ChemPath 5S: Metabolic Disorders 1 Flashcards

1
Q

What are the types of inherited disorders?

A
  • Chromosomal
  • Polygenic (by Mendelian inheritance)
  • Monogenic (by Mendelian inheritance)
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2
Q

What is the most common mode of inheritance of inherited metabolic disorders?

A

Autosomal is most common

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3
Q

How do inherited metabolic disorders most commonly present?

A

Typically present at a young age with non-specific symptoms

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4
Q

What may be the causes of deficient enzyme activity?

A
  • Lack of enzyme
  • Reduced enzyme activity due to defects of…
    • Post-translational modification
    • Transportation
    • Assembly
    • Defects of co-factor activation
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5
Q

Deficient enzyme activity can lead to… BIOCHEMICAL HALLMARKS (of the metabolic disorder).

Name some of these…

A
  • Lack of end-products
  • Build-up of precursors
  • Abnormal, often toxic, metabolites (due to large amount of substrate that does not usually react with the enzyme, start reacting → toxic metabolites)
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6
Q

What are the requirements of any screening scheme?

A

Important health problem

Accepted treatment

Facilities for diagnosis and treatment

Latent or early symptomatic stage

Suitable test or examination

Test should be acceptable for population

Natural history understood

Agreed policy on whom to treat as patients

Economically balanced

Continuing process

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7
Q

Name some inherited metabolic disorders

A
  • Phenylketonuria (PKU)
  • Cystic fibrosis
  • MACD (Mitochondrial Fatty acid Beta-oxidation)
  • Homocystinuria
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8
Q

What is the pathophysiology of PKU?

A
  • Phenylalanine hydroxylase (PAH) deficiency
  • PAH converts phenylalanine into tyrosine
  • If the enzyme is deficient, you get:
    • Build-up of phenylalanine (toxic)
    • Abnormal metabolites:
      • Phenylpyruvate
      • Phenylaceticacid (detected in urine)
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9
Q

Summarise PKU

A
  • IQ<50
  • Test – check for serum phenylalanine
  • 400 different gene mutations can cause PKU
  • Tx: phenylalanine restriction
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10
Q

What is the pathophysiology of cystic fibrosis?

A
  • Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) defect
    • 6 classes of defect
  • Failure of Cl- ion movement from inside epithelial cells into the lumen → increased reabsorption of Na+/water → viscous secretions → duct blockage
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11
Q

What are the different classes of CF?

A
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12
Q

Symptoms of CF?

A
  • Lungs → recurrent infection
  • Pancreas → malabsorption, steatorrhoea, diabetes
  • Liver → cirrhosis
  • Testicles → infertility
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13
Q

Screening test for CF?

A
  • high immune reactive trypsin (IRT)
  • If the IRT is above the 99.5th centile in 3 bloodspots → do mutation detections
    • There are >500 mutations that can cause cystic fibrosis, but 4 are very commonF508 is the most common
  • If you get 2 mutations of these 4 common types → diagnose CF
  • If you get 1 mutation out of 4 → extend the test to a panel of 28 mutations
  • If you pick up 0 mutations out of 4 → do another IRT at 21-28 days
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14
Q

What can mass spectrometry be used to detect?

A
  • up to 30 inherited metabolic disorders (abnormal metabolites)
  • illegal in the UK - cannot afford to pick up and treat all these diseases
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15
Q

What is MCAD?

A
  • MACD is a fatty acid oxidation disorder
  • Incidence 1: 10,000
  • MCADD = Medium Chain Acyl-CoA Dehydrogenase Deficiency
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16
Q

Pathophysiology of MCAD?

A
  • The carnitine shuttle allows you to get fat into the mitochondria so that it can be broken down
  • Fatty acid oxidation is a process of sequentially breaking down a fatty acid into smaller and smaller chains
  • If MCAD is missing, you are NOT going to produce acetyl-CoA from fatty acids
    • Acetyl-CoA is necessary in the TCA cycle to produce ketones, which spares glucose
    • You use fat. when. you’re fasting or between meals, in order to spare. your glucose stores
17
Q

Whar can MCAD cause?

A

MCAD deficiency is a classic cause of cot death – If a baby can’t break down fats, when they are not feeding, they will get massively hypoglycaemic and die

18
Q

Screening and Tx for MCAD?

A
  • Screening = measuring C6-C10 Acylcarnitine using tandem Mass Spectometry
  • Treatment = make sure the child NEVER becomes hypoglycaemic, and hence never becomes reliant on fats for energy
19
Q

What is Homocystinuria?

A

Homocystinuria is a failure of remethylating homocysteine

20
Q

Clinical features of Homocystinuria?

A
  • Lens dislocation
  • Mental retardation
  • Thromboembolism
21
Q

What is the Guthrie test?

A
  • At 5-8 days of life (UK), a Heel prick capillary is performed on the posterior medial third of the foot
  • Blood is spotted onto a Guthrie card (thick filter paper) → sent to lab (UKNSLN – 17 labs in UK)
    • UK New-born Screening Laboratories Network (UKNSLN)

Tests for:

  • Sickle cell disease
  • CF
  • Congenital hypothyroidism
  • Inherited metabolic diseases:
    • phenylketonuria (PKU)
    • medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
    • maple syrup urine disease (MSUD)
    • isovaleric acidaemia (IVA)
    • glutaric aciduria type 1 (GA1)
    • homocystinuria (pyridoxine unresponsive) (HCU)
22
Q

Define:

  • sensitivity
  • specificity
  • positive predictive value
  • negative predictive value
A