Inborn Errors of Metabolism

Question 1

1. Who is the father of Inborn errors of metabolism and why?

Answer 1

Archibold E Garrod (1857-1936): Father of IEM – published/printed book ‘Inborn Errors of Metabolism’.

Question 2

2. What did Archibold propose in his book?

Answer 2

Proposed:

• Alkaptonuria (dark urine –> functional enzyme that breaks down AA’s phenylamine and tyrosine is missing)
• Cystinuria (high conc of cysteine in urine)
• Albinism (loss of pigment)
• Pentosuria (high conc of sugar xylitol (a pentose) in urine)

We’re all congenital, inborn and had the discontinuous distribution of a Mendelian Trait?

Question 3

3. What is meant by the term “inborn” mean

Answer 3

transmitted through the gametes

Question 4

4. What does “the discontinuous distribution of a Mendelian trait” mean?

Answer 4

• traits with only a few possible phenotypes that fall into discrete classes; phenotype is controlled by one or only a few genes and it doesn’t change throughout your life eg blood type

Question 5

5. Is Alkaptonuria caused by dominant or recessive genes?

Answer 5

•Autosomal recessive

Question 6

6. What is Alkaptonuria?

Answer 6

Homogentisic acid oxidase deficiency so cannot process amino acids e.g. tyrosine

Question 7

7. What are some signs/symptoms of Alkaptonuria?

Answer 7

•Urine turns black on standing (and alkalisation), arthritis and black ochronotic pigmentation of cartilage & collagenous tissue.

Question 8

8. Is Cystinuria recessive or dominant?

What is the prevalence of Cystinuria

Answer 8

autosomal recessive

1:7000.

Question 9

9. What mutation results in Cystinuria?

Answer 9

•Mutations of SLC3A1 amino acid transporter gene (Chr 2p) & SLC7A9 (Chr 19)• Mutations of SLC3A1 amino acid transporter gene (Chr 2p) & SLC7A9 (Chr 19)

Question 10

10. What is Cystinuria?

Answer 10

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

Question 11

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

Answer 11

Beadle and Tatum in 1945 (Got a nobel prize for it in 1958)

Question 12

12. What is the one gene- one enzyme concept?

Answer 12

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

Question 13

13. Using the one gene-one enzyme concept, what is the effect of a mutation of a single gene?

Answer 13

Mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction

Question 14

14. Summarise the one gene - one enzyme concept into one sentence?

Answer 14

each gene directly produces a single enzyme, which consequently affects an individual step in a metabolic pathway.

Question 15

15. Who invented the molecular disease concept and when ?

Answer 15

Pauling

1949

Question 16

16. What is the molecular disease concept?

Answer 16

• Work on haemoglobin in sickle cell disease - evidence that human gene mutations produce an alteration in the primary structure of proteins
• Inborn errors of metabolism are caused by mutations in genes which produce abnormal, non-functional proteins

Question 17

17. Following questions refer to Autosomal Recessive inheritance:
    - What is the risk of getting the disease if both parents are carriers
    - What increases the risk of autosomal recessive conditions
    - What are some examples of autosomal recessive conditions?

Answer 17

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

Question 18

18. Are autosomal dominant conditions rare or common in inborn errors of metabolism?

Answer 18

Rare

Question 19

19. What are some examples of autosomal dominant conditions?

Answer 19

Huntingdon disease,
Marfan’s
Familial hypercholesterolaemia

Question 20

20. The following questions refer to X Linked Recessive conditions
    - Which line are they passed through (maternal or paternal)
    - Will the condition be expressed in males or females
    - Who will carry the mutation –> what is a consequence of this?

Answer 20

• Passed through maternal line
• Condition appears in males
• Female carry the condition but not usually expressed , however may manifest condition ( Lyonisation= random inactivation of ONE of the X chromosomes)

Question 21

21. Why is it more common for males to express X linked recessive disorders than females?

Answer 21

Recessive X-linked disorders tend to be more common in males, because it’s less likely that a female will get 2 copies of the recessive mutation.

Question 22

22. For Dominant X-Linked recessive who can it pass it on to sons/daughters?
    - Can a father pass it on to his son?

Answer 22

passed on from either affected parent; fathers only pass the condition to daughters while mothers can pass the condition to both sons and daughters.
oNo male to male transmission (father only passes on Y chromosome)

Question 23

23. What are some examples of X-Linked Dominant conditions?

Answer 23

Fragile X (learning disabilities, speech impairment) 
 Ornithine carbamoyl transferase deficiency (excess ammonia)

Question 24

24. What are some examples of X-Linked recessive conditions?

Answer 24

Haemophilia A (clotting factor issues , increased bleeding)

Duchenne muscular dystrophy (weakness and loss of muscles)

Fabry’s disease (lysosomal storage disorder)

Question 25

25. What is meant by “codominant” inheritance?

Answer 25

• 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.

