IEM Flashcards
1
Q
What is alkaptonuria?
A
- Autosomal recessive condition
- Urine turns black on standing and alkalinisation
- Black ochrontic pigmentation of cartilage and collagenous tissue
- Arthritis
- Homogentisic acid oxidase deficiency
2
Q
What is cystinuria?
A
- 1:7000
- defective transport of cysteine and dibasic AAs through epithelial cells of renal tubule and intestinal tract
- Cysteine has low solubility - formation of calculi in renal tract
- Mutations in SLC3A1 AA transporter gene (Chr2p) and SLC7A9 (Chr 19)
3
Q
What is the cause of albinism?
A
Tyrosinase negative
- Type 1a - complete lack of enzyme activity due to production of inactive tyrosinase
- Type 1b - reduced activity of tyrosinase
Tyrosinase positive
- Type II - AR, biosynthesis of melanin reduced in skin, hair and eyes
- most individuals do acquire a small amount of pigment with age
4
Q
What is pentosuria?
A
- Pentose in urine
- Excrete 1-4g pentose sugar daily
- Benign
- Almost exclusively Ashkenazi jews of Polish-Russian extraction (1:2500 births)
5
Q
What is the one gene- one enzyme concept?
A
- All biochemical processes in all organisms are under genetic control
- These processes are resolvable into a series of stepwise reactions
- Each biochemical reaction is under the ultimate control of a different single gene
- Mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction
6
Q
What are the different mechanisms of inheritance?
A
- AR - both parents carry a mutation affecting the same gene; 1/4 risk; consaguinity increases risk; e.g. CF and sickle cell
- AD - rare in IEMs, e.g. Huntingdons, Marfans
- X-linked - females passing on condition to their affected sons; no male to male; female carriers can have random inactivation of one of the X chromosomes, leading to manifestation
- Codominant - two different alleles of a gene are expressed, each makes a slightly different protein; both alleles influence genetic trait; e.g. ABO
- Mitochondrial inheritence - inherit mtDNA from mother; only females can pass on
7
Q
What is the frequency of IEMs?
A
- Individually rare, but collectively present a sizeable problem
- Account for approx 42% of deaths within 1st year of life
- Make a significant contribution to the 1% of children at school with physical handicap, and the 0.3% with severe learning difficulties
8
Q
When do the IEMs present?
A
Neonatal
- Maple syrup urine disease
- Tyrosinaemia
- OTC (urea cycle defect)
Adult
- Wilson’s
- Haemochromatosis
9
Q
What are the defects that cause neonatal presentation?
A
- AA metabolism
- Organic acid metabolism
- Carbohydrate metabolism
- Urea cycle defects
- Respiratory chain defects
10
Q
How do we do newborn blood spot screening?
A
- Samples should be taken on day 5
- All four circles on card need to be completely filled with a single drop of blood which soaks through
11
Q
What are the clues in neonates for IEM?
A
- Consanguinity
- Family history of similar illness in sibs or unexplained deaths
- Infant who was well at birth, but starts to deteriorate for no obvious reason
12
Q
What is the classic presentation?
A
- Full term pregnancy
- Non-specific symptoms - poor feeding, lethargy, vomiting, hypotonia, fits
- Specific - abnormal smell (sweet, must, cabbage-like); cataracts, hyperventilation secondary after metabolic acidosis, neurological dysfunction with respiratory alkalosis
13
Q
What are the first line lab investigations?
A
- Blood gas analysis
- Blood glucose
- Plasma ammnia
- LFTs
- Urinary ketones and reducing substances
14
Q
What are the second line investigations?
A
- Plasma and urine AAs
- Urinary organic acids and orotic aid
- Blood acyl carnitines, lactate and pyruvate
- Urinary glycosaminoglycans
- Plasma very long chain FAs
15
Q
What are the confirmatory investigations?
A
- Enzymology - red cell galactose-1-phosphate uridyl transferase and lysosomal enzyme screening
- Muscle/liver biopsy
- Fibroblast studies
- Complementation studies
- Mutation analysis