ChemPath: Metabolic Screening and Disorders 1
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Which database keeps track of all inherited metabolic disorders?
OMIM Online Mendelian Inhertiance in Man
What is the basic pathogenesis of inherited metabolic disorders?
Enzyme deficiency
What are the main consequences of deficient enzyme activity in the context of inherited metabolic disorders?
Lack of end-product Build-up of precursors Abnormal or toxic metabolites
What are the criteria for inherited metabolic disorder screening (Wilson and Junger)?
• 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)
What is phenylketonuria caused by?
Phenylalanine hydroxylase deficiency • This enzyme is responsible for converting phenylalanine to tyrosine • Deficiency results in an accumulation of phenylalanine which is toxic
Which metabolite would be detected in urine in PKU?
Phenylacetic acid
What is the main consequence of untreated PKU? (characteristics)
Progressive developmental delay and learning disability Blue eyes and fair hair/skin Retardation
How is PKU investigated?
Blood phenylalanine level (detected in Guthrie test)
Describe the treatment of PKU.
• 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
When is the Guthrie test performed in the UK?
5-8 days after birth
What is congenital hypothyroidism usually caused by? How is diagnosed?
• Thyroid dysgenesis or agenesis • Diagnosis is based on high TSH
How is cystic fibrosis detected in the neonate (Guthrie test)?
High blood immune reactive trypsin (IRT)
Outline the pathophysiology of cystic fibrosis.
• 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
Describe the pathophysiology of MCAD deficiency.
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
What is the screening test for MCAD deficiency?
Measuring C6-C10 acylcarnitines by tandem MS (part of Guthrie test)
Outline the treatment of MCAD deficiency.
• Strict avoidance of fasting • Diet high in carbohydrate and low in fats
What is homocystinuria caused by?
Failure of homocysteine metablism Numerous enzymes deficiencies responsible e.g. methionine synthase deficiency (converts homocysteine to methionine)
What are the clinical features of homocystinuria?
• Lens subluxation • Mental retardation • Thromboembolism