Question 26

26. What are some examples of codominant inheritance?

Answer 26

ABO Blood group (eg parents A and B, child AB)

α1AT

Question 27

27. What is meant by “Mitochondrial “ Inheritance?

Which parent can pass on Mitochondrial inheritance and why?

Answer 27

• Mitochondrial gene mutations are exclusively inherited from mother and affects both male and female offspring.
o As only the egg contributes mitochondria to the developing embryo, only females can pass mutations to offspring and fathers cannot pass their mutations on.

Question 28

28. Two examples of mitochrondrial inheritance conditions are :
    -MERFF
    and
    -MELAS
    What do they stand for and what are the symptoms?

Answer 28

. MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures

MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes :seizures, headaches, brain function

Question 29

29. What affects the presentation of mitochondrial inherited conditions?

Answer 29

• Distribution of affected mitochondria determine presentation – diseases vary in symptoms, severity and onset.
• High energy-requiring organs more frequently affected

Question 30

30. There is a current debate on three parent babies- in 2017 what significant event occurred regarding this topic?

Answer 30

2017 – UK granted first licence to Newcastle fertility centre

Question 31

31. What is Heteroplasmy?

Answer 31

Cell contains varying amounts of normal mitochondrial DNA and also mutated mitochondrial DNA

Question 32

32. If individual cases of IEM are rare, why do they account for such a high mortality rate in the first year of life?

Answer 32

•There are many types of diseases of IEM that are individually rare (1:10,000 - 1:500,000) but these are collectively common and account for high mortality within the first year of life.

Question 33

33. Fill in the blank:
    “ IEM pay a significant contribution to the *% of children of school age with physical handicap and the *% with severe learning difficulties.

Answer 33

1%

0.3%

Question 34

34. Its important to recognise IEM early on in sick neonates for treatment, how can we do this?

Answer 34

by newborn screening programmes

Question 35

35. What is the presentation of IEM in neonates?•

Answer 35

Neonatal presentation often acute and caused by defects in energy metabolism:

o Maple syrup urine disease (body cant break down branched amino acid, urine smells sweet) Tyrosinaemia (can’t breakdown tyrosine)

o OTC (urea cycle defect) – partial deficiency of enzyme for converting nitrogen into urea.

Question 36

36. What is the presentation of IEM in Adults?

Answer 36

Wilson’s disease (error of copper metabolism) or Haemochromatosis (iron overload).

Question 37

37. Most neonates with IEM are born at term with normal birthweight and no abnormal features, so when do symptoms present?

Answer 37

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

Question 38

38. What are some clues for IEM?

Answer 38

o Consanguinity or family history of similar illness in siblings or unexplained deaths.

o Infant who was well at birth but starts to deteriorate for no obvious reason.

Question 39

39. What can IEM non-specific symptoms be mistaken for?

Answer 39

Sepsis

Question 40

40. What are the non-specific symptoms of IEM?

Answer 40

Poor feeding, lethargy, vomiting, hypotonia, fits

Question 41

41. What are specific symptoms of IEM?

Answer 41

o Abnormal smell (sweet, musty, cabbage-like) and cataracts (opaque lens – blurred vision).

o Hyperventilation 2 degree to metabolic acidosis.

o Hypernatraemia (too much sodium) and ambiguous genitalia.

o Neurological dysfunction with respiratory alkalosis.

Question 42

42. What are some biochemical abnormalities seen in patients with IEM?

Answer 42

Hypoglycaemia, Hyperammonaemia, Unexplained metabolic acidosis/ketoacidosis or Lactic acidosis.

Question 43

43. What are some clinical scenarios seen in patients with IEM?

Answer 43

Cognitive decline, Epileptic encephalopathy (loss of cerebral function), Floppy baby (low muscle tone), Exercise intolerant, Cardiomyopathy, Dysmorphic features, Sudden unexpected death in infancy (SUDI), Fetal hydrops (fluid accumulation).

Question 44

44. What are the routine laboratory tests that would be given to a patient with IEM symptoms?

Answer 44

Blood gas analysis
Blood glucose
Plasma ammonia

Question 45

45. What specialist investigations could take place for a patient with IEM?

Answer 45

•Plasma amino acids, Urinary organic acids + orotic acid, Blood acyl carnitines, Blood lactate and pyruvate, Urinary glycosaminoglycans, Plasma very long chain fatty acids.

Question 46

46. What investigations can we do to confirm IEM?

Answer 46

• Enzymology
• Biopsy (muscle, liver)
• Fibroblast studies
• Mutation analysis – whole genome sequencing

Question 47

47. What do we investigate in an enzymology?

Answer 47

o Galactosemia: Red cell galactose-1-phosphate uridyl transferase (catalyses formation of galactose)

o Lysosomal enzyme screening

Question 48

48. How many babies are screened per year in the uk?

What is the importance of neonatal screening?

