Inborn Errors Of Metabolism

Question 1

How do inborn errors of metabolism (IEM) affect the organism?

Answer 1

Toxic accumulation of substrates
Defects in energy production/ use due to deficiency of products
Or a combination of the two

Question 2

What things can accumulate toxically in inborn errors of metabolism?

Answer 2

Substrates

Intermediates from alternative metabolic pathways

Question 3

What can inborn errors of metabolism vary in?

Answer 3

Age of onset and clinical severity

Question 4

What are the four disorders studied in the croonian lectures?

Answer 4

Alkaptonuria
Cystinuria
Albinism
Pentosuria

Question 5

What did Archibold Garrod propose the disorders were?

Answer 5

Congenital
Inborn
Followed mendels laws of inheritance

Question 6

Who came up with the one gene - one enzyme concept?

Answer 6

Beadle and tatum

Question 7

What does the one gene-one enzyme concept mean?

Answer 7

One mutated gene causes a non functional enzyme

Question 8

What is an example of molecular disease concept?

Answer 8

Gene mutations produce an alteration in the primary structure of proteins by hamoglobin in sickle cell diesase

Question 9

What are the four mechanisms of inheritance?

Answer 9

Autosomal recessive
Autosomal dominant
X-linked
Mitochondrial

Question 10

Who transfers autosomal recessive inheritance?

Answer 10

Both parents carry a mutation affecting the same gene

Question 11

What is the risk size in each autosomal recessive pregnancy?

Answer 11

1 in 4

Question 12

What increases the risk of autosomal recessive conditions?

Answer 12

Cosanguinity

Question 13

What are some examples of autosomal recessive diseases?

Answer 13

PKu, alkaptonuria, McADD

Question 14

Are autosomal dominant conditions rare or common in IEMs?

Answer 14

Rare

Question 15

What are some examples of autosomal dominant diseases?

Answer 15

Marfans, acute intermittent porphyria

Question 16

How are X-linked mutations passed down?

Answer 16

Maternal line

Question 17

Where do X-linked diseases appear and where are they carried?

Answer 17

Appear in men, carried in women

Question 18

What are some examples of X-linked conditions?

Answer 18

Fabrys disease, ornithine carbamoyl transferase deficiency

Question 19

Where are mitochondrial diseases inherited from?

Answer 19

Mother

Question 20

Which gender do mitochondrial diseases affect?

Answer 20

Male and female offspring

Question 21

Why are mitochondrial diseases exclusively inherited from the mother?

Answer 21

Only the egg contributes mitochondria to the developing embryo

Question 22

What are some examples of mitochondrial IEM diseases?

Answer 22

MERFF and MELAS

Question 23

What does MERFF stand for?

Answer 23

Myoclonic epilepsy and red ragged fibre disease

Question 24

What does MERFF cause?

Answer 24

Deafness, dementia, seizures

Question 25

What does MELAS stand for?

Answer 25

Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes

Question 26

How do you establish the pattern of inheritance?

Answer 26

Accurate family history

Question 27

What determines the presentation of mitochondrial inheritance?

Answer 27

Distribution of affected mitochondria

Question 28

What are more frequently affected in mitochondrial inheritance?

Answer 28

High-energy requiring organs

Question 29

What are IEM treated by?

Answer 29

Dietary control restriction and/or compound supplementation

Question 30

What are the classifications of IEM?

Answer 30

Toxic accumulation Deficiency in energy production/utilisation Disorders of complex molecules involving organelles

Question 31

What are the types of toxic accumulation?

Answer 31

Protein metabolism | Carbohydate intolerance

Question 32

What are the categories of deficiency in energy production/utilisation IEMs?

Answer 32

Fatty acid oxidation Carbohydrate utilisation/production Mitochondrial disorders

Question 33

What is an example of a fatty acid oxidation deficiency IEM?

Answer 33

MCADD

Question 34

What is an example of a deficiency of carbohydrate utilisation/production?

Answer 34

GSD

Question 35

What are the deficiencies of mitochondria?

Answer 35

MERFF

Question 36

What is an example of a lysosomal storage disorder?

Answer 36

Fabrys

Question 37

What is an example of a peroxisomal disorder?

Answer 37

Zellwegers

Question 38

How do IEM present?

Answer 38

Depends on the severity of the metabolic defect

Question 39

What are neonatal IEMs often caused by?

Answer 39

Defects in carb intolerance and energy metabolism

Question 40

What are late onset IEMs caused by?

Answer 40

Accumulation of toxic molecules

Question 41

What do late onset IEMS present with?

Answer 41

Organ failure, encephalopathy and seizures

Question 42

When do IEM symptoms start to present in neonates?

Answer 42

First week of life when starting full milk feeds

Question 43

What are the clues for IEM?

Answer 43

Cosanguinity Family history of similar illness and siblings or unexplained deaths Infants who was well at birth and starts to deteriorate for no obvious reason

Question 44

What are the clinical scenarios of neonate IEM presentation?

Answer 44

``` Poor feeding, lethargy, vomiting Epileptic encephalopathy Profound hypotonia Organomegaly Dysmorphic features Sudden unexpected death in infancy ```

Question 45

What are the biochemical abnormalities in neonate IEM presentation?

Answer 45

Hypoglycaemia Hyperammonia Unexplained metabolic acidosis/ketoacidosis Lactic acidosis

Question 46

What are the routine blood tests for IEMs?

Answer 46

Blood gas Blood glucose and lactate Plasma ammonia

Question 47

What are the specialist lab investigations for IEMs?

Answer 47

``` Plasma amino acids Urinary organic and orotic acid Blood acyl carnitines Urinary glycosaminoglycans Plasma very long chain fatty acids CSF tests ```

Question 48

What are the confirmatory investigations that you can do for IEM?

Answer 48

Enzymology Biopsy Fibroblasts studies Mutation analysis (WGS)

Question 49

What are the wilson and junger criteria for screening?

Answer 49

Condition should be an important health problem Must know prevelence in screening population History of condition understood Easy and reliable screening test Availibility of an accepted treatment Diagnosis and treatment should be cost effective

Question 50

What conditions are tested for in newborn blood spot screening?

Answer 50

``` PKU congenital hypothyroidism Sickle cell disease Cystic fibrosis MCADD ```

Question 51

When are newborn blood spot screening samples taken?

Answer 51

Day 5 (day of birth is day 0)

Question 52

What are the guidlines for a good quality bloodspot of newborn blood spot screening?

Answer 52

All four circles on ‘guthrie’ card need to be completely filled with a single drip of blood which soaks through to the back of the card

Question 53

What is Tyrosinaemia type 1?

Answer 53

Genetic deficiency in fumarylacetoacetase

Question 54

What is the function of fumarylacetoacetase?

Answer 54

Catalyses the final step in tyrosine metabolism

Question 55

What is the treatment for tyrosinaemia type 1 and how does it work?

Answer 55

Nitisinone inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites

Question 56

What are the symptoms of ornithine transcarbamylase deficiency?

Answer 56

Ataxia, seizures, Hyperammonaemic encephalopathy

Question 57

What can trigger a hyperammonaemic crisis?

Answer 57

Increased endogenous protein catabolism (infection, fasting, trauma, steroid administration) High protein intake