This document discusses the diagnosis and presentation of inborn errors of metabolism. It begins by defining inborn errors of metabolism as inherited enzyme deficiencies that disrupt normal metabolism. There are three main types of clinical presentation: silent disorders, acute metabolic crises, and progressive neurological deterioration. For diagnosis, the document outlines important history and examination factors and provides guidance on initial laboratory tests and specialized investigations. Common metabolic presentations like metabolic acidosis and hypoglycemia are reviewed. Specific disorders are then discussed in terms of their typical diagnostic considerations and laboratory findings.

1. Diagnosis of
Metabolic Disorders
Prof. Imran Iqbal
Prof of Paediatrics (2003-2018)
Prof of Pediatrics Emeritus, CHICH
Multan, Pakistan

3. Inborn errors of metabolism
A group of diseases caused by
a defect in the activity of an enzyme
that affect a wide variety of
metabolic processes;
defective processing or transport of
amino acids, fatty acids, sugars or metals

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Inborn Errors of Metabolism
• An inherited enzyme deficiency leading to
the disruption of normal bodily
metabolism
• Impaired formation of a product normally
produced by the deficient enzyme
• Accumulation of a toxic substrate
(compound acted upon by an enzyme in a
chemical reaction)

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What is a metabolic disease?
• Garrod’s hypothesis
product deficiency
substrate excess
toxic metabolite
A
D
B C

6. Inborn Errors of Metabolism
• Uneventful delivery
• Normal birth weight
• No dysmorphic features
• Uneventful days /months /years
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7. Clinical Presentations
• Type 1: Silent Disorders
• Type 2: Acute Metabolic Crises
• Type 3: Neurological Delay or Deterioration
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8. Type 1: Silent Disorders
• Do not manifest life-threatening crises
• Untreated could lead to brain damage and
developmental disabilities
• Example: Wilson disease
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9. Type 2: Acute Metabolic Crisis
• Life threatening in infancy
• Children are protected in utero by maternal
circulation which provide missing product or
remove toxic substance
• Example: OTC (Urea Cycle Disorders)
MSUD
MMA
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10. Type 3: Progressive Neurological
Deterioration
• Examples
• Tay Sachs disease
• Gaucher disease
• Metachromatic leukodystrophy
• Phenylketonuria
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12. How do metabolic diseases present in
the neonate ??
• Acute life threatening illness
–encephalopathy - lethargy, irritability,
coma
–vomiting
–respiratory distress
• Seizures, Hypertonia
• Hepatomegaly , Hepatic dysfunction
• Dysmorphism,
• FTT (failure to thrive)
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13. Acute IEM Presentation
• Poor feeding
• Persistent vomiting
• Lethargy
• Convulsions
• Hypotonia or spasticity,
• Tachypnea /Kussmaul breathing /apnea,
• Coma

14. Chronic IEM Presentation
• Development delay
• FTT / Poor Weight gain
• Seizures resistent to anticonvulsant therapy
• Hypoglycemia
• Metabolic acidosis
• Cardiomyopathy / Peripheral muscle weakness
• Hepatosplenomegaly
• Cataracts
• Retinal abnormalities
• Dysmorphic features
• Unsual body odours

15. Types of
Metabolic Disorders
 Disorders of Acute or Progressive
Intoxication or Encephalopathy
 Disorders Associated with Energy
Deficiency
 Disorder of Biosynthesis &
Breakdown of Complex Molecules

16. Disorders of Acute or Progressive
Intoxication or Encephalopathy
 Organic acidemias
 Aminoacidurias
 Urea cycle defects
 Disorders of carbohydrate
intolerance (Galactosemia)

17. Disorders Associated with Energy
Deficiency
 Glycogen Storage disorders
 Gluconeogenesis dissorders
 Fatty acid Oxidation defects
 Mitochondrial deisorders

18. Disorders of Biosynthesis &
Breakdown of Complex Molecules
 Lysosomal storage disorders
 Peroxisomal disorders

19. Diagnosis of
Global Developmental Delay

20. Global Developmental Delay –
causes and differential diagnosis
 Perinatal factors
 Syndromes
 Cerebral malformations
 Progressive diseases
(degenrative, metabolic, storage)

21. Global developmental delay / Cerebral Palsy
due to Perinatal factors
 H/O Delayed cry / lethargy at
birth
 Microcephaly
 Hypertonia / Hypotonia
 Hyper reflexia

22. Global developmental delay due to
Cerebral malformations
 Delayed development
 Epilepsy
 Hypotonia
 Hyporeflexia
 Macrocephaly / normal

23. Global developmental delay due
to Syndromes
 Dysmorphic features
 Failure to gain weight
 Look at skull, face, limbs,
abdomen, skin, bones

24. Dysmorphic features
 Morphology
 Facial appearance
 Skin
 Bones
 Hair
 Extremities
 Complete physical examination

25. Dysmorphic Features

26. Low-set ears: >1/3rd of the ears lower than the line connecting the 2 pupils.
Low nasal bridge: common sign, which is also seen in Down.

