Alkaptonuria: One Hundred Years After Garrod An Introduction L Ranganath Consultant in Clinical Bioc

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Alkaptonuria One Hundred Years After GarrodAn
IntroductionL RanganathConsultant in Clinical
Biochemistry Metabolic Medicine
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Sir Archibald Garrod Physician Scientist Chemical
Pathologist 1857-1936
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History of Alkaptonuria

• Boedecker alkapton 1859
• Wolkow HGA 1891
• Baumann
• Garrod inherited disorder 1902
  
• ? Enzyme deficiency
• LaDu et al Homogentisic acid oxidase
• deficiency
  proved 1958
• Pollak et al AKU gene on 3q2 1993

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Alkaptonuria Inborn error of metabolism Autosomal
recessive
Homogentisate 1,2 dioxygenase
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ENZYME ACTIVITY IN AKU

• Mutations lead to inactive HGD
• Enzyme activity Tyrosine umol/h/g liver
  g/day
• metabolised
• Normal 270 1600
• AKU lt0.05 -
• Heterozygote 140 800

Homogentisate 1,2 dioxygenase
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Metabolic Pathway of Ochronotic Pigment Production
CONNECTIVE TISSUE MACROMOLECULES
Adapted from Stanbury, Wyngaarden, Frederichson
Metabolic Basis of Inherited Disease
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Clinical Features of AKU

• Dark urine
• Ochronosis
• Arthritis
• Musculoskeletal (muscle and ligament tears)
• Cardiovascular (valvulitis, fibrosis,
  calcification)
• Genitourinary (renal and prostatic calculi, renal
  failure)
• Hearing loss

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