basic idea regarding different IEM, when to suspect it and approach to common IEM algorhythm wise. adopted and compiled from aiims protocol 2014

1. Dr. Hemang Mendpara
Dept of pediatrics,
choithram hospital, indore.

2. We have patients of
• Galactosemia
• Pompe disease
• Molybdanum co facor deficiency
• Neurotransmitter deficiency disorder (GTPCH def. disorder)
• Carnitine deficiency
• Creatine deficiency
• OTC deficiency (urea cycle disorder)
• Transient hyper ammonemia of new born
• Neimann pick disease
• Tyrosinemia
• 3 keto thiolase deficiency
• GM2 gangliosidosis

3. METABOLISM
• Metabolism Catabolism (Breaking down)
Anabolism (Building up)
• Enzymes play an important role in
facilitating the process by serving as
catalysts in the conversion of one chemical
(metabolite) to another.

4. • Catabolism :
• Catabolism is the set of metabolic pathways
that break down molecules into smaller units
and release energy.

5. • Catabolism :
• Catabolism is the set of metabolic pathways
that break down molecules into smaller units
and release energy.

6. • Anabolism :
• Anabolism is the set of metabolic pathways that
construct molecules from smaller units. These
reactions require energy.

7. • Anabolism :
• Anabolism is the set of metabolic pathways that
construct molecules from smaller units. These
reactions require energy.

8. • Anabolism :
• Anabolism is the set of metabolic pathways that
construct molecules from smaller units. These
reactions require energy.

9. • Inborn errors of metabolism (IEM)
- Inborn errors of metabolism (IEM) are disorders in
which there is a block at some point in the normal
metabolic pathway
- IEMs occur due to mutations in DNA.
DNA Enzyme
which code for a Receptor
Specific protein Transport vehicle
Membrane pump
Structural element

10. • Example of mechanisms in IEM:
Precursor Substrate End-product
A B C

11. • Example of mechanisms in IEM:
Precursor Substrate End-Product
A B C
Abnormal metabolic
pathway
Toxic Metabolite D

12. • The number of diseases due to inherited point
defects in metabolism now exceeds 500.
• While the diseases individually are rare, they
collectively account for a significant proportion
of neonatal and childhood morbidity and
mortality.
• Diagnosis is important not only for treatment
but also for genetic counseling and antenatal
diagnosis in subsequent pregnancies.

13. • CLASSIFICATION OF IEM:
1. Amino acid metabolism
2. Carbohydrate metabolism
3. Lipid metabolism
4. Protein metabolism
5. Pigment metabolism
6. Unknown biochemical defects

14. • CLASSIFICATION OF IEM:
1. Amino acid metabolism
- Phenylketonuria
- Tyrosinosis
- Albinism
- Alkaptonuria
- hawkinsinuria
- Cystinosis
- Cystinuria
- Homocysteinuria
- Hartnup disease
- Maple syrup disease
- glutaric aciduria
- canavan disease ( aspartic acid)
Hyper methioninemia
Molybdanum co factor deficiency
Cystathioninemia
Isovaleric acidemia
Multiple carboxylase deficiency
Mevalonic aciduria
Propionic acidemia
Methyl malonic acidemia
Non ketotic hyper glycinemia
Hyper oxaluria
Creatine deficiency
Infantile parkinsonism
GTPCH def
Urea cycle disorder
-Carbamyl phosphate synthatase def
- OTC def
-Arginosuccinate synthatase def
-Arginosuccinate synthatase def
-Arginase def
-Transient hyper ammonemia of new born
-Pyridoxin dependant epilepsy

15. 2. Carbohydrate synthesis:
-Congenital lactose intolerance
-Galatosemia
-Glycogen storage disease
- fructose disorder
- essential fructosuria
- herediatery fructose intolerence
- disorder of gluconeogenesis
- fructose 1-6 di phosphatase def
- phophoenol pyruvate carboxy kinase def
- disorder of pyruvate metabolism
- PDH complex defect
- respiratory chain defect
- pyruvate carboxylase def
- disorder of pantose metabolism

