IEM

Question 1

What is alkaptonuria?

Answer 1

• Autosomal recessive condition
• Urine turns black on standing and alkalinisation
• Black ochrontic pigmentation of cartilage and collagenous tissue
• Arthritis
• Homogentisic acid oxidase deficiency

Question 2

What is cystinuria?

Answer 2

• 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)

Question 3

What is the cause of albinism?

Answer 3

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

Question 4

What is pentosuria?

Answer 4

• Pentose in urine
• Excrete 1-4g pentose sugar daily
• Benign
• Almost exclusively Ashkenazi jews of Polish-Russian extraction (1:2500 births)

Question 5

What is the one gene- one enzyme concept?

Answer 5

• 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

Question 6

What are the different mechanisms of inheritance?

Answer 6

• 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

Question 7

What is the frequency of IEMs?

Answer 7

• 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

Question 8

When do the IEMs present?

Answer 8

Neonatal

• Maple syrup urine disease
• Tyrosinaemia
• OTC (urea cycle defect)

Adult

• Wilson’s
• Haemochromatosis

Question 9

What are the defects that cause neonatal presentation?

Answer 9

• AA metabolism
• Organic acid metabolism
• Carbohydrate metabolism
• Urea cycle defects
• Respiratory chain defects

Question 10

How do we do newborn blood spot screening?

Answer 10

• 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

Question 11

What are the clues in neonates for IEM?

Answer 11

• 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

Question 12

What is the classic presentation?

Answer 12

• 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

Question 13

What are the first line lab investigations?

Answer 13

• Blood gas analysis
• Blood glucose
• Plasma ammnia
• LFTs
• Urinary ketones and reducing substances

Question 14

What are the second line investigations?

Answer 14

• Plasma and urine AAs
• Urinary organic acids and orotic aid
• Blood acyl carnitines, lactate and pyruvate
• Urinary glycosaminoglycans
• Plasma very long chain FAs

Question 15

What are the confirmatory investigations?

Answer 15

• Enzymology - red cell galactose-1-phosphate uridyl transferase and lysosomal enzyme screening
• Muscle/liver biopsy
• Fibroblast studies
• Complementation studies
• Mutation analysis

Question 16

What are the possible metabolic causes for acute liver disease in a neonate?

Answer 16

• Classical galactosaemia
• Hereditary fructose intolerance
• An organic acidaemia
• Tyrosinaemia type 1