Approach to Inborn Errors of Metabolism for an Endocrinologist. Presented at ESICON 2018 in Bhubnewshwar.

1. INBORN ERRORS OF
METABOLISM
DR. OM J LAKHANI
MD, DNB (ENDO)
CONSULTANT ENDOCRINOLOGIST, ZYDUS HOSPITAL, AHMEDABAD

2. OUTLINE OF TALK
1. Introduction to Inborn errors of metabolism
2. Discussion of a Case of IEM in Neonate
3. Take home messages

3. INTRODUCTION

4. Garrod’s Hypothesis

5. Quick Quiz
Which disease is Dr. Garrod famous for ?
Hint: Something to do with ‘Diapers’

6. Answer-
Dr. Archibald Garrod is famous for
Alkaptonuria - this is the first time
Mendelian laws were applied to a human
disease
His father Dr. Alfred Garrod is famous for
discovering that abnormal uric acid
metabolism lead to Gout !

7. CLASSIFICATION OF IEM
1. Disorders of intermediary metabolism: eg-
Disorder of Fatty Acid oxidation
2. Disorders of biosynthesis and breakdown of
complex molecules: eg- Lysosomal storage disorders
3. Disorders of neurotransmitter metabolism. eg:-
pyridoxine-dependent seizures

8. SPECIALITIES INVOLVED
1. Pediatrics/Neonatology
2. Endocrinology
3. Genetic medicine
3. Neurology
4. Gastroenterology and Hepatology
5. Haematology
6. Cardiology

10. 1. Hypoglycemia +/- Metabolic acidosis
2. Short stature +/- Dysmorphic features
3. Adrenal insufficiency
4. Dyslipidemia
5. Atypical Genitalia
6. Other Endocrine involvement

11. CLINICAL CASE

12. 16 month old female child
Parents are first cousins of each other
(Consanguinity)
CLINICAL CASE

13. Clinical Pearl
Most IEM are autosomal recessive, hence
history of Consanguinity is very
important.

14. The child was normal at birth
However symptoms precipitated after an
episode of gastroenteritis
CLINICAL CASE

15. Clinical Pearl
An Infant born with IEM - will be
NORMAL at birth and become
symptomatic LATER.

16. Clinical Pearl
Sometimes IEM is precipitated by
introduction of certain diet.

17. The Child worsened and brought to
hospital in an unconscious state
On evaluation she had Hypoglycemia
with RBS of 35 mg/dl
CLINICAL CASE

18. The parents give a history that the child
had not taken either breast milk or any
complimentary feed for nearly 24 hours
CLINICAL CASE

19. Clinical Pearl
The timing of the hypoglycaemia gives an
important clue to possible aetiology

21. History of two previous Unexplained
Sibling deaths at around the same age.
CLINICAL CASE

22. Clinical Pearl
History of Sudden Infant deaths in
siblings is again an important point in
history.

23. IEM WITH HISTORY OF ‘SIDS’
1. Fatty acid oxidation disorder- most common
2. Organic acidemias
3. Disorder of ammonia acid metabolism
These disorder can be screened on neonatal
blood screening panel

24. Ideally all of these must be screened with
Newborn screening.

25. SAMPLE COLLECTION
Safe Puncture sites

26. LABS

27. A Critical sample drawn during the
hypoglycaemia reveals
Insulin and C-peptide - suppressed
CLINICAL CASE

28. Clinical pearl
Insulin levels <2 mIU/ml and
undetectable C-peptide are suggestive of
Insulin independent hypoglycaemia

29. Urine ketone was negative
Beta-hydroxybutyrate was <2.5 mmol/l
which was inappropriately low for the
situation
CLINICAL CASE

30. Clinical Pearl
Hypoglycemia WITHOUT ketoacidosis
suggests two very important conditions
a) Hyperinsuliemia
b) Disorder of Fatty acid oxidation

31. Quick Quiz
Q. Which Disorder of fatty acid oxidation
presents with Congenital
hyperinsulinemia ?

32. Answer
Short-chain 3-hydroxyacyl-CoA
dehydrogenase deficiency (SCHADD)

33. Proven SCHAD mutations have recurrent
hypoglycemia that is associated with
diazoxide-responsive hyperinsulinism

34. Quick Quiz
Q. So if you were to suffer from
hypoglycemia, would you like to develop
hypoglycaemia WITH ketoacidosis or
WITHOUT ketoacidosis ?

35. CLINICAL PEARL
Hypoglycemia WITHOUT ketoacidosis /
lactic acidosis produces more
neurological damage than hypoglycaemia
WITH ketoacidosis / lactic acidosis
because ketones & Lactate act as alternate
source of fuel for the brain.

37. ABG analysis was suggestive of metabolic
acidosis (High Anion gap)
CLINICAL CASE

39. No elevated ammonia
Mildly elevated lactate.
Uric acid and Creatine kinase were
elevated
CLINICAL CASE

40. CLINICAL PEARL- COLLECTION
OF SAMPLE FOR AMMONIA
Should be obtained without a tourniquet.
2 hours of fasting
Use EDTA for sampling
The sample should be free-flowing
The tube should be placed on ice for transport to the laboratory
and analyzed immediately.
If the plasma ammonia concentration is >100 micromol/L (1.7
mcg/mL), the measurement should be repeated immediately.