17. • CLASSIFICATION OF IEM:
3. Lipid metabolism:
- defect in beta oxidation
- defect in carnitine cycle
- defect in ketone synthesis and utilization
- peroxisomal disorder
zelweger syndrome
adreno leucodystrophy
refsum disease
- Lysosomal storage disorder
- GM -1, 2 gangliosidosis ( tay sachs, sandoff , krabbe diseaseetc.)
- Neimann pick disease
- Faber disease
- Metachromatic leuco dystrophy
-Abetalipoproteinemia
-Progressive lipodystrophy
- Hyperlipoproteinemia
Corse facial features, organomegaly, skeletal dysplasia, severe skin
change or NIHF

18. • Mucopolysaccharidosis
• Disorder of purine/pyrimidine metabolism
– Gout
– HPRT def ( lesch Nyhan synd )
– Adenosine deaminase deficiency
– Hereditary orotic aciduria

19. • CLASSIFICATION OF IEM:
4. Protein Metabolism:
- Immunoglobulin deficiencies
- Absent clotting factors
(Hemophilia, Christmas dis,
Hypoprothrombinemia)
- Metal binding protein deficiency
(Wilson hepatolenticular degeneration)
- Alpha-1 anti trypsin deficiency

20. • CLASSIFICATION OF IEM:
5. Pigment metabolism:
- Porphyrias
- Methemoglobinemias
- Albinism
- Crigler-Najjar disease
- Dubin-Johnson disease
- Gilbert disease
- Rotor syndrome
- Primary hemochromatosis

21. • CLASSIFICATION OF IEM:
6. Unknown biochemical defect:
- Osteogenesis imperfecta
- Marfan syndrome
- Achondroplasia
- Ehler danlos synd

22. APPROACH TO IEM

23. 1. Suspecting
Inborn Errors:

24. • Suspecting Inborn Errors:
• Inborn errors should be suspected when
• HISTORY:
(1) Symptoms accompany starting/changes in diet,
(2) Deterioration after a period of apparent normalcy
(3) Rapidly progressive encephalopathy with seizure of unexplained
cause
(4) Severe metabolic acidosis
(5) Developmental delay,
(6) Recurrent vomiting,
(7) Unusual odour of urine,
(8) Parental consanguinity,
(9) Problems suggestive of inborn error such as retardation or
unexplained deaths in first- and second-degree relatives.
(10) acute fatty liver of pregnancy ( HELLP synd ) a/w long chain 3
hydroxyacyl co enzyme dehydrogenase def (LCHADD)

25. Suspecting Inborn Errors:
CLINICALLY:
IEM must 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,
• Corneal opacity, cataract or dislocation of lens,
• Hyperammonemia, and
• Hypoglycemia

26. • Clinical pointers towards specific IEMs:

28. Patterns of Presentation:
1. Encephalopathy with or without metabolic
acidosis.
2. Acute liver disease:
- Jaundice alone
- Hepatic failure
- Neonatal cholestasis
- Hypoglycemia
3. Dysmorphic features.
4. Cardiac disease.
5. Diarrhea
6. Hepatomegaly +/- Splenomegaly
7. Predominant Neurological symptoms

29. • 1) Encephalopathy with or without
metabolic acidosis:
• Encephalopathy, seizures,and tone abnormalities
 organic acidemias,
 urea cycle defects,and
 congenital lactic acidosis.
• Intractable seizures are prominent
 pyridoxine dependency,
 non-ketotic hyperglycinemia,
 molybdenum co-factor deficiency
 folinic-acid responsive seizures.
 neuronal ceroid lipofusinosis
 Biotinidase deficiency
 Creatine deficiency
Stroke or stroke like event
1. Homocystinuria
2. Fabery disease
3. Organic acidopathy
4. Methyl malonic acidemia
5. Propionic acidemia
6. Isovaleric acidemia
7. Glutaric aciduria type 1,2
8. OTC deficiency
9. MELAS
10. Carbohydrate deficient
Glycoprotein syndrome

30. • 2) Acute liver disease: could manifest as-
• Jaundice alone:
 Gilbert syndrome,
 Criggler-Najjar syndrome
• Hepatic failure (jaundice, ascites, hypoglycemia, coagulopathy):
 Tyrosinemia,
 galactosemia,
 neonatal hemochromatosis,
 glycogen storage disease type IV.
• Neonatal cholestasis:
 α-1 antitrypsin deficiency,
 Niemann-Pick disease type C.
• Persistent and severe hypoglycemia:
 Galactosemia,
fatty acid oxidation defects,
organic acidemias,
glycogen storage disorders
disorders of gluconeogenesis.

