Common Inborn Errors of Metabolism

Question 1

What is the role of the hepatic enzyme Phenylalanine hydroxylase?

Answer 1

This enzyme that catalyses the hydroxylation of Phenylalanine’s aromatic side chain, to produce tyrosine.

Question 2

What are symptoms of PKU?

Answer 2

Microcephaly, mental retardation, seizures, autistic-like behaviour, fair/light complexion, and a musty odour to the urine

Question 3

What is PKU’s pattern of inheritance?

Answer 3

Autosomal recessive

Question 4

How do you screen for PKU?

Answer 4

Because there are over 800 mutations in phenylalanine hydroxylase, it’s difficult to screen for genetically
PKU is tested for in new-borns with a blood spot - within the first few days of life, phenylalanine levels will rise to 500-2500 umol/L, and phenylketones will be elevated in urine and blood

Question 5

What are the three enzymes responsible for converting galactose to glucose, and which is usually defective in Galactosaemia?

Answer 5

1. Galactose monophosphate uridyltransferase (GALT) is usually deficient
2. GALE
3. GALK

Question 6

Describe the nature of Galactosaemia

Answer 6

This is an autosomal recessive disorder that is usually a result of very low levels of GALT. Galactose levels usually rise to toxic concentrations if not diagnosed

Question 7

What are the clinical manifestations of Galactosaemia and what are treatment options?

Answer 7

Hepatomegaly, cirrhosis, renal failure, cataracts, brain damage and ovarian failure
Only treatment option is to remove lactose and galactose from the diet

Question 8

How will infants with undiagnosed Galactosaemia present?

Answer 8

Lethargy, vomiting, diarrhoea, failure to thrive and jaundice

Question 9

Describe the screening test for Galactosaemia

Answer 9

Blood or urine is tested for GALT activity, galactose and galactose metabolites

Question 10

Describe the cause of Cystic Fibrosis and the results of the defect

Answer 10

CFTR, a chloride ion channel that regulates the movement of Cl and Na ions + water across epithelial membranes, is not functional.
This causes thick viscous secretions, as CFTR regulates components of sweat, digestive fluids and lung mucous
CF affects the lungs, pancreas, liver and intestine

Question 11

What is the genetic inheritance of CF, the most common mutation, and CF’s incidence

Answer 11

Autosomal recessive
The mutation F508-CFTR occurs in over 90% european patients
Incidence is 1:2500

Question 12

How is CF diagnosed in new borns?

Answer 12

Immunoreactive trypsin is tested as the first tier. If this is greater than the 99th percentile, a mutation analysis of the four most common mutations is performed.
If an infant is heterozygous, they’re recalled for a sweat test

Question 13

Describe the sweat test used in CF diagnosis

Answer 13

Pilocarpine solution is applied to the skin to stimulate sweating in a new born. Stimulation is delivered by electrodes called ionsphoresis. Sweat is then collected on filter paper, and sweat levels of chloride and sodium are measured

Question 14

Would a sweat chloride result of 65 mmol/L be suggestive of CF?

Answer 14

Yes-

60mmol/L is abnormal and supports a CF diagnosis

Question 15

What are some causes of congenital hypothyroidism?

Answer 15

1. structurally normal gland with defects in T3 or T4 synthesis
2. Thyrotropin resistance
3. Iodine trapping defect
4. Organification defect
5. Iodotyrosine deiodinase deficiency

Question 16

What are the two main sequelae of hypothyroidism?

Answer 16

Cretinism and severe mental retardation

Question 17

What are the tests for new born screening of hypothyroidism?

Answer 17

Blood spot TSH measurement on the second or third days of life

Question 18

Describe new born population screening

Answer 18

All babies have a blood spot taken onto a guthrie card to test for a list of conditions that are treatable, but not clinically evident in the newborn period

Question 19

What are the clinical features of MCAD deficiency?

Answer 19

Fasting intolerance, hypoketotic hypoglycaemia, hepatomegaly, acute encephalopathy, and potentially coma/death

Question 20

How does MCAD deficiency cause problems?

Answer 20

Fatty acids are bound to carnitine to be transported into the mitochondria. These are metabolized by dehydrogenase enzymes, which remove acetyl-CoA groups, until the fatty acid chains reach C8. At this point, MCAD would usually convert C8 to C6. With an MCAD deficiency, the body has insufficient acetyl’CoA for the TCA cycle, and the excess C8s are converted to other metabolites

Question 21

What is an indication of MCAD in the blood?

Answer 21

C8 acylcarnitine