Inherited metabolic disorders

Question 1

Fair hair, fair skin, blue eyes
Developmental delay, then severe IQ impairment
Musty smell

Answer 1

Phenylketonuria
Phenylalanine hydroxylase deficiency = phenylalanine build-up in blood
Ix: Blood phenylalanine
Rx - dietary avoidance

Question 2

Hyperammonaemia >200 (>300 lethal)
Tachypnoea w/ neuro signs (encephalopathy)
Respiratory alkalosis

Answer 2

Urea cycle disorders
Deficiency in one of 6 enzymes in urea cycle = ammonia builds up in blood, which is highly neurotoxic
Need free flowing venous sample delivered to lab on ice
Rx - low protein diet + remove ammonia (sodium benzoate or dialysis)

Question 3

Conjugated hyperbilirubinaemia (jaundice)
Sepsis
Cataracts

Answer 3

Galactosaemia (GA1)
Deficiency in Gal-1-PUT = raised Gal-1-phosphate levels causing liver + kidney disease
Tx: Galactose-free diet

Question 4

High blood immune reactive trypsin (IRT)

Answer 4

Cystic fibrosis

Question 5

Sweet / cheesy smelling urine
Sweaty feet
Canadian

Answer 5

Maple syrup urine disease (MSUD)
Impaired metabolism of branched chain amino acids (isoleucine, leucine, valine) = build up of a.a. in blood + urine
Rx: Avoid causative a.a.

Question 6

Hypoketotic hypoglycaemia - hypoglycaemic seizures, coma, SIDS
Can present with acute liver failure + hepatomegaly
Low ketones
Tandem MS for acylcarnitine

Answer 6

Fatty acid B-oxidation disorder (MCADD)
Deficiency of MCAD = unable to break down fatty acids to ketones during hypoglycaemia
Ix: Tandem MS for Acylcarnitine
Rx: Feed continuously to prevent hypoglycaemia

Question 7

Hypoglycaemia + lactic acidosis
Floppy baby
Liver + kidney enlargement

Answer 7

Glycogen storage disease (incl. Von Gierke’s)

Reduced glycogen metabolism

Question 8

Defective ATP production
Affects high energy organs - CNS, muscle, heart (multi-system disease)
Chronic muscle weakness
Elevated lactate + CK
Muscle biopsy diagnostic - ragged red fibres

Answer 8

Mitochondrial disorders (incl. Barth (at birth), MELAS (5-15yo), Kearns-Sayre)

Question 9

Dysmorphic
Cardiomyopathy
Abnormal fat distribution
Transferrin glycoforms

Answer 9

Glycosylation disorder

Question 10

Very long chain fatty acids
Dysmorphic
Hypotonic babies + early blindness in infants

Answer 10

Peroxisomal disease

Peroxisomes responsible for degrading very long chain fatty acids

Question 11

Very fair skin + brittle hair
Previous convulsions
Inability to walk
Pyridoxine (B6) supplements can help)

Answer 11

Homocystinuria (HCU)

Cystathionine synthetase deficiency needed for methionine (a.a.) processing

Question 12

Unusual smelling urine
Metabolic acidosis 
Neutropenia
Trunk hypotonia, limb hypertonia
Myoclonic jerks

Answer 12

Organic aciduria (e.g. MSUD, IVA)
Impaired metabolism of branch chain amino acids (leucine, isoleucine, valine)

Question 13

Guthrie Spot conditions

Answer 13

Screens for 9 rare but serious diseases day 5-8

• SCD, CF (by IRT), congenital hypothyroidism (by TSH)
• IMDs (MCADD (by tandem MS for acylcarnitine), PKU (by serum phenylalanine), MSUD (by urine organic acids), IVA (by urine organic acids), GA1 (by raised galactose + Gal-1-P), HCU) “PIMM HG”

Question 14

Cherry red spot

Answer 14

Fabry’s disease

Question 15

Main IMDs to know

Answer 15

PKU
GA1 (galactosaemia)
Organic aciduria (e.g. MSUD, IVA)
HCU
Urea cycle defects