Inborn Errors of Metabolism Flashcards Preview

Clinical Biochem and Immunology Exam > Inborn Errors of Metabolism > Flashcards

Flashcards in Inborn Errors of Metabolism Deck (43):

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
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
Hereditary fructose intolerance
Pyruvate Metabolism Disorders


Are IEM's common or rare?



Give examples of Pyruvate Metabolism Disorders

Pyruvate dehydrogenase complex deficiency
Pyruvate caroboxylase absence


Give examples of Amino Acid Metabolism Disorders



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


Give examples of Population Screening Programmes

Antenatal (carrier analysis)
- Thalassemia*
- Sickle Cell
- Tay-Sachs*
- Cystic Fibrosis

- Phenylketonuria
- Hypothyroidism

*Analysed in some countries/certain ethnic groups successfully


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

Sickle Cell Anemia
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 methods are used for prenatal screening and diagnosis?

Ultrasound screening
Mother’s markers
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



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


Cystic Fibrosis

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


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)