31. • 3) Dysmorphic features: seen in
-Peroxisomal disorders,
-Pyruvate dehydrogenase deficiency,
-Congenital disorders of glycosylation ,
-Lysosomal storage diseases.
non-immune hydrops fetalis
-lysosomal storage disorders,
-Congenital disorders of glycosylation.

32. • 4) Cardiac disease:
Cardiomyopathy is a prominent feature in some
IEM like in:
-Fatty acid oxidation defects,
-Glycogen storage disease type II , and
-Mitochondrial electron transport chain
defects.

33. • 6. Diarrhea :
a. Severe watery diarrhea:
- Congenital chloride diarrhea
- Galactosemia
- Primary lactase,sucrase,isomaltase deficiency.
b. Chronic diarrhea:
-Bile acid disorders
-Infantile Refsum disease
-Respiratory chain disorders asso with
steatorrhea
-Vitamin deficiency osteopenia
-Hypocholesterolemia
c. Diarrhea,Failure to thrive,hypotonia,hepatomegaly:
-Glycogen storage dis 1
- Wolmans disease

34. • 7. Hepatomegaly :
-Tyrosinemia
-Galactosemia
-Fructosemia
-Alpha 1 antitrypsin deficiency.
• 8. Hepatomegaly + Splenomegaly:
-Mucolipidosis
-Gaucher’s dis
-Niemann-Pick type A

35. 9. Predominant Neurological Symptoms:
a. Psychomotor delay:
-Aminoacidopathies
-Organic acidemias
-CNS storage diseases
b. Recurrent Reye :
-Urea cycle defect
-Systemic carnitine deficiency
c. Ataxia:
-Hartnup dis
-Urea cycle disorders
-Pyruvate decarboxylase deficiency
d. Extrapyramidal signs:
- Wilsons disease
e. Hypotonia :
- Zellweger synd
-Mitochondrial myopathies
-Muscle carnitine deficiency

36. INVESTIGATIONS:
• Metabolic investigations should be initiated as soon as
the possibility is considered.
• The outcome of treatment of many IEM especially
those associated with hyperammonemia is directly
related to the rapidity with which problems are
detected and treated.

37. • First line investigations (metabolic screen):
• The following tests should be obtained in all babies with suspected IEM.
• 1) Complete blood count: (neutropenia and thrombocytopenia
seen in propionic and methylmalonic academia)
• 2) Arterial blood gases and electrolytes
• 3) Blood glucose
• 4) Plasma ammonia (Normal values in newborn: 90-150 mg/dl or
64-107 mmol/L)
• 5) Arterial blood lactate (Normal values: 0.5-1.6 mmol/L)
• 6) Liver function tests,
• 7) Urine ketones,
• 8) Urine reducing substances,
• 9) Serum uric acid (low in molybdenum cofactor deficiency).

38. Suspected Metabolic disease
Plasma Ammonia
High Normal
Blood pH, CO2 Blood pH, CO2
Normal Acidosis Normal
PKU, Non Ketotic hyper
-glycinemia, Peroxisomal
No Ketosis disorders
Urea Cycle No Ketosis Ketosis with/without lactic acidosis
defect
Fatty acid Organic acidemias
oxidation defect Mitochondrial disorders

