Chemical Pathology: Metabolic disorders and screening 1

Question 1

Outline the definition of a metabolic disorder

Answer 1

• Deficient enzyme activity due to either lack, defects of post-translational modification, defects of assembly, defects of transport or defects of co-factor function.
• This reduced activity leads to lack o fend product, build up of precursors and abnormal (toxic) metabolites.

Question 2

What diseases are currently screened for?

Answer 2

• Phenylketonuria (PKU)
• Congenital Hypothyroidism
• Sickle Cell disease
• Cystic fibrosis
• Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

Question 3

Outline the clinical and lab features of Phenylketonuria (PKU)

Answer 3

• Defect in mental development (<50 IQ)
• High Phenylalanine (Phe) (Ferric chloride)
• (Due to Phenylalanine hydroxylase deficiency)

Question 4

How is cystic fibrosis screened for and diagnosed?

Answer 4

• Immune reactive trypsin (3 blood spots)
• DNA mutation 4 panel
• 2 mutations found: diagnosis

Question 5

In screening tests, what is meant by sensitivity?

Answer 5

• How good the test is at detecting a disease

- Number of true positives/ total number of disease present

Question 6

In screening tests, what is meant by specificity?

Answer 6

• How good a test is at excluding healthy people

- Number of true negatives/ total number of unaffected people

Question 7

-In screening tests, what is meant by positive predictive value?

Answer 7

• How many positives actually have the disease

- Number of true positives/ total number of positives

Question 8

-In screening tests, what is meant by negative predictive value?

Answer 8

• How many negatives are actually unaffected individuals

- Number of true negatives/ total number of negatives

Question 9

What effect does prevalence have on the predicitve value of a test?

Answer 9

-An increased prevalence causes a decreased predictive value

Question 10

How is screening for metabolic disorders performed?

Answer 10

• Heel prick of neonates within 5-8 days of life
• From capillary from posterior medial third of foot.
• Blood is spotted into guthrie card (Spotted paper)
• Tandem MS (Mass spectrometry)
• Capable of detecting levels of abnormal metabolites

Question 11

What diseases are currently being considered for screening?

Answer 11

• Homocystinuria
• Isovaleric acidaemia
• Glutaric aciduria type 1
• Maple syrup urine disease
• Long chain acyl CoA DH deficiency

Question 12

Outline the clinical features of congenital hypothyroidism

Answer 12

• High TSH
• Dysgenesis/agenesis of thyroid gland
• Hypothyroidism

Question 13

Outline pathophysiology of Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

Answer 13

• Affects mitochondrial fatty acid Beta oxidation
• Prevents fatty acid breakdown
• Metabolism of acetyl CoA is defective, leading to build of acylcarnitines
• Clinical features: Vomiting, lack of energy, hypoglycaemia.

Question 14

Outline features of cystic fibrosis

Answer 14

• Frequent coughing, wheezing, or bouts of pneumonia or sinusitis
• Difficulty breathing that keeps getting worse
• Big appetite but poor weight gain
• Bulky, smelly, greasy bowel movements