Review Question - QID 219316

Alkaptonuria is a rare inborn error of metabolism caused by a deficiency of the enzyme homogentisic oxidase, which leads to the buildup of homogentisic acid in fibrillary collagens and the resultant characteristic bluish-black discoloration of cartilage and connective tissues (Figure B).

In the normal enzymatic pathway, homogentisic oxidase regulates the metabolism of the aromatic amino acids phenylalanine and tyrosine. When this pathway is disrupted, as is the case in patients with alkaptonuria, the intermediary product homogentisic acid cannot be broken down further and becomes deposited in excess in connective tissues, resulting in "ochronosis" or the bluish-black discoloration described above. orthopaedic manifestations of the disease include ochronotic arthropathy, in which the excess homogentisic acid polymerizes in the joint, leading to early cartilage destruction and resulting in arthritis. This can lead to ochronotic spondylitis with calcification and disc space narrowing in the spine. Diagnosis is made with the detection of homogentisic acid in the urine, and the typical treatments for the orthopaedic manifestations are the same as for primary osteoarthritis, with many going on to early arthroplasty. Of note, accumulation also tends to occur in the Achilles and patellar tendons, placing them at risk for spontaneous rupture.

Lal et al. review nine cases of ochronosis with sporadic presentation and varied orthopedic manifestations of alkaptonuria. The authors note that alkaptonuria, with its sequela, ochronosis, is a rare disease, with an incidence of 1:125,000 to 1:1 million worldwide. They conclude that clinicians need a high index of suspicion and awareness to diagnose ochronosis.

Ando et al. present a case report of a patient with ochronosis and bilateral Achilles tendon ruptures. The authors note that tendon ruptures in patients with ochronosis should be treated as pathologic ruptures because histologic examination reveals that both ends of the ruptured tendon and the insertion site at the calcaneus have extensive black pigment depositions where homogentisic acid and its metabolites have accumulated with no normal collagen bundles present. They conclude that even if an Achilles tendon rupture is clinically diagnosed as an acute injury, the ruptured Achilles tendon should be primarily repaired and reinforced with autologous tissue because there are a few viable cells at the ruptured site and because the tendon typically ruptures mainly at the insertion site of the calcaneus.

Figure A is an AP radiograph of a right knee showing significant arthrosis of both the medial and lateral compartments. Figures B and C are intra-operative photographs showing the characteristic black discoloration associated with ochronotic arthropathy.

Incorrect Answers:
Answer 1: The buildup of uric acid with subsequent crystalline deposition is associated with gouty arthropathy, not with ochronosis.
Answer 2: Chronic low-level consumption of lead causes plumbism, not ochronosis.
Answer 4: Insufficient response to hepcidin resulting in iron overload is associated with hereditary hemochromatosis.
Answer 5: Lipoprotein receptor gene (LDLR) mutation is associated with familial hypercholesterolemia.