Inborn Errors of Metabolism

Question 1

What did Garrod propose

Answer 1

Garrod proposed that:
Alkaptonuria
Cystinuria
Albinism
Pentosuria
Congenital (present at birth)
Inborn (transmitted through the gametes)
Had the discontinuous distribution of a Mendelian trait

Question 2

Alkaptonuria - define

Answer 2

Black ochrontic pigmentation of cartilage & collagenous tissue

Question 3

Alkaptonuria - characteristics

Answer 3

Autosmal recessive
Urine turns black
on standing (and 
alkalinisation)
Arthritis
Homogentisic acid oxidase deficiency

Question 4

Cystinuria - define

Answer 4

Defective transport of cystine and dibasic aa’s through epithelial cells of renal tubule and intestinal tract

Question 5

Cystinuria - cause

Answer 5

Mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19)

AR

Question 6

What 4 things did Beadle and Tatum propose

Answer 6

All biochemical processes in all organisms are under genetic control

These biochemical 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 7

Inborn errors of metabolism are caused by

Answer 7

Inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered

Question 8

Mechanisms of inheritance - list 5

Answer 8

Autosomal recessive
Autosomal dominant
X-linked
Codominant
Mitochondrial

Question 9

Autosomal recessive - describe action, effect and examples

Answer 9

Both parents carry a mutation affecting the same gene
1 in 4 risk each pregnancy
Consanguinity increases risk of autosomal recessive conditions
Examples: Cystic fibrosis, sickle cell disease

Question 10

Autosomal dominant - in IEMs and examples

Answer 10

Rare in IEMs

Examples: Huntingdon disease, Marfan’s, Familial hypercholesterolaemia

Question 11

Describe passing of recessive X linked conditions - explain

Answer 11

Recessive X linked conditions passed through the maternal line

condition appears in males

condition carried in females, but not usually expressed. Female carriers may manifest condition –Lyonisation (random inactivation of one of the X chromosomes)

Question 12

Describe passing of dominant X linked conditions - explain

Answer 12

Dominant X-linked conditions passed on from either affected parent

Affected father will only pass the condition to his daughters

Affected mother can pass the condition to sons and daughters

Question 13

X-linked dominant: examples

Answer 13

X-linked dominant: Fragile X, Ornithine carbamoyl transferase deficiency

Question 14

X-linked recessive: examples

Answer 14

X-linked recessive: Haemophilia A, Duchenne muscular dystrophy, Fabry’s disease

Question 15

Codominant - describe w/examples

Answer 15

Codominant

two different versions (alleles) of a gene are expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition.

Example: ABO Blood group, α1AT

Question 16

Mitochondrial inheritance - describe and explain

Answer 16

Inherited exclusively from mother

only the egg contributes mitochondria to the developing embryo

only females can pass on mitochondrial mutations to their children

Fathers do not pass these disorders to their daughters or sons

Question 17

Heteroplasmy - define

Answer 17

Heteroplasmy - Cell contains varying amounts of normal mt DNA and also mutated mt DNA

Question 18

Presentation of IEM - neonate to adult

Answer 18

Neonate to adult

Neonatal presentation often acute

Often caused by defects in energy metabolism:
Maple syrup urine disease
Tyrosinaemia
OTC (urea cycle defect)

Adult
Wilson’s
Haemochromatosis

Question 19

Neonates with IEM - weight significance

Answer 19

Most are born at term with normal birthweight and no abnormal features

Question 20

Neonates with IEM - symptoms

Answer 20

Symptoms present frequently in the first week of life when starting full milk feeds

Question 21

Neonates with IEM - clues

Answer 21

Clues for IEMs:
Consanguinity
FH of similar illness in siblings or unexplained deaths
Infant who was well at birth but starts to deteriorate for no obvious reason

Question 22

IEM - presentation (specific vs unspecific)

Answer 22

Symptoms - can be very non-specific
Poor feeding, lethargy, vomiting, hypotonia, fits

Or specific
Abnormal smell (sweet, musty, cabbage-like)
Cataracts
Hyperventilation 2° to metabolic acidosis
Hyponatraemia and ambiguous genitalia
Neurological dysfunction with respiratory alkalosis

Question 23

IEM clinical scenarios - Biochemical abnormalities list

Answer 23

Biochemical abnormalities:

Hypoglycaemia
Hyperammonaemia
Unexplained metabolic acidosis / ketoacidosis
Lactic acidosis

Question 24

IEM clinical scenarios - clinical list = 8

Answer 24

Clinical:

Cognitive decline
Epileptic encephalopathy
Floppy baby
Exercise intolerant
Cardiomyopathy
Dysmorphic features
Sudden unexpected death in infancy (SUDI)
Fetal hydrops

Question 25

Routine laboratory investigations (IEM) - list 3

Answer 25

Blood gas analysis Blood glucose Plasma ammonia

Question 26

Specialist investigations for IEM - list 6

Answer 26

Specialist investigations: ``` Plasma amino acids Urinary organic acids + orotic acid Blood acyl carnitines Blood lactate and pyruvate Urinary glycosaminoglycans Plasma very long chain fatty acids ```

Question 27

Confirmatory investigations - list 4

Answer 27

Enzymology - Red cell galactose-1-phosphate uridyl transferase - Lysosomal enzyme screening Biopsy (muscle, liver) Fibroblast studies Mutation analysis – whole genome sequencing

Question 28

Neonatal Screening - benefits

Answer 28

Early identification of life-threatening disease in pre-symptomatic babies Earlier initiation of medical treatment Reduction of morbidity and mortality

Question 29

Criteria for screening | (Wilson and Jungner) - neonatal

Answer 29

Condition should be an important health problem Must know incidence/prevelence in screening population Natural history of the condition should be understood - there should be a recognisable latent or early symptomatic stage Availability of a screening test that is easy to perform and interpret - acceptable, accurate, reliable, sensitive and specific Availability of an accepted treatment for the condition - more effective if treated earlier Diagnosis and treatment of the condition should be cost-effective

Question 30

Criteria for a good screening test, neonatal

Answer 30

Accurate and reproducible Cheap and produces rapid result Ethical Good statistical performance - How well the diagnosis influences the test result (sensitivity and specificity) - How well the test result predicts the diagnosis (positive and negative predictive values)

Question 31

Newborn blood spot screening - Initial National programme included:

Answer 31

PKU | Congenital hypothyroidism

Question 32

Newborn blood spot screening - extended to include

Answer 32

Extended to include: Cystic fibrosis Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) Haemoglobinopathies

Question 33

Newborn blood spot screening - From 2015, the screening in England expanded to include four additional conditions

Answer 33

``` Maple syrup urine disease (MSUD) Homocystinuria (pyridoxine unresponsive) (HCU) Isovaleric acidaemia (IVA) Glutaric aciduria type 1 (GA1) ```

Question 34

Taking blood spots for screening (neonates) - requirements

Answer 34

Samples should be taken on day 5 (day of birth is day 0) All four circles on card need to be completely filled with a single drop of blood which soaks through to the back of the Guthrie card

Question 35

Acute liver failure - treatment

Answer 35

Treatment: iv dextrose, bicarbonate, antibiotics and FFP

Question 36

Possible metabolic causes for acute liver disease in neonate

Answer 36

Classical galactosaemia Hereditary fructose intolerance An organic acidaemia Tyrosinemia type 1

Question 37

Tyrosinaemia type1 - define + cause

Answer 37

Most severe form of tyrosinemia, a buildup of too much of the amino acid tyrosine in the blood and tissues due to an inability to metabolize it. It is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase.