerisk.
 Therefore when the diagnosis is known and confirmed in the index case,prenatal
diagnosis can be offered wherever available for the subsequentpregnancies.
 The samples required are Chorionic Villous tissue or Amniotic fluid.
 Modalities availableare:
-Substrate or metabolite detection: useful in phenylketonuria, peroxisomal
defects.
-Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick
disease, Gaucherdisease.
-DNAbased(molecular) diagnosis:Detection of mutation in proband/
carrier parents is aprerequisite.

61. Dr.Padmesh.V
 2)Neonatal screening:
 Tandem massspectrometry is usedin somecountries for
neonatal screening forIEM.
 Disorders which canbe detected byTMSinclude
-Aminoacidopathies (
phenylketonuria, MSUD, Homocystinuria,Citrullinemia,Argini
nosuccinic aciduria, hepatorenaltyrosinemia),
-Fatty acid oxidationdefects,
-Organic acidemias (glutaricaciduria, propionic
acidemia, methylmalonic acidemia, isovalericacidemia).
 Thecost of this procedure is very high.
 Also, though the test is highly sensitive, the specificity is
relatively low; and there are difficulties in interpretation of
abnormal test results in apparently healthy infants.

62. Dr.Padmesh.V
 Reference:
1. Nelson’s textbook of Pediatrics, 18th ed.
2. Essential Pediatrics, 7th ed.,O.P.Ghai.
3. Careof the Newborn, 6th ed., MeharbanSingh.
4. Current Pediatric Diagnosis &Treatment
(CPDT),18th ed.
5. AClinicalGuideto Inherited Metabolic
Diseases,2nd ed,JoeT.R.Clarke.
6. AIMS NICU Protocol2008.
7. Indian Journal of Pediatrics,Vol 72-Apr,2005

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