Answer 48

• UK >770000 babies screened/year
• Early identification of life-threatening disease in pre-symptomatic babies means medical treatment is initiated earlier - reduction of morbidity and mortality.

Question 49

49. What are Wilson and Jugners criteria for screening patients seeing as we cant screen for every disease?

Answer 49

• Conditions needs to be an important health problem and relatively prevalent (not extremely rare).
• Condition’s natural history should be understood – needs a recognisable latent or early symptomatic stage.
• Easy to perform/interpret screening test available- 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 50

50. What is the criteria for a good screening test?

Answer 50

• Accurate and reproducible, cheap and produces rapid result, ethical.
• Good statistical performance.
o How well the diagnosis influences the test result (sensitivity and specificity).
o How well the test result predicts the diagnosis (positive and negative predictive values).

Question 51

51. Initially, what did the newborn blood spot screen for?

- In 2015, what was it extended to include?

Answer 51

PKU and Congenital hypothyroidism

2015 - Cystic fibrosis, Haemoglobinopathies and Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

Question 52

52. In England , from 2015 the newborn blood spot screening was extended to include 4 additional components - what are these?

Answer 52

Maple syrup urine disease (MSUD),

Homocystinuria (pyridoxine unresponsive) (HCU), Isovaleric acidaemia (IVA), Glutaric aciduria type 1 (GA1).

Question 53

53. How are newborn blood spots taken?

Answer 53

•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 54

54. Case Study:

Patient :

• Male infant
• Consanguineous parents

Symptoms:
•Strange, cabbage-like smell
-heart murmur (HM investigated but no abnormalities were found)

What initial investigations do you think should take place?

Answer 54

Test for Plasma amino acid and urine sugars

Question 55

55. Following from case study ^
    Initial Investigations showed Tyrosine and Methionine present and urine sugars -gross galactosuria

Further investigations and result:

Galactosuria = formulae changed to lactose free
Alanine aminotransferase (high)
Aspartate transaminase (high), Glucose, Methionine and Tyrosine (high),
Prothrombin time (very long), partial prothrombin time (very long). 

A thin layer chromatography urine reducing sugars showed presence of galactose
Completed a plasma amino acid by HPLC

4 days after admission (4/52): Very ill, acidotic, grey, pyrexial (fever), gross ascites with distended abdomen and plasma albumin falls.

What does the baby have?
What treatment would be appropriate?

Answer 55

Acute Liver Failure
(Tyrosinaemia type 1)

•Treatment: iv dextrose, bicarbonate, antibiotics and FFP (fresh frozen plasma).

Question 56

56. What are 4 Possible metabolic causes for acute liver disease in neonate

Answer 56

Classical galactosaemia

Hereditary fructose intolerance

An organic acidaemia

Tyrosinaemia type 1

Question 57

57. What specifically happens in Tyrosinaemia type 1?

Answer 57

• Blockage/deficiency of fumarylacetoacetate hydrolase (FAH) causes abnormal tyrosine breakdown which results in accumulation of toxic metabolites such as succinyl-acetate (damages the liver and kidneys).
• Treatment stops the building up of these metabolites by stopping the pathway slightly higher up.

Question 58

58. Case Study:
    • 15 year old male referred from local DGH to King’s College Hospital - Fulminant Hepatic Failure?
    • History:
    o Well in morning, went to bed (tired) and was woken up at dinner – walked downstairs, slumped on sofa, started shaking and lost consciousness – taken to a district general hospital where he had fluctuating consciousness with intermittent screaming but no focal neurological signs.
    • On Examination:
    o Sleepy but wakes up, orientated, slurred but appropriate speech (talked endlessly),
    o No neurological signs, no hepatosplenomegaly, nor signs of chronic liver disease, scleral jaundice and normal heart and lungs.
    • Initial Investigations (mostly normal reflected the liver damage starting to occur): transferred to liver centre hospital.
    o Paracetamol + Salicylate screen negative so no overdose but NH3 was very high.
    o Normal brain CT and CSF examination.
    • Past Medical History:
    o No friends, special needs school (behavioural and learning difficulties), decreased weight due to dieting, iron and vitamin supplements, large cheese (carbohydrate) intake of the day of collapse.
    • Family History:
    o Mother has nephritis and Mother’s brother died of Herpes simplex encephalitis 9 years ago.
    • Further Investigations:
    o Second line tests and ultrasound (looking at liver with mild splenomegaly): normal.
    o EEG- diffuse encephalopathy of moderate severity.
    o Liver biopsy - minimal hepatitic changes and focal fatty infiltration
    o Organic acids by GCMS showed: Increased uracil and orotic acid excretion.

What diagnostic test can take place?
Whats the diagnosis?

Answer 58

oOrnithine transcarbamylase (OTC) low and Carbamylphosphate synthase within range

•Diagnosis: Block at OTC caused a build-up of ammonia as it is not oxidised in the urea cycle.