Inborn Errors of Metabolism Flashcards
What is the function of an enzyme?
An enzyme catalyses a reaction with a substrate
Define Inborn Errors of Metabolism
A genetically inherited metabolic defect, which results in deficient enzyme production or synthesis of an abnormal enzyme
How do single gene defects cause IEM?
Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, or fats
How can IEM be exacerbated?
The onset and severity may be exacerbated by environmental factors, such as diet and intercurrent illness
What are the categories of IEM?
Disorders of protein metabolism Disorders of carbohydrate metabolism c Lysosomal storage disorders Fatty acid oxidation defects Mitochondrial disorders Peroxisomal disorders
Give examples of disorders of protein metabolism
Amino acidopathies
Organic acidopathies
Urea cycle defects
Give examples of disorders of carbohydrate metabolism
Carbohydrate intolerance disorders Glycogen storage disorders Disorders of gluconeogenesis and glycogenolysis Galactosemia Hereditary fructose intolerance Fructosuria Pyruvate Metabolism Disorders
Are IEM’s common or rare?
Rare
Give examples of Pyruvate Metabolism Disorders
Pyruvate dehydrogenase complex deficiency
Pyruvate caroboxylase absence
Give examples of Amino Acid Metabolism Disorders
PKU
Tyrosinemia
Homocystinuria
What is a key symptom of IEM?
Failure to thrive
Why is identifying IEM early key?
If you can identify conditions early in a child’s life, there may be treatments available
What is involved in the conventional approach to diagnosing IEM?
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
What are the screening programme principles?
Used before patient shows overt disease symptoms Method available Clearly defined disorder Appreciable frequency Advantage of early diagnosis to allow treatment or prenatal diagnosis Low false positive rate Low false negative rate Benefits outweigh the costs
What are the Wilson Criteria for Screening?
Clinically and biochemically well-defined disorder
Known incidence in populations relevant to the UK
Disorder associated with significant morbidity or mortality
Effective treatment available
Period before onset during which intervention improves outcome
Ethical, safe, simple and robust screening test
Cost-effectiveness of screening
Give examples of Population Screening Programmes
Antenatal (carrier analysis) Thalassemia* Sickle Cell Tay-Sachs* Cystic Fibrosis
Neonatal
Phenylketonuria
Hypothyroidism
*Anlalysed in some countries/certain ethnic groups successfully
What conditions are tested for in the UK Neonatal Screening Programme?
Sickle Cell Anemia Thalassemia Phenylketonuria Cystic fibrosis Congenital Hypothyroidism Medium Chain acyl-CoA Dehydrogenase (MCAD)
Other than early treatment, what benefit can come from screening for IEM’s?
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
What are the Prenatal Diagnosis Criteria?
Parents with a previously affected child High risk groups Severe disorder There is no available treatment Early treatment advantageous Reliable test
What methods are used for prenatal screening and diagnosis?
Ultrasound screening Mother’s markers Amniocentesis Chorionic Villus Sampling (transcervical, transabdominal) Fetal Blood Sampling (cordocentesis)
How is ultrasound screening used for prenatal screening and diagnosis?
Abnormality checks
When is ultrasound screening used for prenatal screening and diagnosis?
- If pregnant woman has a high alpha-fetoprotein level
- Family history of birth defects
Give an example of how is mother’s markers are used for prenatal screening and diagnosis?
Alpha-fetoprotein (high level indicates spina bifida)
When is amniocentesis performed?
15 and 17 weeks of pregnancy
When is Chorionic Villus Sampling performed?
10-12 weeks of pregnancy
What is the function of Chorionic Villus Sampling?
DNA analysis, for example for CF
How is Fetal Blood Sampling (cordocentesis) performed?
Small needle is inserted into the site where the cord joins the placenta
Blood is cultured for foetal karyotype analysis
Hurler Syndrome
Autosomal Recessive
Biochemical Test
Hemophilia A
X Linked
DNA/Biochemical Test
Ornithine carbamoyltransferase
Autosomal Recessive
Biochemical Test
Lesch-Nyhan syndrome
X Linked
Biochemical Test
How is a definitive diagnosis made?
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
Phenylketonuria
Caused by mutation at 12q22-24.1
AR disorder
Heel stick (Guthrie test) - ~5 days old
24-48 hrs old
Incidence - 1 in 12,000 (1 in 6000 in UK, 1 in 200,000 in Japan
Caused by low levels of phenylalanine hydroxylase
F>Y
Phenylalanine accumulation results in a child with severe mental retardation
Treatment: low protein diet with amino acid supplement is an effective treatment
Cystic Fibrosis
Mutation in CFTR gene (7q31.2) - causes alteration in chloride pump that uses ATP
Cystic fibrosis 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
How common is Medium Chain Acyl-CoA dehydrogenase (MCAD)?
1 in 10,000 babies
Congenital Hypothyroidism
1 in 4,000 babies
Defects of thyroxine synthesis
Thyroxine deficiency - can cause cretinism
Hereditary Haemachromatosis
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
Tay-Sachs Disease
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.
Give examples of other IEMs
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)
What are the benefits of DNA testing over Biochemical testing for IEMs?
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
What are the cons of DNA testing over Biochemical testing for IEMs?
Cost of transferral to DNA testing would be expensive
How could DNA testing be of benefit as an adjunct to conventional testing?
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
What are the potential problems with DNA testing as an adjunct to conventional testing?
Penetrance needs to be considered if mutation found
Heterozygote analysis
- education and counseling would be necessary
- insurance issues, workplace discrimination
What is involved in genetic counselling?
Formal genetic counseling for affected families
- patient prognosis
- recurrence risk
- possibility of prenatal diagnosis
- screening of other family members
What is Tandem Mass Spectrometry?
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
Why is Tandem Mass Spectrometry important in detecting IEMs?
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)