39. Normal Plasma Ammonia
No Acidosis
Phenyl ketonuria
Nonketotic hyperglycinemia
Galactosemia
Paroxysomal disorder

40. High Plasma Ammonia
No Acidosis
No Ketosis
UREA CYCLE DEFECT

41. Normal or High Plasma Ammonia
Acidosis
Ketosis
Organic acidemias, Mitochondrial disorders

42. Normal or High Plasma Ammonia
Acidosis
No Ketosis
Fatty acid oxidation defects

49. Categorization of neonatal IEM using metabolic screening tests:

52. • Second line investigations
(ancillary and confirmatory tests)
• These tests need to be performed in a targeted manner, based on
presumptive diagnosis after first line investigations:
• 1) Gas chromatography mass spectrometry (GCMS) of urine- for
diagnosis of organic acidemias.
• 2) Plasma amino acids and acyl carnitine profile: by Tandem mass
spectrometry (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 acidemias and aminoacidopathies.

53. • 4) Lactate/pyruvate ratio- in cases with elevated lactate.
• 5) Urinary orotic acid- in cases with hyperammonemia for
classification of urea cycle defect.
• 6) Enzyme assay: This is required for definitive diagnosis,
but not available for most IEM’s.
Available enzyme assays include:
-Biotinidase assay- in cases with suspected biotinidase
deficiency (intractable seizures, seborrheic rash, alopecia);
-GALT (galactose 1-phosphate uridyl transferase )
assay- in cases with suspected galactosemia (hypoglycemia,
cataracts, reducing sugars in urine).

54. • 7) Neuroimaging: MRI
• Some IEM may be associated with structural
malformations . Examples:
• Zellweger syndrome has diffuse cortical migration and
sulcation abnormalities.
• Agenesis of corpus callosum has been reported in Menke’s
disease, pyruvate decarboxylase deficiency and nonketotic
hyperglycinemia.
• Maple syrup urine disease (MSUD): brainstem and
cerebellar edema.
• Propionic & methylmalonic acidemia: basal ganglia signal
change.
• Glutaric aciduria: frontotemporal atrophy, subdural
hematomas.

55. • 8) Magnetic resonance spectroscopy (MRS): may be helpful in
selected disorders
• E.g. lactate peak elevated in mitochondrial disorders, leucine peak
elevated in MSUD.
• 9) Electroencephalography (EEG):
• Comb-like rhythm in MSUD,
• Burst suppression in Non Ketotic Hyperglycemia and holocarboxylase
synthetase deficiency.
• 10) Plasma very long chain fatty acid (VLCFA) levels: elevated in
peroxisomal disorders.
• 11)Mutation analysis when available.
• 12) CSF aminoacid analysis: CSF Glycine levels elevated in NKH.

56. TREATMENT:
• In most cases, treatment needs to be instituted empirically
without a specific diagnosis.
• The metabolic screen helps to broadly categorize the patient’s
IEM (e.g. urea cycle defect, organic academia,
congenital lactic acidosis etc), on the basis of which, empirical
treatment can be instituted

57. • Aims of treatment
• 1. To reduce the formation of toxic metabolites by decreasing
substrate availability (by stopping feeds and preventing endogenous
catabolism)
• 2. To provide adequate calories.
• 3. To enhance the excretion of toxic metabolites.
• 4. To institute co-factor therapy for specific disease and also
empirically if diagnosis not established.
• 5. Supportive care-
-Treatment of seizures (avoid sodium valproate –
may increase ammonia levels),
-Maintain euglycemia and normothermia,
-Fluid, electrolyte & acid-base balance,
-Treatment of infection,
-Mechanical ventilation if required.

58. • Management of hyperammonemia:
• 1) Discontinue all feeds. Provide adequate calories by intravenous glucose and
lipids. Maintain glucose infusion rate 8-10mg/kg/min. Start intravenous lipid
0.5 g/kg/day (up to 3 g/kg/day). After stabilization gradually add protein 0.25
g/kg till 1.5 g/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 250 mg/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 250 mg/kg
followed by 250-500 mg/kg/day.
-L-arginine (oral or IV)- 300 mg/kg/day (IV preparation not available in India)
-L-carnitine (oral or IV)- 200 mg/kg/day
• 4) Supportive care: Treatment of sepsis,seizures,ventilation.
Avoid sodium valproate.

