ChemPath: Metabolic Screening and Disorders 1

Question 1

Which database keeps track of all inherited metabolic disorders?

Answer 1

OMIM

Online Mendelian Inhertiance in Man

Question 2

What is the basic pathogenesis of inherited metabolic disorders?

Answer 2

Enzyme deficiency

Question 3

What are the main consequences of deficient enzyme activity in the context of inherited metabolic disorders?

Answer 3

Lack of end-product

Build-up of precursors

Abnormal or toxic metabolites

Question 4

What are the criteria for inherited metabolic disorder screening (Wilson and Junger)?

Answer 4

• It has to be an important health problem
• Must be accepted treatment
• Facilities for diagnosis and treatment
• Latent or early symptomatic stage
• Suitable test or examination
• Test should be acceptable to the population
• Natural history is understood
• Agreed policy on whom to treat as patients
• Economically balanced
• Continuing process (keep updating what is screened for)

Question 5

What is phenylketonuria caused by?

Answer 5

Phenylalanine hydroxylase deficiency

• This enzyme is responsible for converting phenylalanine to tyrosine
• Deficiency results in an accumulation of phenylalanine which is toxic

Question 6

Which metabolite would be detected in urine in PKU?

Answer 6

Phenylacetic acid

Question 7

What is the main consequence of untreated PKU?
(characteristics)

Answer 7

Progressive developmental delay and learning disability
Blue eyes and fair hair/skin
Retardation

Question 8

How is PKU investigated?

Answer 8

Blood phenylalanine level (detected in Guthrie test)

Question 9

Describe the treatment of PKU.

Answer 9

• Diet low in phenylalanine and high in tyrosine (avoid high protein foods e.g. meat, fish, eggs, dairy, consume medical foods e.g. bars, powders etc that contain other essential nutrients)
• Regular monitoring of blood phenylalanine

Question 10

When is the Guthrie test performed in the UK?

Answer 10

5-8 days after birth

Question 11

What is congenital hypothyroidism usually caused by? How is diagnosed?

Answer 11

• Thyroid dysgenesis or agenesis
• Diagnosis is based on high TSH

Question 12

How is cystic fibrosis detected in the neonate (Guthrie test)?

Answer 12

High blood immune reactive trypsin (IRT)

Question 13

Outline the pathophysiology of cystic fibrosis.

Answer 13

• Defective CFTR function
• Reduced chloride secretion in lumen by epithelial cell
• Increased sodium reabsorption, which results in increased water reabsorption
• Increased viscosity of secretions
• Lumen blockage

Question 14

Describe the pathophysiology of MCAD deficiency.

Answer 14

Medium-chain acyl-CoA dehydrogenase deficiency

This is a fatty acid oxidation disorder

• Without MCAD, patients will not produce acetyl-CoA from fatty acids, which is necessary in the TCA cycle to produce ketones
• Patient is unable to utilise fat in carbohydrate deficient states (fasting, infection, exercise), resulting in severe hypoketotic hypoglycaemia

Question 15

What is the screening test for MCAD deficiency?

Answer 15

Measuring C6-C10 acylcarnitines by tandem MS (part of Guthrie test)

Question 16

Outline the treatment of MCAD deficiency.

Answer 16

• Strict avoidance of fasting
• Diet high in carbohydrate and low in fats

Question 17

What is homocystinuria caused by?

Answer 17

Failure of homocysteine metablism

Numerous enzymes deficiencies responsible
e.g. methionine synthase deficiency (converts homocysteine to methionine)

Question 18

What are the clinical features of homocystinuria?

Answer 18

• Lens subluxation
• Mental retardation
• Thromboembolism