28. Simian palmer crease

29. Global developmental delay due
to Progressive diseases
 Neuro Degenrative
 Neuro Metabolic
 Storage

30. Neuro Degenrative
 Grey matter
 White matter
 Basal ganglia

31. Neuro Metabolic
 Organic acidemias
 Aminoacidurias
 Fatty acid oxidation defects
 Mitochondrial disorders
 Peroxisomal disorders

32. Storage Disorders
 MPS
 Sphingolipidosis
 Coarse features
 Organomegaly
 Skeletal changes

33. Global developmental delay –
How to make a Specific Diagnosis
 Birth history
 Complete Physical Examination
 Neurological Examination
 Appropriate investigations

34. Diagnosis of
Metabolic Disorders

36. How do you recognize a metabolic
disorder ??
• Lethargy / Delayed development / Regression
• Simple laboratory tests
– Glucose, LFT, CPK
– Electrolytes, Anion gap
– BUN (blood urea nitrogen), Creatinine
– Venous Blood Gases,
– Urine Ketones, reducing substances
– Lactate, Ammonia,
• Specialized studies
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37. Special Investigations
• MRI Brain
• Plasma aminoacids
• Urine organic acids
• Plasma acylcarnitine profile
• DNA specific Metabolic panel / Neuro panel
• Whole exome sequencing
• Whole genome sequencing

39. GALACTOSEMIA
 HYPERCHLOREMIC METABOLIC
ACIDOSIS
 LIVER DISEASE
 CATARACTS
 HYPERBILIRUBINEMIA
 REDUCING SUBSTANCES

40. GLYCOGEN STORAGE DISEASE
(MUSCLE) Or FAOD
 WEAKNESS
 RHABDOMYOLYSIS

41. FATTY ACID OXIDATION DEFECT
 METABOLIC ACIDOSIS
 HYPOGLYCEMIA
 INAPPROPRIATELY LOW KETONES

42. NON KETOTIC
HYPERGLYCINEMIA
 ENCEPHALOPATY < 24 HRS OLD,
 BURST SUPPRESSION EEG
 KETONES NEGATIVE

43. ORGANIC ACIDEMIA
 WIDE ANION GAP
 METABOLIC ACIDOSIS
 KETONURIA
 HYPERAMMONEMIA

44. Organic Acidemia

45. UREA CYCLE DISEASE
 RESPIRATORY ALKALOSIS
 HYPERAMMONEMIA

46. Lysosomal Storage Disorder
(MPS)
 DEVELOPMENTAL REGRESSION
 SKELETAL DYSPLASIA
 ORGANOMEGALY
 VARIABLE CLOUDY CORNEA

47. Lysosomal Storage Disorder
(Glycolipids)
 DEVELOPMENTAL REGRESSION
 ORGANOMEGALY
 CHERRY RED MACULA

48. Glycogen Storage Disease
 HYPOGLYCEMIA
 HEPATOMEGALY

49. HYPERCHLOREMIC
METABOLIC ACIDOSIS
LIVER DISEASE
CATARACTS
HYPERBILIRUBINEMIA
REDUCING SUBSTANCES
Selected Presentations/Diagnostic Considerations
INFANT/CHILD WITH
SUSPECTED
METABOLIC DISEASE
KETONES NEGATIVE
ENCEPHALOPATY < 24 HRS
OLD, BURST SUPPRESSION
EEG
METABOLIC
ACIDOSIS
HYPOGLYCEMIA
INAPPROPRIATELY LOW
KETONES
RESPIRATORYALKALOSIS
HYPERAMMONEMIA
FATTYACID
OXIDATION
DEFECT
ORGANIC
ACIDEMIA
UREA CYCLE
DISEASE
GALACTOSEMIA
NON KETOTIC
HYPERGLYCINEMIA
HYPOGLYCEMIA
HEPATOMEGALY
GLYCOGEN
STORAGE
DISEASE (LIVER)
DEVELOPMENTAL
REGRESSION
SKELETAL DYSPLASIA
ORGANOMEGALY
VARIABLE CLOUDY CORNEA
Lysosomal storage
(MPS)
WIDE ANION GAP
METABOLIC ACIDOSIS,
KETONURIA,
HYPERAMMONEMIA
DEVELOPMENTAL
REGRESSION
ORGANOMEGALY
CHERRY RED MACULA
Lysosomal storage
(glycolpids))
WEAKNESS
RHABDOMYOLYSIS
GLYCOGEN
STORAGE
DISEASE (MUSCLE)
Or FAOD

50. Common Metabolic Presentations
• Metabolic acidosis
• Hyperammonemia
• Hypoglycemia

51. Finding MSUD OA UCD DCM FAO
Metabolic Acidosis ± ++ - ± ±
Respiratory Alkoalosis - - + - -
Hyperammonemia ± + ++ - ±
Hypoglycemia ± ± - + +
Ketones A/H H A A/H A/L
Lactic Acidosis ± ± - + ±

52. MSUD: Maple syrup urine disease, - usually absent
OA: Organic academia, ± sometimes present
UCD: Urea cycle disorders, + usually present
DCM: Disorders of carbohydrate
metabolism
++ always present
FAO: Fatty acid oxidation A appropriate
H inappropriate high
L inappropriate low

53. Neonatal Encephalopathy –
metabolic causes
 Organic Acidemias
 Urea cycle defects
 MSUD
 Fatty acid Oxidation defects

54. Approach to sick Neonate with
Hyperammonemia
Hyperammonemia
Metabolic
Acidosis
No acidosis
Lactic
acidosis
Abnormal urine
Organic acids
Abnormal
Plasma amino
acids
Early onset
sepsis
and normal
amino acids

55. Suspected
metabolic
disorder
in a newborn

60. Thankyou