Alkaptonuria
Genetics & Metabolism
Illness script · Genetics & Metabolism
Alkaptonuria
Autosomal recessive deficiency of homogentisate 1,2-dioxygenase causing homogentisic acid accumulation, ochronosis, and progressive arthropathy.
This illness script for Alkaptonuria covers predisposing factors, classic presentation, mechanism, workup, management, and the clinical pivots that separate it from look-alikes—written for USMLE Step 1 and clerkship reasoning.
01
Predisposing factors
- Autosomal recessive inheritance (HGD gene mutation)
- Consanguinity is a major risk factor
- Higher prevalence in Slovakia and Dominican Republic
- Equal male-to-female incidence
- Presents across all ages; arthropathy emerges in 3rd–4th decade
02
Presentation
- Dark urine (darkens on standing or with alkali) — often first clue in infancy via stained diapers
- Ochronosis: blue-black/gray pigmentation of sclerae, ear cartilage, nasal bridge
- Debilitating arthropathy predominantly affecting spine and large joints (knee, hip)
- Dense calcification of intervertebral discs on imaging — hallmark radiographic finding
- Cardiac valve involvement (aortic stenosis) and renal/prostate calculi in adults
03
Pathophysiology
- HGD enzyme deficiency → homogentisic acid (HGA) cannot be catabolized in tyrosine pathway
- Excess HGA is oxidized and polymerizes → ochronotic (blue-black) pigment deposits in connective tissue
- Pigment accumulation degrades cartilage collagen → severe joint destruction
- HGA freely filtered and excreted in urine → urine darkens on standing/oxidation
04
Diagnostics
- Spot urine: darkens on standing or after adding NaOH (alkalinization test)
- Gold standard: quantitative urine or plasma homogentisic acid (markedly elevated)
- Spine X-ray: disc calcification/ossification is near-pathognomonic
- Genetic testing for HGD mutations confirms diagnosis
- Pitfall: urine may appear normal when freshly voided — observe over time
05
Management
- Nitisinone (NTBC): inhibits 4-HPPD upstream, sharply reduces HGA production — first disease-modifying agent
- Dietary restriction of phenylalanine and tyrosine (adjunct, less impactful alone)
- High-dose ascorbic acid (vitamin C) — antioxidant; modest benefit on ochronosis progression
- Orthopedic management: NSAIDs, physical therapy; joint replacement for severe arthropathy
- Cardiac valve replacement if hemodynamically significant stenosis develops
06
Clinical pivots
How to separate this script from the look-alikes that show up on exams and on the wards.
Wilson's disease
Wilson's causes Kayser-Fleischer rings and hepatic/neuropsychiatric disease — no dark urine or disc calcification.
Porphyria (acute intermittent)
Porphyria also darkens urine but causes neurovisceral crises and elevated porphyrins — no ochronosis or arthropathy.
Ochronotic arthropathy vs. ankylosing spondylitis
Alkaptonuria shows dense disc calcification (not sacroiliitis) and sclerae/ear pigmentation absent in AS.
Hemochromatosis
Hemochromatosis causes bronze skin and liver/pancreas damage via iron overload — no dark urine or ochronotic pigment.
Keep reading
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Educational use only. This illness script is a study framework, not medical advice. Confirm decisions with current guidelines and your clinical supervisors.