Inborn Errors of Metabolism

Question 1

What is the function of an enzyme?

Answer 1

An enzyme catalyses a reaction with a substrate

Question 2

Define Inborn Errors of Metabolism

Answer 2

A genetically inherited metabolic defect, which results in deficient enzyme production or synthesis of an abnormal enzyme

Question 3

How do single gene defects cause IEM?

Answer 3

Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, or fats

Question 4

How can IEM be exacerbated?

Answer 4

The onset and severity may be exacerbated by environmental factors, such as diet and intercurrent illness

Question 5

What are the categories of IEM?

Answer 5

Disorders of protein metabolism 
Disorders of carbohydrate metabolism 
Lysosomal storage disorders 
Fatty acid oxidation defects 
Mitochondrial disorders 
Peroxisomal disorders

Question 6

Give examples of disorders of protein metabolism

Answer 6

Amino acidopathies
Organic acidopathies
Urea cycle defects

Question 7

Give examples of disorders of carbohydrate metabolism

Answer 7

Carbohydrate intolerance disorders
Glycogen storage disorders
Disorders of gluconeogenesis and glycogenolysis
Galactosemia
Hereditary fructose intolerance
Fructosuria
Pyruvate Metabolism Disorders

Question 8

Are IEM’s common or rare?

Answer 8

Rare

Question 9

Give examples of Pyruvate Metabolism Disorders

Answer 9

Pyruvate dehydrogenase complex deficiency

Pyruvate caroboxylase absence

Question 10

Give examples of Amino Acid Metabolism Disorders

Answer 10

PKU
Tyrosinemia
Homocystinuria

Question 11

What is a key symptom of IEM?

Answer 11

Failure to thrive

Question 12

Why is identifying IEM early key?

Answer 12

If you can identify conditions early in a child’s life, there may be treatments available

Question 13

What is involved in the conventional approach to diagnosing IEM?

Answer 13

Conventional approaches to diagnosing and monitoring IEM’s rely on biochemical analysis of metabolites, hormones or certain proteins
- e.g. for diagnosis of congenital adrenal hyperplasia, 17-hydroxyprogesterone is measured

Question 14

Give examples of Population Screening Programmes

Answer 14

Antenatal (carrier analysis)

• Thalassemia*
• Sickle Cell
• Tay-Sachs*
• Cystic Fibrosis

Neonatal

• Phenylketonuria
• Hypothyroidism

*Analysed in some countries/certain ethnic groups successfully

Question 15

What conditions are tested for in the UK Neonatal Screening Programme?

Answer 15

Sickle Cell Anemia 
Thalassemia
Phenylketonuria
Cystic fibrosis
Congenital Hypothyroidism
Medium Chain acyl-CoA Dehydrogenase (MCAD)

Question 16

Other than early treatment, what benefit can come from screening for IEM’s?

Answer 16

The parents may have a recessive condition. The results from the screening test may mean that the parents decide not to have any more children

Question 17

What methods are used for prenatal screening and diagnosis?

Answer 17

Ultrasound screening
Mother’s markers
Amniocentesis
Chorionic Villus Sampling (transcervical, transabdominal)
Fetal Blood Sampling (cordocentesis)

Question 18

How is ultrasound screening used for prenatal screening and diagnosis?

Answer 18

Abnormality checks

Question 19

When is ultrasound screening used for prenatal screening and diagnosis?

Answer 19

If pregnant woman has a high alpha-fetoprotein level- Family history of birth defects

Question 20

Give an example of how is mother’s markers are used for prenatal screening and diagnosis?

Answer 20

Alpha-fetoprotein (high level indicates spina bifida)

Question 21

When is amniocentesis performed?

Answer 21

15 and 17 weeks of pregnancy

Question 22

When is Chorionic Villus Sampling performed?

Answer 22

10-12 weeks of pregnancy

Question 23

What is the function of Chorionic Villus Sampling?

Answer 23

DNA analysis, for example for CF

Question 24

How is Fetal Blood Sampling (cordocentesis) performed?

Answer 24

Small needle is inserted into the site where the cord joins the placenta
Blood is cultured for foetal karyotype analysis

Question 25

Hurler Syndrome

Answer 25

Autosomal Recessive Biochemical Test

Question 26

Hemophilia A

Answer 26

X Linked DNA/Biochemical Test

Question 27

Ornithine carbamoyltransferase

Answer 27

Autosomal Recessive Biochemical Test

Question 28

Lesch-Nyhan syndrome

Answer 28

X Linked Biochemical Test

Question 29

How is a definitive diagnosis made?

