IMDs

Question 1

Define IMDs (inherited metabolic diseases)

Answer 1

Inherited metabolic diseases (IMDs) = a group of diseases that manifest as a result of dysfunction of a single or multiple enzymes in one or more of the metabolic pathways

Question 2

Why is it important to diagnose IMDs as early as possible?

Answer 2

Early diagnosis of IMDs can potentially enable life saving treatment and prevent long term morbidity

Question 3

What are the likely (paediatric) presentations of IMDs?

Answer 3

• In all neonates with unexplained overwhelming progressive disease after normal pregnancy and delivery
• All children who are acutely unwell with decreased consciousness particularly if preceded by fasting, fever or vomiting
• Unexplained neurology, hypoglycaemia, acidosis or decreased consciousness
• Unexplained instances of – cardiomyopathy, liver disease, myopathy, CNS manifestation, dysmorphia and in a metabolic emergency
• Family history of unexplained disease or premature deaths

Question 4

What is screened for in the new born heel prick test?

Answer 4

• Sickle Cell Anaemia
• Cystic Fibrosis
• Hypothyroidism
• Phenylketonuria
• MCADD

Question 5

What does PKU stand for?

Answer 5

Phenylketonuria (PKU)

Question 6

Outline normal phenylalanine (Phe) metabolism

Answer 6

Phe = essential amino acid

Normal Metabolism:

• Phe is metabolised by PAH (phenylalanine hydroxylase) to tyrosine
• Tyrosine is a key amino acid – important for the synthesis of catecholamines, melanin and other metabolites

Question 7

Outline what happens in PKU

Answer 7

In PKU PAH is not functional - consequence = increase in phe, decrease in tyr

Note - there is a gradation (it is not a switching off mechanism)

Question 8

What is the cause of most of the sympmtoms of PKU?

Answer 8

Most of the effects are due to the decrease in tyrosine (but also the increase in Phe which can cross the BBB
and competes with try and serotonin in the brain
causing further issues – severe neuro deficits, particularly when caught late)

Question 9

What are the major treatments of PKU

Answer 9

• Reduce phe levels – prevent exogenous sources (i.e. no protein – 3-12 g of protein)
• Special protein supplements to provide full diet

Question 10

How can PKU affect the foetus?

Answer 10

Phe can cross the placenta therefore it is recommended to have phe levels < 360 µmol/L

Hyper-pheylalaninaemia can cause foetal abnormalities (similar to foetal alcohol syndrome)

• Low weight at birth
• Congenital heart defects
• Digestive tract defects
• Osseous arrangements
• Microcephaly
• Handicap of intellectual development (Maternal PKU syndrome)

Question 11

What does MCADD stand for?

Answer 11

MCADD (medium chain acyl-CoA dehydrogenase deficiency)

Question 12

What is the cause of MCADD?

Answer 12

Congenital – problem is with medium-chain acyl coenzyme A dehydrogenase (MCAD) (due to mutation)

Question 13

What is the treatment for MCADD?

Answer 13

No fasting

Question 14

OUtline the pathogenesis of MCADD

Answer 14

(1) Attempt to break down fat
(2) Defect in MCADD prevent metabolism of medium chain fatty acids → Toxic build-up
(3) Use glucose as an alternative energy source
(4) Hypoglycaemia
(5) Lack of energy supplied

Question 15

What are the two major glycogen storage disorders?

Answer 15

• GSD 1 – most common, mainly hepatopathic + hypoglycaemia

- GSD III – also common – mixed heptaopathic and myopathic + hypoglycaemia

Question 16

What is the main therapies for glycogen storage disorders?

Answer 16

Equent meals, overnight & continuous NG feeding/uncoocked cornstarch

Question 17

Which two sites do glycogen storage disorders present?

Answer 17

Liver & muscle (skeletal)