14. Paeds

Question 1

Common clinical features of IEM in infancy + childhood

Answer 1

Acidosis
CNS dysfunction; irritability, coma, hypotonia, seizures, etc
Failure to thrive
Frequent vomiting + other GI probs
Hypoglycemia
Unusual odour

Question 2

Essential basic lab tests for 1st line investigation of IEM

Answer 2

FBC
ABG - acid-base status

Serum;

• U&E: electrolytes, urea, creatinine, bicarbonate
• LFTs
• CK
• uric acid

Plasma;

• glucose
• ammonia
• lactate

Urine;
- ketones

Question 3

Second line investigations for investigation/diagnosis of IEM

Answer 3

Bloodspot/plasma acylcarnitines
Galactose 1-phosphate uridyl transferase (RBCs)

Plasma;

• amino acids
• very long chain fatty acids (VLCFAs)

Urine;

• amino acids
• organic acids
• orotic acid
• reducing substances/sugar TLC
• glycosaminoglycans (GAGs)

Question 4

Give example of cofactor supplementation as treatment of IEM

Answer 4

E.g. Classical Homocystinuria

Conversion: homocysteine > cystathionine reqs cystathionine B-synthase
- peroxidase = co factor of cystathionine B-synthase

Homocystinuria sufferers divided into pyroxidine responsive/unresponsive;
- supplementation in responsive = reduced homocysteine in plasma = improved symptoms

Question 5

List the individual IEM disorders examined

Answer 5

Amino acid disorders;

• phenylketonuria (PKU)
• maple syrup urine disease (MSUD)

Urea cycle defects

Organic acid disorders

Fatty acid oxidation defects;
- medium chain acyl-CoA dehydrogenase deficiency (MCADD)

Galactose metabolism defects;
- galactosemia

Question 6

List the 3 deficiencies of galactose metabolism

Answer 6

1. galactokinase
2. galactose-1 phosphate uridyl transferase (gal-1 PUT)
3. UDP-galactose 4’ epimerase

Question 7

Clinical features of untreated PKU

Answer 7

Appear normal to 6 months;

• microcephaly
• severe mental retardation
• agitation + regression
• seizures
• other neuro abn
• blond hair, blue eyes
• ‘mousy’ odour

Question 8

Clinical presentation of MSUD

Answer 8

Lethargy
Feeding difficulties/vomiting
Progressive CNS dysfunction-poor tone, seizures, coma, apnoea
May be fatal/ lead to permanent neuro abn + severely impaired mental development

Question 9

Biochemical abn of MSUD

Answer 9

Metabolic ketoacidosis (not major feature)
Ketosis
Hypoglycemia (uncommon)
Urine + sweat may have distinct sweet odour of maple syrup

Question 10

3 methods of diagnosis for MSUD

Answer 10

1. Positive dinitrophenylhydrazine screen test for ketoacids in urine (old blood spot)
2. Increased branched chain aa in plasma (val/leu/isoleu) + alloisoleu presence;
   - ion exchange HPLC
3. Increased branched chain ketoacids + hydroxyacids in urine (e.g. 2 ketoisocaproic acid (toxic) + 2-OH-isovaleric acid);
   - urine org acid analysis by GC-MS

Question 11

6 enzyme deficiencies in UC disorders

Answer 11

Carbamylphosphate synthetase I (CPS1)
Ornithine transcarbamylase (OTC)
Argininosuccinate synthetase
Argininosuccinate lyase
Arginase
N-acetylglutamate synthetase

Question 12

Clinical features of neonate with UC defect

Answer 12

Well at birth - onset within 48 hours
Lethargy
Poor feeding
Hyperventilation (NH3 = resp stimulant = resp alkalosis)
Seizures
Progressive encephalopathy with deepening coma

Question 13

Clinical features of infant/child with UC defect

Answer 13

FTT
Feeding problems, esp avoidance of protein containing food
Vomiting
Chronic neuro symptoms
Episodic encephalopathy
Ataxia + seizures

Question 14

Clinical features of adolescents/adults with UC defect

Answer 14

Chronic neuro/psychiatric problems

Recurrent encephalopathy associated with high protein intake, catabolism or stress

Question 15

Diagnosis of UCD

Answer 15

Plasma + urine analyses
Urine orotic acid analysis;
 - direct spectrophotometric
 - part of urine org acid analysis GC-MS
Definitive: DNA/enzyme analysis in app tissue

Question 16

Treatment in acute UCD

Answer 16

Stop protein intake
Remove ammonia (drugs/extracorporeal detox)
Replenish UC intermediates with arganine + citrulline (depends on enzyme def in)
Fluid replacement

Question 17

Treatment in long term UCD

Answer 17

Maintain anabolic state
Limit protein intake
Arginine/citrulline supp as app
Remove ammonia;
 - sodium benzoate
 - sodium phenylbutyrate
Vitamins + trace elements
Consider liver TP

Question 18

Clinical presentation of fatty acid ox disorders

Answer 18

Ppted by fasting
Varies with individual condition

Hypoketotic hypoglycemic coma
Liver disease
Muscle weakness + rhabdomyolysis (increased plasma CK)
Cardiac: arrhythmias, cardiomyop, cardiac failure
Neuro: lethargy, coma, hypotonia, seizures
SIDs

Question 19

Abn biochemical findings in fatty acid ox disorders

Answer 19

Hypoglycemia
Inapp low plasma + urine ketones
Metabolic acidosis (lactic acidosis)
Increased ratio FFAs:3-hydroxybutyrate in plasma (lipolysis working but not ketogenesis)

Question 20

Diagnosis fatty acid ox disorders

Answer 20

Blood/urine collected during illness (when hypoglycemia)
Analysis of;
- acylcarnitine in blood spot/plasma by MS/MS
- organic acids in urine by GC/MS
Confirmation: mutation/enzyme assays

Question 21

MCADD diagnosis

Answer 21

Bloodspot/plasma acylcarnitine profile MS/MS;

• increased hexanoylcarn C6 + octanoylcarn C8
• increased ratio C8:C10
• increased C8 = screening blood spot newborns

Urine org acids GC/MS;

• increased C6-C10 dicarboxylic acids (adipic, suberic, sebacic acids)
• presence suberylglycine + hexanoglycine

Question 22

Clinical features classical galactosemia

Answer 22

1st week of life when milk feeding established

Vomiting + diarrhea
FTT
Jaundice/disturbed liver function
Sepsis>death from liver/renal failure
Bilateral cataracts

Question 23

Diagnosis of classical galactosemia

Answer 23

Positive urinary reducing substances (clinitest) spot test
Increased galactose in urine sugar thin layer chromatography (TLC);
- false neg if lactose free diet/severe vom
Definitive: measure gal-1-PUT RBC activity;
- false neg e.g. blood tfn
Screening type assays for RBC gal-1-PUT e.g. Beutler test = rapid results