Answer 29

A definitive diagnosis may be made from screening tests but may also need:

• Specific Enzyme analysis
• May be necessary to biopsy tissues (eg liver/muscle)
• DNA testing, if 1st tier work is inconclusive

Question 30

Phenylketonuria

Answer 30

Caused by mutation at 12q22-24.1 AR disorder
Heel stick (Guthrie test) - ~5 days old
Incidence - 1 in 12,000 (1 in 6000 in UK)
Caused by low levels of phenylalanine hydroxylase
Phenylalanine accumulation results in a child with severe mental retardation
Treatment: low protein diet with amino acid supplement is an effective treatment

Question 31

Cystic Fibrosis

Answer 31

Mutation in CFTR gene (7q31.2) - causes alteration in chloride pump that uses ATP
1 per 1600 people of European descent
Carrier frequency up to 5% (Northern Europeans)
DF508 very common in UK, but multiple mutations make genetic analysis problematic
Autosomal Recessive
DNA Test

Question 32

How common is Medium Chain Acyl-CoA dehydrogenase (MCAD)?

Answer 32

1 in 10,000 babies

Question 33

Congenital Hypothyroidism

Answer 33

1 in 4,000 babies
Defects of thyroxine synthesis
Thyroxine deficiency - can cause cretinism

Question 34

Hereditary Haemachromatosis

Answer 34

Carrier frequency up to 10% (Northern Europeans)
Treatable disorder of iron metabolism
Mutations in HFE, a HLA class 1 -like gene
HFE gene at 6p21.3
No clinical features during childhood
Penetrance must be considered if mutation found
Gradual iron accumulation leads to complications
85% of patients are homozygous for a single mutation C28Y

Question 35

Tay-Sachs Disease

Answer 35

Tay-Sachs disease, a heritable metabolic disorder commonly associated with Ashkenazi Jews
Autosomal recessive disease caused by mutations in both alleles of a gene (HEXA) on chromosome 15.
HEXA codes for the alpha subunit of the enzyme β-hexosaminidase A. This enzyme is found in lysosomes, organelles that break down large molecules for recycling by the cell.
Normally, β-hexosaminidase A helps to degrade a lipid called GM2 ganglioside, but in Tay-Sachs individuals, the enzyme is absent or present only in very reduced amounts, allowing excessive accumulation of the GM2 ganglioside in neurons.
The progressive neurodegeneration seen in the varied forms of Tay-Sachs depends upon the speed and degree of GM2 ganglioside accumulation, which in turn is dependent upon the level of functional β-hexosaminidase A present in the body.

Question 36

Give examples of other IEMs

Answer 36

Maple Syrup Urine Disease (MSUD)Homocystinuria (pyridoxine unresponsive)Glutaric Aciduria Type I (GA1)Isovaleric Acidaemia (IVA)Long-chain 3-hydroxyacyl CoA dehydrogenase deficiency (LCHADD; includes trifunctional protein deficiency)

Question 37

What are the benefits of DNA testing over Biochemical testing for IEMs?

Answer 37

Detection of multiple potential mutations
Identification of multiple genes simultaneously
(BUT sensitivity of DNA testing must be as good as current biochemical testing)
PCR can show selective allele amplification

Question 38

What are the cons of DNA testing over Biochemical testing for IEMs?

Answer 38

Cost of transferral to DNA testing would be expensive

Question 39

How could DNA testing be of benefit as an adjunct to conventional testing?

Answer 39

Mutation identification could clarify borderline cases
Prediction of phenotype severity
Facilitates DNA-based prenatal diagnosis in a future pregnancy
Identify family members that are trait carriers

Question 40

What are the potential problems with DNA testing as an adjunct to conventional testing?

Answer 40

Penetrance needs to be considered if mutation found
Heterozygote analysis
- education and counseling would be necessary
- insurance issues, workplace discrimination

Question 41

What is involved in genetic counselling?

Answer 41

Formal genetic counseling for affected families

• patient prognosis
• recurrence risk
• possibility of prenatal diagnosis
• screening of other family members

Question 42

What is Tandem Mass Spectrometry?

Answer 42

Tandem mass spectrometry is a procedure used in medical laboratories consisting of two mass spectrometers in series connected by a chamber known as a collision cell.
The sample to be examined is essentially sorted and weighed in the first mass spectrometer, then broken into pieces in the collision cell, and a piece or pieces sorted and weighed in the second mass spectrometer.
Tandem mass spectrometry is used in newborn screening to detect molecules such as amino acids (the building blocks of proteins) and fatty acids

Question 43

Why is Tandem Mass Spectrometry important in detecting IEMs?

Answer 43

In inherited metabolic diseases, specific enzymes that facilitate the breakdown of amino acids or conversion of fat to energy, do not function.
If a particular enzyme is not functioning, the breakdown of a compound by this enzyme does not occur.In other instances, products are not produced that are important for cell function.
Because the compound cannot be metabolised, it will accumulate in the blood and tissues.
The tandem mass spectrometer, by measuring the amounts of the specific compounds present, can identify whether there is too much in the blood, which may suggest which condition a patient is suffering from (other tests may be required to confirm)