1. Inborn errors of metabolism (IEM) are genetic disorders caused by defects in metabolic pathways. 2. IEM are individually rare but collectively affect around 1 in 1000 people. Diagnosis is important for treatment, genetic counseling, and screening in subsequent pregnancies. 3. Clinical suspicion is paramount in identifying potential IEM. Presentations can include vomiting, lethargy, seizures, and developmental delay. Initial emergency management focuses on stabilizing blood glucose, acid-base status, and hemodynamics while diagnostic tests are pending.

1. Inborn Errors of Metabolism
Ehab Zahran

2. Introduction:
IEM are disorders in which there is a block at some
point in the normal metabolic pathway caused by a
genetic defect of a specific enzyme.

3.  IEM are individually rare, but collectively >500
conditions, at an incidence of 1:1000.
 Diagnosis is important not only for treatment, but
also for genetic counselling and antenatal
diagnosis in subsequent pregnancies.
Introduction: (Cont’d)

4. Classification of IEM:
OA UCD AA FAO Carbohydrate Mitochondrial
GA OTC PKU MCADD Galactosaemia MELAS
IVA ASA Tyrosinemia CPT1D Fructosaemia MERRF
MSUD Citrullinaemia Homocystinuria LCHCDD Pyruvate DD

5. Metabolic Referrals to CATS: (Jan 19 – Feb 21)
DKA
Metabolic
Diseases
Electrolyte
Disturbances
60%
30%
10%

6. Metabolic Referrals (excluding DKA) to CATS:
8
12
10
6
9
18
10 10
0
2
4
6
8
10
12
14
16
18
20

7. When to suspect a Metabolic disorder?

8. When to suspect a Metabolic disorder?

9. A high index of suspicion is
paramount!

10. Differentials: What if not Metabolic?

11. Case 6 days old child
Vomiting for >24 hrs Lethargy
Blood gas:
pH 7.0
PCO2 3
HCO3 8
BE -16
Glu 2.5
Lac 3.5
What will be
your first action?
Seizures

12. History
Examination Investigations

13. History: 3x2
 Poor feeding/Vomiting.
 Symptoms accompany start/change in diet.
 Seizures.
 Developmental delay.
 Parental consanguinity.
 FH of MR or unexplained deaths.

14. Examination: Patterns of presentation

15. Examination: Clinical pointers
Clinical pointer Disorder
Coarse facies Lysosomal disorders
Cataract Galactosemia - Zellweger
Cherry red spot Lipidosis
Hepatomegaly Storage disorders - UCD
Eczema/Alopecia Biotinidase deficiency
Abnormal kinky hair Menke disease
Hypopigmentation Phenylketonuria
Retinitis pigmentosa Mitochondrial disorders

16. Examination: Peculiar odours
Peculiar odour Disorder
Sweaty feet GA type II - IVA
Boiled cabbage Tyrosinaemia
Swimming pool Hawkinsuria
Maple syrup MSUD
Mousy/Musty Phenylketonuria
Rotting fish Trimethylaminuria
Tomcat urine Multiple carboxylase deficiency

17. ❓ Quick Quiz ❓
🤔 The only AA disorder presenting during the
neonatal period?

18. Investigations: First line
*AG = [Na + K] - [Cl + HCO3] (N <12 mmol)
Blood Urine
Glucose Ketones
Ammonia Reducing substances
ABG (AG*) Uric acid
FBC - U&E - LFT
Lactate - Pyruvate

19. Investigations: First line (Cont’d)
Glucose
Lactate
Ketones
AA/OA
Needs urgent treatment Help diagnosing

20. Investigations: First line (Cont’d)
Acidosis Ketosis Ammonia Diagnosis
- + - MSUD
+ + +/- OA - Mitochondrial
+ +/- - Lactic acidosis
- - + UCD
+ +/- - FAO defect
- - -
NK Hyperglycinemia
PKU - Galactosemia

21. ❓ Quick Quiz ❓
🤔 IEM that is commonly associated with
Respiratory alkalosis?

22. Investigations: Second line
Test Disorder
GCMS OA
TMS OA - UCD - FAOD
HPLC OA
L:P High lactate
U. Orotic acid UCD
Enzyme assay Biotinidase - GALT

23. Investigations: Second line (Cont’d)
Test Disorder
MRI MSUD - Zellweger - GA
MRS Mitochondrial
EEG MSUD - NKH
VLCFA Peroxisomal
CSF AA ⬆️ Glycine in NKH

24. Management:
A. Supportive therapy.
B. Specific therapy.
C. Long-term management.
D. Prevention.

25. “
In most cases, treatment needs to
be started empirically before
reaching a specific diagnosis.

26. Management: Supportive Therapy
Problem Action
Hypotension Volume expansion +- Vasoactive
Metabolic acidosis Volume expansion +- NaHCO3
Hemodynamic instability NBM + D10% [GIR >7]
Hyperglycemia Insulin
Refractory seizures Pyridoxine - Biotin - Folinic

27. Management: Specific therapy
Problem Action
Hyperammonaemia Nitrogen scavengers - CVVH
Organic acidaemia L-Carnitine - Biotin - Thiamine - B12
Congenital lactic acidosis Thiamine - Riboflavin - L-Carnitine

28. Management: Long-term management
 Dietary treatment
 Enzyme replacement therapy
 Co-factor replacement therapy

29. Management: Long-term treatment (Cont’d)
MSUD Thiamine
Pyruvate dehydrogenase def.
Biotinidase deficiency Biotin
Propionic acidaemia
Glutaric acidaemia Riboflavin
Respiratory chain disorders
Homocystinuria Pyridoxine - Folic - B12
Methylmalonic acidaemia Hydroxycobolamin
Hartnup disease Nicotinic acid

30. Prevention:
 Genetic counselling:
* Chorionic villous sampling
* Amniocentesis
 Neonatal screening:
* Tandem mass spectrometry (TMS)
 Management of an asymptomatic sibling

31. Prevention: Genetic counselling
 Advanced maternal age (>35 years).
 Positive maternal serum screening.
 FH of metabolic disorder, MR or birth defect.
 Prior pregnancy with a chromosomal disorder.
 Fetal anomalies by sonogram.
 Recurrent abortions or stillbirth.
 Consanguinity.

32. Prevention: Neonatal screening
CF
SCD CHT
PKU
IVA
MCADD
GA1
HCU
MSUD

33. Management: Asymptomatic sibling
 At birth : Metabolic screen -> Oral D10% feeds
 At 24 hrs : Repeat metabolic screen -> Breast feeds
 At 48 hrs : Repeat metabolic screen -> Urine OA
 Close follow-up for a few months

34. Case 6 days old child
Vomiting for >24 hrs Lethargy
Blood gas:
pH 7.0
PCO2 3
HCO3 8
BE -16
Glu 2.5
Lac 3.5
How would you
manage?
Seizures

35. Emergency Management
1. ABC.
2. Bloods (Glucose + Ammonia + BG).
3. Correct hypoglycemia/acidosis/hypotension.
4. D10% + NBM.
+-
Hyperammonaemia : Scavengers.
OA : L-Carnitine.

36. The most important step in the diagnosis of IEM is
clinical suspicion.
You don’t need to know what the problem is to
make a big difference.
Take-Home Message
⏳ Time = Brain ⏳
The diagnosis can wait..

37. References

38. Thank You