Flashcards in Common Inborn Errors of Metabolism Deck (21):
What is the role of the hepatic enzyme Phenylalanine hydroxylase?
This enzyme that catalyses the hydroxylation of Phenylalanine's aromatic side chain, to produce tyrosine.
What are symptoms of PKU?
Microcephaly, mental retardation, seizures, autistic-like behaviour, fair/light complexion, and a musty odour to the urine
What is PKU's pattern of inheritance?
How do you screen for PKU?
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
What are the three enzymes responsible for converting galactose to glucose, and which is usually defective in Galactosaemia?
1. Galactose monophosphate uridyltransferase (GALT) is usually deficient
Describe the nature of Galactosaemia
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
What are the clinical manifestations of Galactosaemia and what are treatment options?
Hepatomegaly, cirrhosis, renal failure, cataracts, brain damage and ovarian failure
Only treatment option is to remove lactose and galactose from the diet
How will infants with undiagnosed Galactosaemia present?
Lethargy, vomiting, diarrhoea, failure to thrive and jaundice
Describe the screening test for Galactosaemia
Blood or urine is tested for GALT activity, galactose and galactose metabolites
Describe the cause of Cystic Fibrosis and the results of the defect
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
What is the genetic inheritance of CF, the most common mutation, and CF's incidence
The mutation F508-CFTR occurs in over 90% european patients
Incidence is 1:2500
How is CF diagnosed in new borns?
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
Describe the sweat test used in CF diagnosis
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
Would a sweat chloride result of 65 mmol/L be suggestive of CF?
60mmol/L is abnormal and supports a CF diagnosis
What are some causes of congenital hypothyroidism?
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
What are the two main sequelae of hypothyroidism?
Cretinism and severe mental retardation
What are the tests for new born screening of hypothyroidism?
Blood spot TSH measurement on the second or third days of life
Describe new born population screening
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
What are the clinical features of MCAD deficiency?
Fasting intolerance, hypoketotic hypoglycaemia, hepatomegaly, acute encephalopathy, and potentially coma/death
How does MCAD deficiency cause problems?
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