Metabolic Testing Wk1 Flashcards

1
Q

What are inherited metabolic disorders?

A

Heterogeneous group of genetic conditions
Individually rare, collectively numerous
1 in 1000 live births
Ranges from neonatal lethal - benign
Diagnosed in infancy = life long treatment/monitoring

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2
Q

Once inherited metabolic disorders are identified genetically they can be tested for by…

A

Antenatal diagnosis
Genetic counselling required

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3
Q

Autosomal recessive mode of inheritance

A

One copy required from both unaffected parents

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4
Q

Autosomal dominant

A

One copy from parent

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5
Q

X-linked

A

Gene is located on X chromosome

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6
Q

Mitochondrial (maternal) inheritance

A

Males carry mothers mtDNA, but only females pass to children

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7
Q

Mitochondrial heteroplasmy

A
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8
Q

Mutations in enzymes affect metabolism by..

A

If pathway is blocked, substrates will accumulate = toxic/cause build up of toxic metabolites.
After blocked pathway compounds become deficient

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9
Q

Potential treatment for mutations/metabolism

A

Restriction of substrates/removal of metabolites
Improve/replace defective enzyme
Replace deficient compounds (after mutation line)

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10
Q

Strategies for IMD treatment

A

Treatment goal| Principle used |Example
Substrate reduction |Dietary restriction |Low Phe in PKU
ditto |Decrease flux upstream of defective enzyme
ditto |Removal of substrate |Dialysis
Correct product deficiency |Supply the product /substrate |Give glucose in glycogen storage disease
Decrease toxicity of metabolites |Remove toxic metabolites by conjugation|Sodium benzoate /phenylbutyrate in hyperammonaemia
Stimulate residual enzyme activity |Increase cofactor (vitamin), give drug |Vit B12 in methylmalonic aciduria
Enzyme replacement |Organ transplant, enzyme therapy, gene therapy|Liver/ bone marrow transplant

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11
Q

Laboratory testing for IMDs

A

Blood test

Glucose hypo/hyperglycaemia
Ammonia hyperammonaemia is a medical emergency
Acid-base status metabolic acidosis in cancer
Liver function clotting factor changes can indicate abnormal liver function

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12
Q

Techniques used lab testing IMDs

A

Basic biochemical stains, eg ninhydrin and TLC for amino acids
Fluorimetry
Chromatography (HPLC, GC, ion-exchange)
Mass spectroscopy
DNA sequencing

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13
Q

Who do u investigate? ££££

A

Family history = X-linkage inheritance
Clinical features
Developmental regression evidence
Age of onset
Symptoms =/ feeding

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14
Q

Classes of IMD

A

• Amino acid metabolism
• Urea cycle
• Organic acid metabolism
• Fatty acid metabolism
• Carbohydrate metabolism
• Glycogen storage
• Gluconeogenesis
• Lysosome function
• Peroxisome function

• Respiratory chain
• Mitochondrial DNA
abnormalities
• Cholesterol biosynthesis and
bile acid synthesis
• Haeme metabolism
(Porphyrias)
• Creatine metabolism
• Glycosylation
• Neurotransmitter
• Purine and pyrimidine

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15
Q

Screening priorities

A

The condition
The test
The treatment
The program

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16
Q

English newborn screening program

A

Heel prick test, 5-8 days old

17
Q

Phenylketonuria (PKU)

A

Amino acid disorder

18
Q

Recognise PKU early = important

A

Increased phenylalanine conc = developmental delay
In neonates conc rises quickly after milk
Treatment : low protein + Phenylalanine-free amino acid supplement

19
Q

1-3% of Phenylketonuria (PKU) dont respond to low Phe diet

A

Because they have deficiency in biopterin metabolism
Cofactor for Phe hydrolyse
BH2 needs to be reduced back to BH4 by dihydrobiopterin reductase

20
Q

Fatty acid oxidation disorders

A

MCAD deficiency
Hypoketotic hypoglycaemia
Test : octanoyl carnitine
Treatment: avoid fasting,

21
Q

Antenatal testing

A
22
Q

Metabolic testing biomarkers

A

Biological molecule whose conc changes in response to a specific disease
E.g. enzyme
Cell signalling molecule
Proteins
Molecule of intermediate metabolism

23
Q

Good biomarker?

A

Not present in blood of healthy ppl
Specific to particular tissue
Structurally/functionally stable
Easy to assay
Changes in con related to disease

24
Q

Enzymes as biomarkers

A

Measure activity using spectrophometer + colorimetric assay
Product/substrate coloured

Diff to measure enzyme levels as a protein