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