41. Investigations
Routine
Investigations/Screening
tests
Specialised biochemical
testing
Genetic testing

42. IMPORTANT ROUTINE TESTS
NOT TO MISS OUT
1. Ammonia
2. Urine ketones and Beta-hydroxybutraye
3. Lactate
4. Plasma glucose
5. CSF

43. It is important to order Amino acid
quantification and especially glycine
levels in CSF

44. Store (Frozen) extra urine sample
collected during the episode - this may be
particularly useful.

45. EMERGING DIAGNOSTIC PATTERNS
FROM ROUTINE INVESTIGATIONS

46. Hypoglycemia - Present
Metabolic Acidosis - +/-
Ketones - Absent
Ammonia - +/-
Lactate - +/-
Disorder of Fatty Acid oxidation

47. Clinical Pearl
Hypoglycemia with Absence of Ketosis is
THE characteristic of Disorder of fatty
acid oxidation

48. Hypoglycemia - +/-
Metabolic Acidosis - ++
Ketones - High
Ammonia - +
Lactate - +/-
Organic acidemias

49. Clinical Pearl
Organic acidemias are important IEM
presenting during neonatal period

50. Clinical Pearl
Presentation is very similar to disorder of
fatty acid oxidation

51. Clinical Pearl
Biochemical markers help differentiate,
Increased ammonia and metabolic
acidosis are classical of Organic
academia while hypoglycaemia may or
may not be present.

52. Hypoglycemia - +/-
Metabolic Acidosis - +/-
Ketones - Absent/High
Ammonia - +/-
Lactate - +/-
Maple syrup urine disease (MSUD)

53. Clinical Pearl
MSUD is the only amino acid disorder
(aminoacidopathy) presenting during the
neonatal period

54. Hypoglycemia - Absent
Metabolic Acidosis - Absent
Ketones - Absent
Ammonia - ++
Lactate - Absent
Urea cycle disorder

55. Increase
Ammonia
Normal
Ammonia
Metabolic
acidosis
Organic
Acidemia
Disorders of
Amino acid
metabolic
No Metabolic
acidosis
Urea cycle
disorder
-

56. Clinical Pearl
Severe Hyperammonia WITHOUT
metabolic acidosis differentiates Urea
cycle disorder from Organic acidemias

57. Quick Quiz
Q. Why does Hyperammonia lead to CNS
symptoms ?

58. Increase ammonia —> increase
glutamine —> increase GABA —>
inhibitory neurotransmitter —> stops
everything in brain

59. Clinical pearl
Hyperammonia may also be a part of
liver failure which accompanies many of
these IEM which presently acutely.

60. BACK TO THE CASE

61. STORY SO FAR FROM
BIOCHEMISTRY
Hypoglycemia (with suppressed insulin in
critical sample)
Metabolic acidosis
Ammonia- not elevated
Inappropriately low ketosis
CLINICAL CASE

62. Clinical pearl
Narrow down the DD to Disorder of Fatty
acid oxidation

63. Free Fatty acid levels were elevated
CLINICAL CASE

64. SPECIALISED BIOCHEMICAL
TESTS

65. A large number of metabolites can be
tested nowadays using Tandem mass
spectrometry (TMS)

66. Two profiles which are especially useful
a) Acylcarnitine profile
b) Amino acid profile

67. Acylcarnitine profile helps identify fatty
acid and organic acid

68. Elevation of Medium chain Acylcarnitine
C6-C10 is classically suggestive of Fatty
acid oxidation disorder
While Acylcarnitine C3 or C5 are
typically elevated in Organic acidemias

69. In this case the acylcarnitine profiling
reveals elevated C6-, C8-, C10-, and C10:1-
species with an increased C8/C10:1 ratio
This was consistent with Medium-chain
acyl-CoA dehydrogenase deficiency
(MCADD)
CLINICAL CASE

70. Further diagnosis can be confirmed with
genetic testing.

71. TAKE HOME MESSAGES

72. A neonate normal at birth but worsening
after an intercurrent illness/Specific
dietary substance
with
History of Unexplained sibling deaths
and parental Consanguinity should alert
a clinician to a possibility of IEM.

73. ABG analysis, Plasma glucose levels,
Ammonia, Ketones and lactate levels can
help narrow down the differentials of
various IEM which present acutely
during neonatal period.

74. Hypoglycemia with Relative hypoketosis
is characteristic of Disorder of fatty acid
oxidation

75. Elevated ammonia with Metabolic acid is
often indicative of Organic acidemias

76. Plasma acylcaritine profiles can help
confirm the diagnosis of Disorder of fatty
acid oxidation and help in sub typing it
and also differentiating it from Organic
acidemias.

77. THANK YOU.