59. • Acute management of newborn with
suspected organic acidemia:
• 1) The patient is kept nil per orally and intravenous glucose is provided.
• 2) Supportive care: hydration, treatment of sepsis, seizures, ventilation.
• 3) Carnitine: 100 mg/kg/day IV or oral.
• 4) Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-
2mEq/kg/hr)
• 5) Start Biotin 10 mg/day orally.
• 6) Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms of
methylmalonic acidemias)
• 7) Start Thiamine 300 mg/day (useful in Thiamine-responsive variants of
MSUD).

60. • Management of congenital lactic acidosis:
• 1) Supportive care: hydration, treatment of sepsis, seizures, ventilation.
Avoid sodium valproate.
• 2) Treat acidosis: sodium bicarbonate 0.35-0.5mEq/kg/hr
(max 1-2mEq/kg/hr)
• 3) Thiamine: up to 300 mg/day in 4 divided doses.
• 4) Riboflavin: 100 mg/day in 4 divided doses.
• 5) Add co-enzyme Q: 5-15 mg/kg/day
• 6) L-carnitine: 50-100 mg/kg orally.

61. • 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 100 mg
intravenously. If intravenous preparation not available, oral
pyridoxine can be given (15 mg/kg/day).
• 2) If seizures persist despite pyridoxine, give trial of biotin 10
mg/day and folinic acid 15 mg/day (folinic acid responsive
seizures).
• 3) Rule out glucose transporter defect: measure CSF and blood
glucose. This disorder responds to the ketogenic diet.

62. • 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 gases and urine ketones, blood ammonia Q6
hourly.
• 3) Some recommend starting medium chain triglycerides (MCT oil)
before starting breast feeds,
• 4) After 48 hours, repeat metabolic screen. Obtain samples for urine
organic acid tests.
• 5) The infant will need careful observation and follow-up for the first
few months, as IEM may present in different age groups in members
of the same family.

63. • Long term treatment of IEM
• 1) Dietary treatment: This is the mainstay of treatment in
phenylketonuria, maple syrup urine disease, homocystinuria,
galactosemia, and glycogen storage disease Type 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): ERT is 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 ERT is now
available.

64. 3) Cofactor replacement therapy:
The catalytic properties of many enzymes depend on the participation of non protein prosthetic
groups, such as vitamins and minerals,as obligatory cofactors.

65. PREVENTION

66. 1.Genetic counselling and prenatal diagnosis:
Most of the IEM are single gene defects, inherited in an autosomal recessive manner,
with a 25% recurrence risk.
• Therefore when the diagnosis is known and confirmed in the index case, prenatal
diagnosis can be offered wherever available for the subsequent pregnancies.
• The samples required are Chorionic Villous tissue or Amniotic fluid.
• Modalities available are:
-Substrate or metabolite detection: useful in phenylketonuria, peroxisomal
defects.
-Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick
disease, Gaucher disease.
-DNA based (molecular) diagnosis: Detection of mutation in proband/
carrier parents is a prerequisite.

67. • 2) Neonatal screening:
• Tandem mass spectrometry is used in some countries for
neonatal screening for IEM.
• Disorders which can be detected by TMS include
-Aminoacidopathies ( phenylketonuria, MSUD,
Homocystinuria, Citrullinemia,Argininosuccinic aciduria,
hepatorenal tyrosinemia),
-Fatty acid oxidation defects,
-Organic acidemias (glutaric aciduria, propionic acidemia,
methylmalonic acidemia, isovaleric acidemia).
• The cost 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.

68. • Reference:
1. Nelson’s textbook of Pediatrics, 20th ed.
2. Essential Pediatrics, 7th ed., O.P.Ghai.
3. Care of the Newborn, 6th ed., Meharban Singh.
4. Current Pediatric Diagnosis & Treatment
(CPDT), 22nd ed.
3. A Clinical Guide to Inherited Metabolic
Diseases, 2nd ed, Joe T. R. Clarke.
4. AIMS NICU Protocol 2014.
5. Indian Journal of Pediatrics, Vol 72- Apr,2005